Economic evaluation of fulvestrant as an extra step in the treatment sequence for ER-positive advanced breast cancer

Drug therapies for advanced breast cancer in hormone-receptor-positive disease include both hormonal and chemotherapies. Current UK practice is to minimise toxicity by using sequential hormonal agents for as long as clinically appropriate. A Markov model was developed to investigate the cost effectiveness of different sequences of therapies, particularly exploring the effects of adding an additional hormonal agent, fulvestrant, to the treatment pathway. A systematic review was undertaken and a panel of seven UK oncologists validated assumptions used for treatment efficacy, treatment pathways and resources used. Fulvestrant was found to be a cost-effective treatment option when added to the treatment sequence as a second- or third-line hormonal therapy for advanced disease. For a cohort of 1000 patients, fulvestrant as a second-line hormone therapy provided an additional 47 life years and 41 quality-adjusted life years (QALYs), at an additional cost of £301 359. This equated to £6500 per life years gained and £7500 per QALY. When used as a third-line option, the fulvestrant arm was dominant providing an increase in health benefit of 27 QALYs for the whole cohort, at a mean overall cost reduction of £430 per patient. Sensitivity analyses showed these results to be robust, demonstrating that fulvestrant is an economically viable additional endocrine option in the United Kingdom for the treatment of hormone responsive advanced breast cancer

Compressive properties of min-mod-type limiters in modelling shockwave-containing flows

The long-ignored compressive properties of Min-mod-type limiter is investigated in this manuscript by demonstrating its potential in numerically modelling shockwave-containing flows, especially in shock wave/boundary layer interaction (SWBLI) problems. Theoretical studies were firstly performed based on Sweby’s total variation diminishing (TVD) limiter region and Spekreijse’s monotonicity-preserving limiter region to indicate Min-mod-type limiters’ compressive properties. The influence of limiters on the solution accuracy was evaluated using a hybrid-order analysis method based on the grid-independent study in three typical shockwave-containing flows. The conclusions are that, Min-mod-type limiter can be utilized as a dissipative and/or compressive limiter, but depending on the reasonable value of the compression parameter. The compressive Min-mod limiter tends to be more attractive in modelling shockwave-containing flows as compared to other commonly preferred limiters because of its stable computational process and its high-resolution predictions. However, the compressive Min-mod limiter may suffer from its slightly poor convergence, as that observed in other commonly accepted smooth limiters in modelling SWBLI problems. © 2020, The Author(s)

Isotope sensitive measurement of the hole-nuclear spin interaction in quantum dots

Decoherence caused by nuclear field fluctuations is a fundamental obstacle to the realization of quantum information processing using single electron spins. Alternative proposals have been made to use spin qubits based on valence band holes having weaker hyperfine coupling. However, it was demonstrated recently both theoretically and experimentally that the hole hyperfine interaction is not negligible, although a consistent picture of the mechanism controlling the magnitude of the hole-nuclear coupling is still lacking. Here we address this problem by performing isotope selective measurement of the valence band hyperfine coupling in InGaAs/GaAs, InP/GaInP and GaAs/AlGaAs quantum dots. Contrary to existing models we find that the hole hyperfine constant along the growth direction of the structure (normalized by the electron hyperfine constant) has opposite signs for different isotopes and ranges from -15% to +15%. We attribute such changes in hole hyperfine constants to the competing positive contributions of p-symmetry atomic orbitals and the negative contributions of d-orbitals. Furthermore, we find that the d-symmetry contribution leads to a new mechanism for hole-nuclear spin flips which may play an important role in hole spin decoherence. In addition the measured hyperfine constants enable a fundamentally new approach for verification of the computed Bloch wavefunctions in the vicinity of nuclei in semiconductor nanostructures

Occlusion of Regulatory Sequences by Promoter Nucleosomes In Vivo

Nucleosomes are believed to inhibit DNA binding by transcription factors. Theoretical attempts to understand the significance of nucleosomes in gene expression and regulation are based upon this assumption. However, nucleosomal inhibition of transcription factor binding to DNA is not complete. Rather, access to nucleosomal DNA depends on a number of factors, including the stereochemistry of transcription factor-DNA interaction, the in vivo kinetics of thermal fluctuations in nucleosome structure, and the intracellular concentration of the transcription factor. In vitro binding studies must therefore be complemented with in vivo measurements. The inducible PHO5 promoter of yeast has played a prominent role in this discussion. It bears two binding sites for the transcriptional activator Pho4, which at the repressed promoter are positioned within a nucleosome and in the linker region between two nucleosomes, respectively. Earlier studies suggested that the nucleosomal binding site is inaccessible to Pho4 binding in the absence of chromatin remodeling. However, this notion has been challenged by several recent reports. We therefore have reanalyzed transcription factor binding to the PHO5 promoter in vivo, using ‘chromatin endogenous cleavage’ (ChEC). Our results unambiguously demonstrate that nucleosomes effectively interfere with the binding of Pho4 and other critical transcription factors to regulatory sequences of the PHO5 promoter. Our data furthermore suggest that Pho4 recruits the TATA box binding protein to the PHO5 promoter

The Transformation of Citizenship in Complex Societies

The main purpose of this paper is to propose a theoretical framework for understanding the transformation of citizenship in complex societies. To this end, the paper is divided into six sections. The first section elucidates the main reasons for the renaissance of the concept of citizenship in the contemporary social sciences. The second section argues that a comprehensive sociological theory of citizenship needs to account for the importance of four dimensions: the content, the type, the conditions, and the arrangements of citizenship. The third section suggests that in order to understand the sociological significance of T.H. Marshall’s account of legal, political, and social rights we need to explore the particular historical contexts in which citizenship rights became ideologically and institutionally relevant. The fourth section offers some critical reflections on the main shortcomings of the Marshallian approach to citizenship. The fifth section draws an analogy between the transformation of social movements and the transformation of citizenship. The sixth section sheds light on the fact that contemporary citizenship studies are confronted with a curious paradox: the differentiation of citizenship has led to both the relativistic impoverishment and the pluralistic enrichment of contemporary accounts of ‘the social’ and ‘the political’.The paper concludes by arguing that, under conditions of late modernity, the state’s capacity to gain political legitimacy increasingly depends on its ability to confront the normative challenges posed by the ubiquity of societal complexity

Differential Methylation of the HPV 16 Upstream Regulatory Region during Epithelial Differentiation and Neoplastic Transformation

High risk human papillomaviruses are squamous epitheliotropic viruses that may cause cervical and other cancers. HPV replication depends on squamous epithelial differentiation. Transformation of HPV-infected cells goes along with substantial alteration of the viral gene expression profile and preferentially occurs at transformation zones usually at the uterine cervix. Methylation of the viral genome may affect regulatory features that control transcription and replication of the viral genome. Therefore, we analyzed the methylation pattern of the HPV16 upstream regulatory region (URR) during squamous epithelial differentiation and neoplastic transformation and analyzed how shifts in the HPV URR methylome may affect viral gene expression and replication. HPV 16 positive biopsy sections encompassing all stages of an HPV infection (latent, permissive and transforming) were micro-dissected and DNA was isolated from cell fractions representing the basal, intermediate, and superficial cell layers, each, as well as from transformed p16INK4a-positive cells. We observed fundamental changes in the methylation profile of transcription factor binding sites in the HPV16 upstream regulatory region linked to the squamous epithelial differentiation stage. Squamous epithelial transformation indicated by p16INK4a overexpression was associated with methylation of the distal E2 binding site 1 leading to hyper-activation of the HPV 16 URR. Adjacent normal but HPV 16-infected epithelial areas retained hyper-methylated HPV DNA suggesting that these viral genomes were inactivated. These data suggest that distinct shifts of the HPV 16 methylome are linked to differentiation dependent transcription and replication control and may trigger neoplastic transformation

The LRRK2 signalling system

The LRRK2 gene is a major contributor to genetic risk for Parkinson's disease and understanding the biology of the leucine-rich repeat kinase 2 (LRRK2, the protein product of this gene) is an important goal in Parkinson's research. LRRK2 is a multi-domain, multi-activity enzyme and has been implicated in a wide range of signalling events within the cell. Because of the complexities of the signal transduction pathways in which LRRK2 is involved, it has been challenging to generate a clear idea as to how mutations and disease associated variants in this gene are altered in disease. Understanding the events in which LRRK2 is involved at a systems level is therefore critical to fully understand the biology and pathobiology of this protein and is the subject of this review

Genome-Wide Analysis of Glucocorticoid Receptor Binding Regions in Adipocytes Reveal Gene Network Involved in Triglyceride Homeostasis

Glucocorticoids play important roles in the regulation of distinct aspects of adipocyte biology. Excess glucocorticoids in adipocytes are associated with metabolic disorders, including central obesity, insulin resistance and dyslipidemia. To understand the mechanisms underlying the glucocorticoid action in adipocytes, we used chromatin immunoprecipitation sequencing to isolate genome-wide glucocorticoid receptor (GR) binding regions (GBRs) in 3T3-L1 adipocytes. Furthermore, gene expression analyses were used to identify genes that were regulated by glucocorticoids. Overall, 274 glucocorticoid-regulated genes contain or locate nearby GBR. We found that many GBRs were located in or nearby genes involved in triglyceride (TG) synthesis (Scd-1, 2, 3, GPAT3, GPAT4, Agpat2, Lpin1), lipolysis (Lipe, Mgll), lipid transport (Cd36, Lrp-1, Vldlr, Slc27a2) and storage (S3-12). Gene expression analysis showed that except for Scd-3, the other 13 genes were induced in mouse inguinal fat upon 4-day glucocorticoid treatment. Reporter gene assays showed that except Agpat2, the other 12 glucocorticoid-regulated genes contain at least one GBR that can mediate hormone response. In agreement with the fact that glucocorticoids activated genes in both TG biosynthetic and lipolytic pathways, we confirmed that 4-day glucocorticoid treatment increased TG synthesis and lipolysis concomitantly in inguinal fat. Notably, we found that 9 of these 12 genes were induced in transgenic mice that have constant elevated plasma glucocorticoid levels. These results suggested that a similar mechanism was used to regulate TG homeostasis during chronic glucocorticoid treatment. In summary, our studies have identified molecular components in a glucocorticoid-controlled gene network involved in the regulation of TG homeostasis in adipocytes. Understanding the regulation of this gene network should provide important insight for future therapeutic developments for metabolic diseases

The Telomere Binding Protein TRF2 Induces Chromatin Compaction

Mammalian telomeres are specialized chromatin structures that require the telomere binding protein, TRF2, for maintaining chromosome stability. In addition to its ability to modulate DNA repair activities, TRF2 also has direct effects on DNA structure and topology. Given that mammalian telomeric chromatin includes nucleosomes, we investigated the effect of this protein on chromatin structure. TRF2 bound to reconstituted telomeric nucleosomal fibers through both its basic N-terminus and its C-terminal DNA binding domain. Analytical agarose gel electrophoresis (AAGE) studies showed that TRF2 promoted the folding of nucleosomal arrays into more compact structures by neutralizing negative surface charge. A construct containing the N-terminal and TRFH domains together altered the charge and radius of nucleosomal arrays similarly to full-length TRF2 suggesting that TRF2-driven changes in global chromatin structure were largely due to these regions. However, the most compact chromatin structures were induced by the isolated basic N-terminal region, as judged by both AAGE and atomic force microscopy. Although the N-terminal region condensed nucleosomal array fibers, the TRFH domain, known to alter DNA topology, was required for stimulation of a strand invasion-like reaction with nucleosomal arrays. Optimal strand invasion also required the C-terminal DNA binding domain. Furthermore, the reaction was not stimulated on linear histone-free DNA. Our data suggest that nucleosomal chromatin has the ability to facilitate this activity of TRF2 which is thought to be involved in stabilizing looped telomere structures