Optimizing Clinical Benefits of Bisphosphonates in Cancer Patients with Bone Metastases

Malignant bone disease is common in patients with advanced solid tumors or multiple myeloma. Bisphosphonates have been found to be important treatments for bone metastases. A positive benefit-risk ratio for bisphosphonates has been established, and ongoing clinical trials will determine whether individualized therapy is possible

Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain

Glucose homeostasis and growth essentially depend on the hormone insulin engaging its receptor. Despite biochemical and structural advances, a fundamental contradiction has persisted in the current understanding of insulin ligand-receptor interactions. While biochemistry predicts two distinct insulin binding sites, 1 and 2, recent structural analyses have resolved only site 1. Using a combined approach of cryo-EM and atomistic molecular dynamics simulation, we present the structure of the entire dimeric insulin receptor ectodomain saturated with four insulin molecules. Complementing the previously described insulin-site 1 interaction, we present the first view of insulin bound to the discrete insulin receptor site 2. Insulin binding stabilizes the receptor ectodomain in a T-shaped conformation wherein the membrane-proximal domains converge and contact each other. These findings expand the current models of insulin binding to its receptor and of its regulation. In summary, we provide the structural basis for a comprehensive description of ligand-receptor interactions that ultimately will inform new approaches to structure-based drug design.Peer reviewe

Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion. Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations. Methods and measurements: We conducted genome-wide analyses across three independent studies and meta-analysed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. Main results: We identified and replicated three new genome-wide significant (P<5×10−8) signals of association with IPF susceptibility (associated with altered gene expression of KIF15, MAD1L1 and DEPTOR) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF susceptibility variants contribute to IPF susceptibility. Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF, supports recent studies demonstrating the importance of mTOR signalling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility

Association study of human leukocyte antigen (HLA) variants and idiopathic pulmonary fibrosis

IntroductionIdiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF and a prior association of theHLA-DQB1gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Due to the important role that the Human Leukocyte Antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk.MethodsWe performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case-control studies of IPF (comprising a total of 5159 cases and 27 459 controls, including the prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association thresholdp&lt;4.5×10−4and a posterior probability of replication &gt;90% were considered significant. We sought to replicate the previously reportedHLA-DQB1association in the subset of studies independent of the original report.ResultsThe meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. TheHLA-DQB1association was not replicated in the independent IPF studies.ConclusionVariation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF

Electronically Monitored Punishment. International and Critical Perspectives

Electronic monitoring (EM) is a way of supervising offenders in the community whilst they are on bail, serving a community sentence or after release from prison. Various technologies can be used, including voice verification, GPS satellite tracking and – most commonly - the use of radio frequency to monitor house arrest. It originated in the USA in the 1980s and has spread to over 30 countries since then. This book explores the development of EM in a number of countries to give some indication of the diverse ways it has been utilized and of the complex politics which surrounds its use. A techno-utopian impulse underpins the origins of EM and has remained latent in its subsequent development elsewhere in the world, despite recognition that is it less capable of effecting penal transformations than its champions have hoped. This book devotes substantive chapters to the issues of privatisation, evaluation, offender perspectives and ethics. Whilst normatively more committed to the Swedish model, the book acknowledges that this may not represent the future of EM, whose untrammelled, commercially-driven development could have very alarming consequences for criminal justice. Both utopian and dystopian hopes have been invested in EM, but research on its impact is ambivalent and fragmented, and EM remains undertheorised, empirically and ethically. This book seeks to redress this by providing academics, policy audiences and practitioners with the intellectual resources to understand and address the challenges which EM poses

LOWER PALEOCENE DEEP-WATER AGGLUTINATED FORAMINIFERA FROM THE CONTESSA HIGHWAY SECTION (UMBRIA-MARCHE BASIN, ITALY): TAXONOMY, STRATIGRAPHIC DISTRIBUTION AND ASSEMBLAGE TURNOVER ACROSS THE CRETACEOUS/PALEOGENE BOUNDARY

Deep-water agglutinated foraminifera (DWAF) are investigated from the lower Paleocene of the Contessa Highway Paleocene (CHP) section in the Umbria-Marche Basin in Italy. In the lowermost part of the Paleocene corresponding to the P0–Pα interval and lowermost P1 planktonic foraminifera zones, a total of 46 species of DWAF are identified. A comparison with the uppermost Maastrichtian DWAF assemblages documented by Cetean (2009) results in a combined total of 94 DWAF species over the Cretaceous/Paleogene boundary interval at Contessa Highway. Of these, 49 species are listed as extinction taxa, nine are survivor taxa, 19 are Lazarus taxa, and 17 taxa display first occurrences in the Paleocene. The record of DWAF in the Contessa Highway Paleocene section displays a moderate decrease in diversity across the K/Pg boundary, followed by a gradual recovery in the first meter of the Paleocene. The lower Paleocene record is characterized by blooms of opportunistic species belonging to the genera Reophax, Subreophax, Repmanina, and Spiroplectinella. The K/Pg boundary interval records a major change in the proportions of DWAF morphogroups, from a suspension-feeding community in the Maastrichtian to one dominated by epifaunal detritivores in the lower Paleocene, reflecting a fundamental change in marine primary productivity following the bolide impact.