ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer

Fulvestrant is used to treat patients with hormone receptor positive advanced breast cancer but acquired resistance is poorly understood. PlasmaMATCH Cohort A (NCT03182634) investigated the activity of fulvestrant in patients with activating ESR1 mutations in circulating tumor DNA (ctDNA). Baseline ESR1 mutations Y537S associated with poor, and Y537C with good outcome. Sequencing of baseline and EOT ctDNA samples (n=69) revealed 3/69 (4%) patients acquired novel ESR1 F404 mutations (F404L, F404I, F404V), in cis with activating mutations. In silico modelling revealed that ESR1 F404 contributes to fulvestrant binding to ERa through a pi-stacking bond, with mutations disrupting this bond. In vitro analysis demonstrated that single F404L, E380Q, and D538G models were less sensitive to fulvestrant, while compound mutations D538G+F404L and E380Q+F404L were resistant. Several oral ERa degraders were active against compound mutant models. We have identified a resistance mechanism specific to fulvestrant, that can be targeted by treatments in clinical development

Substituted 2-amino-1,3,4-thiadiazines: a novel solid-phase approach

A novel and facile strategy for synthesis of substituted 2-amino-1,3,4-thiadiazines on solid support is described. Resin bound isothiocyanate prepared from an immobilised primary amine and di-(2-pyridyl)thionocarbonate was reacted with hydrazine hydrate to form the intermediate thiosemicarbazide. Further reaction with a range of alpha-bromoketones followed by mild acidic cleavage from the solid support released the substituted 2-amino-1,3,4-thiadiazines in respectable yields and excellent purity. (C) 2002 Elsevier Science Ltd. All rights reserved

The Public Health Risks of Media Violence: A Meta-Analytic Review

Objective: To conduct a meta-analytic review of studies that examine the impact of violent media on aggressive behavior and to determine whether this effect could be explained through methodological problems inherent in this research field. Study design: A detailed literature search identified peer-reviewed articles addressing media violence effects. Effect sizes were calculated for all studies. Effect sizes were adjusted for observed publication bias. Results: Publication bias was a problem for studies of aggressive behavior, and methodological problems such as the use of poor aggression measures inflated effect size. Once corrected for publication bias, studies of media violence effects provided little support for the hypothesis that media violence is associated with higher aggression. The corrected overall effect size for all studies was r = .08. Conclusions: Results from the current analysis do not support the conclusion that media violence leads to aggressive behavior. It cannot be concluded at this time that media violence presents a significant public health risk. © 2009 Mosby, Inc. All rights reserved

Policing terror threats and false positives: Employing a signal detection model to examine changes in national and local policing strategy between 2001 and 2007

This paper presents a theory of agency decision-making regarding homeland security policy over the last decade in the United States and inquires about appropriate modes of study to test its potential effectiveness. The key hypothesis is that the staple strategy of agency decision-making during the last decade has been hypervigilance; defined here as: a state in which agency policy is rationally structured to maximize the pursuit of false positives and gravitate aggressively toward security threats. The related research question is How can we study hypervigilance and false positives in all matters regarding policing terror threats? We argue that increased security measures tend to err toward pursuing false positives. However, we do not claim to understand the overall economic costs and benefits of recent homeland security policy decisions, in tangible financial or other realms. We contend that such an understanding is presently unattainable, considering the lack of raw data availability of how many terrorist attacks have been halted by increased security measures within the last decade. We do argue however, that the signal detection model is an appropriate starting methodology for study of such policing strategies. © 2011 Macmillan Publishers Ltd

Boom to bust or bust to boom? following the effects of weed and seed zoning in New Britain, Connecticut, from 1995 to 2000

This article addresses the effects of weed and seed zoning operations on arrests and calls for assistance in New Britain, Connecticut, during the 24-month before and 36-month after the inception of operations. Data are taken from New Britain police dispatch statistics and applied to a study of arrests and citizen calls for assistance across 738 U.S. Census block collection units (BCUs). The article employs tests of significance to assess the overall effects of zoning on these police activities across pre- and post-intervention periods and uses both weighted displacement quotient (WDQ) and exploratory spatial data analysis (ESDA) models to test for possible displacement associated with zoning. Results indicate that weed and seed zoning was significantly associated with displacement of arrest activity in pre- and post-intervention time periods but displayed no relationship with displacement of calls for assistance (CFAs). Though WDQ analyses do not indicate proximity effects, local indicators of spatial association (LISA) maps show noteworthy changes in the spatial clustering of arrest activity over time. Of principal concern here is the idea that weed and seed may prompt changes in the geography of crime without actually reducing crime rates. An ancillary concern is whether significantly higher arrest rates within weed and seed zones represent advances in community policing. © 2010 SAGE Publications