Search

Breast cancer brain metastases remain largely incurable. Although several mouse models have been developed to investigate the genes and mechanisms regulating breast cancer brain metastasis, these models often lack clinical relevance since they require the use of immunocompromised mice and/or are poorly metastatic to brain from the mammary gland. We describe the development and characterisation of an aggressive brain metastatic variant of the 4T1 syngeneic model (4T1Br4) that spontaneously metastasises to multiple organs, but is selectively more metastatic to the brain from the mammary gland than parental 4T1 tumours. As seen by immunohistochemistry, 4T1Br4 tumours and brain metastases display a triple-negative phenotype, consistent with the high propensity of this breast cancer subtype to spread to brain. In vitro assays indicate that 4T1Br4 cells have an enhanced ability to adhere to or migrate across a brain-derived endothelial monolayer and greater invasive response to brain-derived soluble factors compared to 4T1 cells. These properties are likely to contribute to the brain selectivity of 4T1Br4 tumours. Expression profiling and gene set enrichment analyses demonstrate the clinical relevance of the 4T1Br4 model at the transcriptomic level. Pathway analyses implicate tumour-intrinsic immune regulation and vascular interactions in successful brain colonisation, revealing potential therapeutic targets. Evaluation of two histone deacetylase inhibitors, SB939 and 1179.4b, shows partial efficacy against 4T1Br4 metastasis to brain and other sites in vivo, and potent radio-sensitising properties in vitro. The 4T1Br4 model provides a clinically relevant tool for mechanistic studies and to evaluate novel therapies against brain metastasis. This article has an associated First Person interview with Soo-Hyun Kim, joint first author of the paper., Summary: The authors introduce a new syngeneic mouse model of spontaneous breast cancer brain metastasis, demonstrate its phenotypic, functional and transcriptomic relevance to human TNBC brain metastasis, and test novel therapies.

Background People with multiple sclerosis (MS) are increasingly using the Internet in the daily management of their condition. They search for high-quality information in plain language, from independent sources, based on reliable and up-to-date evidence. The Integrating and Deriving Evidence, Experiences and Preferences (IN-DEEP) project in Italy and Australia aimed to provide people with MS and family members with an online source of evidence-based information, starting from their information needs. This paper reports on the Italian project’s website. Methods Contents, layout and wording were developed with people with MS and pilot-tested. The website was evaluated using an online 29-item questionnaire for ease of language, contents, navigation, and usefulness of information aimed at people with MS, family members and the general population. Results The website (http://indeep.istituto-besta.it/) is structured in multiple levels of information. The first topic was interferons-β for people with relapsing-remitting MS. In all, 433 people responded to the survey (276 people with MS, 68 family members and 89 others). The mean age was 45 years, almost 90 % had a high school diploma, about 80 % had relapsing-remitting MS, and the median disease duration was seven years. About 90 % judged the website clear, understandable, useful, and easy to navigate. Ninety percent of people with MS and family members would recommend it to others. Sixty-two percent reported they felt confident in making decisions on interferons-β after reading the website. Conclusions The model was judged clear and useful. It could be adapted to other topics and diseases. Clinicians may find it useful in their relationship with patients. Electronic supplementary material The online version of this article (doi:10.1186/s12883-016-0552-0) contains supplementary material, which is available to authorized users.

Objectives\ud To identify by systematic review published prevalence estimates of radiographic ankle osteoarthritis (OA) and to subsequently estimate the prevalence of ankle pain and symptomatic, radiographic ankle OA within community-dwelling older adults from North Staffordshire, UK.\ud \ud Methods\ud Electronic databases were searched using terms for ankle, osteoarthritis and radiography. Data regarding population, radiographic methods, definitions and prevalence estimates of ankle OA were extracted from papers meeting predetermined selection criteria. Adults aged ≥50 years and registered with four general practices in North Staffordshire were mailed a health questionnaire. Ankle pain in the previous month was determined using a foot and ankle pain manikin. Respondents reporting pain in or around the foot in the last 12 months were invited to attend a research clinic where weight-bearing, antero-posterior and lateral ankle radiographs were obtained and scored for OA using a standardised atlas. Prevalence estimates for ankle pain and symptomatic, radiographic ankle OA were calculated using multiple imputation and weighted logistic regression, and stratified by age, gender and socioeconomic status.\ud \ud Results\ud Eighteen studies were included in the systematic review. The methods of radiographic classification of ankle OA were poorly reported and showed heterogeneity. No true general population prevalence estimates of radiographic ankle OA were found, estimates in select sporting and medical community-dwelling populations ranged from 0.0–97.1%. 5109 participants responded to the health survey questionnaire (adjusted response 56%). Radiographs were obtained in 557 participants. The prevalence of ankle pain was 11.7% (10.8,12.6) and symptomatic, radiographic ankle OA grade≥2 was 3.4% (2.3, 4.5) (grade≥1: 8.8% (7.9,9.8); grade = 3: 1.9% (1.0,2.7). Prevalence was higher in females, younger adults (50–64 years) and those with routine/manual occupations.\ud \ud Conclusion\ud No general population prevalence estimates of radiographic ankle OA were identified in the published literature. Our prevalence study found that ankle pain was common in community-dwelling older adults, whereas moderate to severe symptomatic, radiographic ankle OA occurred less frequently. Further investigations of the prevalence of ankle OA using more sensitive imaging modalities are warranted.

Traffic congestion continues to be a persistent problem throughout the world. As vehicle-to-vehicle communication develops, there is an opportunity of using cooperation among close proximity vehicles to tackle the congestion problem. The intuition is that if vehicles could cooperate opportunistically when they come close enough to each other, they could, in effect, spread themselves out among alternative routes so that vehicles do not all jam up on the same roads. Our previous work proposed a decentralized multiagent based vehicular congestion management algorithm entitled Congestion Avoidance and Route Allocation using Virtual Agent Negotiation (CARAVAN), wherein the vehicles acting as intelligent agents perform cooperative route allocation using inter-vehicular communication. This paper focuses on evaluating the practical applicability of this approach by testing its robustness and performance (in terms of travel time reduction), across variations in: (a) environmental parameters such as road network topology and configuration; (b) algorithmic parameters such as vehicle agent preferences and route cost/preference multipliers; and (c) agent-related parameters such as equipped/non-equipped vehicles and compliant/non-compliant agents. Overall, the results demonstrate the adaptability and robustness of the decentralized cooperative vehicles approach to providing global travel time reduction using simple local coordination strategies.