Lack of evidence for KRAS oncogenic mutations in triple-negative breast cancer

<p>Abstract</p> <p>Background</p> <p>Mutational analysis of the <it>KRAS </it>gene has recently been established as a complementary <it>in vitro </it>diagnostic tool for the identification of patients with colorectal cancer who will not benefit from anti-epidermal growth factor receptor (EGFR) therapies. Assessment of the mutation status of <it>KRAS </it>might also be of potential relevance in other EGFR-overexpressing tumors, such as those occurring in breast cancer. Although <it>KRAS </it>is mutated in only a minor fraction of breast tumors (5%), about 60% of the basal-like subtype express EGFR and, therefore could be targeted by EGFR inhibitors. We aimed to study the mutation frequency of <it>KRAS </it>in that subtype of breast tumors to provide a molecular basis for the evaluation of anti-EGFR therapies.</p> <p>Methods</p> <p>Total, genomic DNA was obtained from a group of 35 formalin-fixed paraffin-embedded, triple-negative breast tumor samples. Among these, 77.1% (27/35) were defined as basal-like by immunostaining specific for the established surrogate markers cytokeratin (CK) 5/6 and/or EGFR. <it>KRAS </it>mutational status was determined in the purified DNA samples by Real Time (RT)-PCR using primers specific for the detection of wild-type <it>KRAS </it>or the following seven oncogenic somatic mutations: Gly12Ala, Gly12Asp, Gly12Arg, Gly12Cys, Gly12Ser, Gly12Val and Gly13Asp.</p> <p>Results</p> <p>We found no evidence of <it>KRAS </it>oncogenic mutations in all analyzed tumors.</p> <p>Conclusions</p> <p>This study indicates that <it>KRAS </it>mutations are very infrequent in triple-negative breast tumors and that EGFR inhibitors may be of potential benefit in the treatment of basal-like breast tumors, which overexpress EGFR in about 60% of all cases.</p

Impact of screening for breast cancer in high-risk women on health-related quality of life

The effectiveness of intensive surveillance in women at high risk for breast cancer due to a familial or genetic predisposition is uncertain and is currently being evaluated in a Dutch magnetic resonance imaging (MRI) screening (MRISC) study, in which annual imaging consists of mammography and MRI. Unfavourable side effects on health-related quality of life may arise from this screening process. We examined the short-term effects of screening for breast cancer in high-risk women on generic health-related quality of life and distress. A total of 519 participants in the MRISC study were asked to complete generic health-status questionnaires (SF-36, EQ-5D) as well as additional questionnaires for distress and items relating to breast cancer screening, at three different time points around screening. The study population showed significantly better generic health-related quality of life scores compared to age-/sex-adjusted reference scores from the general population. Neither generic health-related quality of life scores nor distress scores among the study sample (n = 334) showed significant changes over time. The impact of the screening process on generic health status did not differ between risk categories. Relatively more women reported mammography as quite to very painful (30.1%) compared to MRI. Anxiety was experienced by 37% of the women undergoing MRI. We conclude that screening for breast cancer in high-risk women does not have an unfavourable impact on short-term generic health-related quality of life and general distress. In this study, high-risk women who opted for regular breast cancer screening had a better health status than women from the general population

Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke.

OBJECTIVE: For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms. METHODS: We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations. RESULTS: There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p < 5 × 10(-6)) from community populations (15 single nucleotide polymorphisms in total) and from stroke patients, 6 independent loci were associated with WMHV in both populations. Four of these are novel associations at the genome-wide level (rs72934505 [NBEAL1], p = 2.2 × 10(-8); rs941898 [EVL], p = 4.0 × 10(-8); rs962888 [C1QL1], p = 1.1 × 10(-8); rs9515201 [COL4A2], p = 6.9 × 10(-9)). CONCLUSIONS: Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease.Funding for collection, genotyping, and analysis of stroke samples was provided by Wellcome Trust Case Control Consortium-2, a functional genomics grant from the Wellcome Trust (DNA-Lacunar), the Stroke Association (DNA-lacunar), the Intramural Research Program of National Institute of Ageing (Massachusetts General Hospital [MGH] and Ischemic Stroke Genetics Study [ISGS]), National Institute of Neurological Disorders and Stroke (Siblings With Ischemic Stroke Study, ISGS, and MGH), the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research (MGH), Deane Institute for Integrative Study of Atrial Fibrillation and Stroke (MGH), National Health and Medical Research Council (Australian Stroke Genetics Collaborative), and Italian Ministry of Health (Milan). Additional support for sample collection came from the Medical Research Council, National Institute of Health Research Biomedical Research Centre and Acute Vascular Imaging Centre (Oxford), Wellcome Trust and Binks Trust (Edinburgh), and Vascular Dementia Research Foundation (Munich). MT is supported by a project grant from the Stroke Association (TSA 2013/01). HSM is supported by an NIHR Senior Investigator award. HSM and SB are supported by the NIHR Cambridge University Hospitals Comprehensive Biomedical Research Centre. VT and RL are supported by grants from FWO Flanders. PR holds NIHR and Wellcome Trust Senior Investigator Awards. PAS is supported by an MRC Fellowship. CML’s research is supported by the National Institute for Health Research Biomedical Research Centre (BRC) based at Guy's and St Thomas' NHS Foundation Trust and King's College London, and the BRC for Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London. This is the final version of the article. It first appeared from Wolters Kluwer via http://dx.doi.org/10.1212/WNL.000000000000226

The ability of societies to adapt to twenty-first-century sea-level rise

Against the background of potentially substantial sea-level rise, one important question is to what extent are coastal societies able to adapt? This question is often answered in the negative by referring to sinking islands and submerged megacities. Although these risks are real, the picture is incomplete because it lacks consideration of adaptation. This Perspective explores societies' abilities to adapt to twenty-first-century sea-level rise by integrating perspectives from coastal engineering, economics, finance and social sciences, and provides a comparative analysis of a set of cases that vary in terms of technological limits, economic and financial barriers to adaptation and social conflicts

Opportunities and pitfalls of using building performance simulation in explorative R&amp;D contexts

One of the promising use cases of building performance simulation (BPS) is its role as a virtual laboratory in research and development (R&amp;D) projects that aim to bring innovative building components from initial idea towards market introduction. By facilitating what-if explorations and whole-building insights, BPS can create complementary value, alongside actual experiments. However, explorative R&amp;D projects tend to be rather erratic and are more ill-defined than typical BPS tasks. This raises several issues concerning application, interpretation and communication of BPS-based performance predictions in explorative contexts. The aim of this paper is to highlight opportunities and potential pitfalls of the use of BPS in this application domain. First, the characteristic properties of exploration-driven R&amp;D projects are contrasted with more conventional BPS projects using a systematic requirements engineering approach. Then, the process and outcomes of three R&amp;D projects of innovative façade systems are discussed. Finally, the lessons learned from these studies are presented

Assisting the development of innovative responsive façade elements using building performance simulation

Thermal mass is usually positively associated with energy efficiency and thermal comfort in buildings. However, the slow response of heavyweight constructions is not beneficial at all times, as these dynamic effects may actually also increase heating and cooling energy demand during intermittent operation or can cause unwanted discomfort. This study investigates the potential of energy simulations to support the exploration-driven development of two innovative responsive building elements: “Spong3D” and “Convective Concrete”. Both use fluid flow (Spong3D: water, Convective Concrete: air) inside the construction to reduce building energy demand by exploiting the use of natural energy sinks and sources in the ambient environment, aiming to make more intelligent use of thermal mass. During the development of these concepts, different simulation tools were used alongside experiments for e.g. materials selection, climate analysis, comfort prediction and risk assessment. By presenting the results from a series of simulation studies and by reflecting on their application, this paper shows how computational building performance analyses can play a useful role in ill-defined R&amp;D processes

Development and prototyping of an integrated 3D-printed façade for thermal regulation in complex geometries

\u3cp\u3eCurrently, several research projects investigate Additive Manufacturing (AM) technology as a possible construction method for future buildings. AM methods have some advantages over other production processes, such as great freedom of form, shape complexity, scale, and material use. These characteristics are relevant for façade applications, which demand the integration of several functions. Given the established capacity of AM to generate complex geometries, most existing research focuses on mechanical material properties and mainly in relation to the load-bearing capacity and the construction system. The integration of additional aspects is often achieved with post processing and the use of multiple materials. Research is needed to investigate properties for insulation, thermal storage, and energy harvesting, combined in one component and one production technology. To this end. the research project SPONG3D' aimed at developing a 3D-printed façade panel that integrates insulating properties with heat storage in a complex, mono-material geometry. This paper gives an overview of the panel development process, including aspects of material selection, printing process, structural properties, energy performance, and thermal heat storage. The development process was guided by experiments and simulations and resulted in the design and manufacturing of a full-scale façade element prototype using FDM printing with PETG. The project proved the possibility of the integration of functions in 3D-printed façades, but also highlighted the limitations and the need for further developments.\u3c/p\u3

Spong3d : 3D printed facade system enabling movable fluid heat storage

Spong3D is an adaptive 3D printed facade system that integrates multiple functions to optimize thermal performances according to the different environmental conditions throughout the year. The proposed system incorporates air cavities to provide thermal insulation and a movable liquid (water plus additives) to provide heat storage where and whenever needed. The air cavities have various dimensions and are located in the inner part of the system. The movable liquid provides heat storage as it flows through channels located along the outer surfaces of the system (on the indoor and outdoor faces of the façade). Together, the composition of the channels and the cavities form a complex structure, integrating multiple functions into a singular component, which can only be produced by using an Additive Manufacturing (AM; like 3D printing) technology