Integrative molecular and functional profiling of ERBB2-amplified breast cancers identifies new genetic dependencies.

Overexpression of the receptor tyrosine kinase ERBB2 (also known as HER2) occurs in around 15% of breast cancers and is driven by amplification of the ERBB2 gene. ERBB2 amplification is a marker of poor prognosis, and although anti-ERBB2-targeted therapies have shown significant clinical benefit, de novo and acquired resistance remains an important problem. Genomic profiling has demonstrated that ERBB2+ve breast cancers are distinguished from ER+ve and 'triple-negative' breast cancers by harbouring not only the ERBB2 amplification on 17q12, but also a number of co-amplified genes on 17q12 and amplification events on other chromosomes. Some of these genes may have important roles in influencing clinical outcome, and could represent genetic dependencies in ERBB2+ve cancers and therefore potential therapeutic targets. Here, we describe an integrated genomic, gene expression and functional analysis to determine whether the genes present within amplicons are critical for the survival of ERBB2+ve breast tumour cells. We show that only a fraction of the ERBB2-amplified breast tumour lines are truly addicted to the ERBB2 oncogene at the mRNA level and display a heterogeneous set of additional genetic dependencies. These include an addiction to the transcription factor gene TFAP2C when it is amplified and overexpressed, suggesting that TFAP2C represents a genetic dependency in some ERBB2+ve breast cancer cell

Spatial interplay of lymphocytes and fibroblasts in estrogen receptor-positive HER2-negative breast cancer

In estrogen-receptor-positive, HER2-negative (ER+HER2−) breast cancer, higher levels of tumor infiltrating lymphocytes (TILs) are often associated with a poor prognosis and this phenomenon is still poorly understood. Fibroblasts represent one of the most frequent cells in breast cancer and harbor immunomodulatory capabilities. Here, we evaluate the molecular and clinical impact of the spatial patterns of TILs and fibroblast in ER+HER2− breast cancer. We used a deep neural network to locate and identify tumor, TILs, and fibroblasts on hematoxylin and eosin-stained slides from 179 ER+HER2− breast tumors (ICGC cohort) together with a new density estimation analysis to measure the spatial patterns. We clustered tumors based on their spatial patterns and gene set enrichment analysis was performed to study their molecular characteristics. We independently assessed the spatial patterns in a second cohort of ER+HER2− breast cancer (N = 630, METABRIC) and studied their prognostic value. The spatial integration of fibroblasts, TILs, and tumor cells leads to a new reproducible spatial classification of ER+HER2− breast cancer and is linked to inflammation, fibroblast meddling, or immunosuppression. ER+HER2− patients with high TIL did not have a significant improved overall survival (HR = 0.76, P = 0.212), except when they had received chemotherapy (HR = 0.447). A poorer survival was observed for patients with high fibroblasts that did not show a high level of TILs (HR = 1.661, P = 0.0303). Especially spatial mixing of fibroblasts and TILs was associated with a good prognosis (HR = 0.464, P = 0.013). Our findings demonstrate a reproducible pipeline for the spatial profiling of TILs and fibroblasts in ER+HER2− breast cancer and suggest that this spatial interplay holds a decisive role in their cancer-immune interactions

Comprehensive evaluation of methods to assess overall and cell-specific immune infiltrates in breast cancer

Background: Breast cancer (BC) immune infiltrates play a critical role in tumor progression and response to treatment. Besides stromal tumor infiltrating lymphocytes (sTILs) which have recently reached level 1B evidence as a prognostic marker in triple negative BC, a plethora of methods to assess immune infiltration exists, and it is unclear how these compare to each other and if they can be used interchangeably. Methods: Two experienced pathologists scored sTIL, intra-tumoral TIL (itTIL), and 6 immune cell types (CD3+, CD4+, CD8+, CD20+, CD68+, FOXP3+) in the International Cancer Genomics Consortium breast cancer cohort using hematoxylin and eosin-stained (n = 243) and immunohistochemistry-stained tissue microarrays (n = 254) and whole slides (n = 82). The same traits were evaluated using transcriptomic- and methylomic-based deconvolution methods or signatures. Results: The concordance correlation coefficient (CCC) between pathologists for sTIL was very good (0.84) and for cell-specific immune infiltrates slightly lower (0.63-0.66). Comparison between tissue microarray and whole slide pathology scores revealed systematically higher values in whole slides (ratio 2.60-5.98). The Spearman correlations between microscopic sTIL and transcriptomic- or methylomic-based assessment of immune infilt

Relational knowledge leadership and local economic development

This paper concerns the role of spatial leadership in the development of the knowledge-based economy. It is argued within academic and practitioner circles that leadership of knowledge networks requires a particular non-hierarchical style that is required to establish an ambience conducive to networking and knowledge sharing across boundaries. In this paper, we explore this hypothesis at both theoretical and empirical levels. Theoretically, we propose a conceptualization of relational knowledge leadership, which is ‘nomadic’ in its capacity to travel across multiple scales and cross sectoral, thematic and geographical boundaries. We have operationalized this type of relational knowledge leadership along four key features, derived from literatures on regional learning, organizational leadership and place leadership. Two empirical case studies are then presented, one from Birmingham in the UK and one from Eindhoven in the Netherlands, exploring how these features are expressed on the sub-national level. Also conclusions are drawn regarding the status of relational knowledge leadership. It is argued that the concept of relational knowledge leadership as viewed through our analytical lens does accord with the experience of leadership in the two cases presented. The cases also show that this style of leadership is confronted with three types of tensions that play through knowledge networking. Furthermore, it is argued that the cases exhibit this style of leadership to different degrees, reflecting their different cultural and political context

BRCA1-mutated and basal-like breast cancers have similar aCGH profiles and a high incidence of protein truncating TP53 mutations

<p>Abstract</p> <p>Background</p> <p>Basal-like breast cancers (BLBC) are aggressive breast cancers for which, so far, no targeted therapy is available because they typically lack expression of hormone receptors and HER2. Phenotypic features of BLBCs, such as clinical presentation and early age of onset, resemble those of breast tumors from <it>BRCA1</it>-mutation carriers. The genomic instability of <it>BRCA1</it>-mutated tumors can be effectively targeted with DNA-damaging agents and poly-(ADP-ribose) polymerase 1 (PARP1) inhibitors. Molecular similarities between BLBCs and <it>BRCA1</it>-mutated tumors may therefore provide predictive markers for therapeutic response of BLBCs.</p> <p>Methods</p> <p>There are several known molecular features characteristic for <it>BRCA1</it>-mutated breast tumors: 1) increased numbers of genomic aberrations, 2) a distinct pattern of genomic aberrations, 3) a high frequency of <it>TP53 </it>mutations and 4) a high incidence of complex, protein-truncating <it>TP53 </it>mutations. We compared the frequency of <it>TP53 </it>mutations and the pattern and amount of genomic aberrations between <it>BRCA1</it>-mutated breast tumors, BLBCs and luminal breast tumors by <it>TP53 </it>gene sequencing and array-based comparative genomics hybridization (aCGH) analysis.</p> <p>Results</p> <p>We found that the high incidence of protein truncating <it>TP53 </it>mutations and the pattern and amount of genomic aberrations specific for BRCA1-mutated breast tumors are also characteristic for BLBCs and different from luminal breast tumors.</p> <p>Conclusions</p> <p>Complex, protein truncating TP53 mutations in BRCA1-mutated tumors may be a direct consequence of genomic instability caused by BRCA1 loss, therefore, the presence of these types of TP53 mutations in sporadic BLBCs might be a hallmark of BRCAness and a potential biomarker for sensitivity to PARP inhibition. Also, our data suggest that a small subset of genomic regions may be used to identify BRCA1-like BLBCs. BLBCs share molecular features that were previously found to be specific for BRCA1-mutated breast tumors. These features might be useful for the identification of tumors with increased sensitivity to (high-dose or dose-dense) alkylating agents and PARP inhibitors.</p

Culturally valuable minority crops provide a succession of floral resources for flower visitors in traditional orchard gardens

Agricultural intensification typically has detrimental effects on pollinator communities, but diverse cropping systems that contain sequentially-flowering crops have the potential to benefit pollinators through the provision of additional floral resources. In this study we investigate the importance of cultivated flora for flower visitors in ten agricultural gardens in South Sinai, Egypt. Insect-flower interactions in gardens and unmanaged plots were surveyed across a four-month period in two environmentally distinct years (pre-flood and post-flood). Despite containing an equal abundance and diversity of wild plants as unmanaged habitat, gardens supported a higher abundance and diversity of flower visitors due to the additional presence of cultivated flora. Visitation networks exhibited dramatic intra-annual changes in composition, with cultivated plants becoming increasingly important in later months. Trends were highly conserved across 2 years despite highly contrasting rainfall. Several key crop species were strongly involved in shaping the structure of the networks, the majority of which were herbs with strong cultural significance (fennel, rosemary, mint) and grown incidentally alongside the primary orchard crops. Minority crops are frequently overlooked in agricultural systems due to their low economic value, but we show that they can have a dramatic influence upon the structure of visitation networks, increasing both pollinator abundance and diversity, and emphasising the link between cultural practices and biodiversity conservation

Virtual Reality as a Tool for Evaluation of Repetitive Rhythmic Movements in the Elderly and Parkinson's Disease Patients

This work presents an immersive Virtual Reality (VR) system to evaluate, and potentially treat, the alterations in rhythmic hand movements seen in Parkinson's disease (PD) and the elderly (EC), by comparison with healthy young controls (YC). The system integrates the subjects into a VR environment by means of a Head Mounted Display, such that subjects perceive themselves in a virtual world consisting of a table within a room. In this experiment, subjects are presented in 1st person perspective, so that the avatar reproduces finger tapping movements performed by the subjects. The task, known as the finger tapping test (FT), was performed by all three subject groups, PD, EC and YC. FT was carried out by each subject on two different days (sessions), one week apart. In each FT session all subjects performed FT in the real world (FTREAL) and in the VR (FTVR); each mode was repeated three times in randomized order. During FT both the tapping frequency and the coefficient of variation of inter-tap interval were registered. FTVR was a valid test to detect differences in rhythm formation between the three groups. Intra-class correlation coefficients (ICC) and mean difference between days for FTVR (for each group) showed reliable results. Finally, the analysis of ICC and mean difference between FTVR vs FTREAL, for each variable and group, also showed high reliability. This shows that FT evaluation in VR environments is valid as real world alternative, as VR evaluation did not distort movement execution and detects alteration in rhythm formation. These results support the use of VR as a promising tool to study alterations and the control of movement in different subject groups in unusual environments, such as during fMRI or other imaging studies