PDGFR\u3b2 and FGFR2 mediate endothelial cell differentiation capability of triple negative breast carcinoma cells

Triple negative breast cancer (TNBC) is a very aggressive subgroup of breast carcinoma, still lacking specific markers for an effective targeted therapy and with a poorer prognosis compared to other breast cancer subtypes. In this study we investigated the possibility that TNBC cells contribute to the establishment of tumor vascular network by the process known as vasculogenic mimicry, through endothelial cell differentiation. Vascular-like functional properties of breast cancer cell lines were investigated in vitro by tube formation assay and in vivo by confocal microscopy, immunofluorescence or immunohistochemistry on frozen tumor sections. TNBCs express endothelial markers and acquire the ability to form vascular-like channels in vitro and in vivo, both in xenograft models and in human specimens, generating blood lacunae surrounded by tumor cells. Notably this feature is significantly associated with reduced disease free survival. The impairment of the main pathways involved in vessel formation, by treatment with inhibitors (i.e. Sunitinib and Bevacizumab) or by siRNA-mediating silencing, allowed the identification of PDGFR\u3b2 and FGFR2 as relevant players in this phenomenon. Inhibition of these tyrosine kinase receptors negatively affects vascular lacunae formation and significantly inhibits TNBC growth in vivo. In summary, we demonstrated that TNBCs have the ability to form vascular-like channels in vitro and to generate blood lacunae lined by tumor cells in vivo. Moreover, this feature is associated with poor outcome, probably contributing to the aggressiveness of this breast cancer subgroup. Finally, PDGFR\u3b2 and FGFR2-mediated pathways, identified as relevant in mediating this characteristic, potentially represent valid targets for a specific therapy of this breast cancer subgroup

po 344 mir 302b as adjuvant therapeutic tool to improve chemotherapy efficacy in human triple negative breast cancer

Introduction MiRNAs are a class of non-coding regulatory RNAs playing key roles in different biological processes including cancer. Triple-negative breast cancer (TNBC) accounts for 15%–20% of all breast cancer cases, with the worst outcome of all subtypes. For TNBC, still lacking targeted therapies, the only therapeutic option is chemotherapy. MiRNAs can modulate chemotherapy response by affecting DNA repair, cell cycle progression, apoptosis and also tumour microenvironment. Macrophages constitute a major component of the immune microenvironment of cancer and pro-tumour M2 macrophages have been associated with response to chemotherapeutic treatments. Here, we investigated the potential of miR-302b as a therapeutic tool to enhance cisplatin sensitivity in a TNBC mouse model and which pathways are involved in this mechanism both in tumour cells and microenvironment. Material and methods TNBC cells were injected into the mammary fat pad of female SCID mice and then treated with lipid nanoparticles containing miR-302b or cel-67 control, alone or in combination with cisplatin. Gene expression profile on collected tumours was performed by microarray. ITGA6 expression was assessed on tumour samples and siRNA tranfection was performed to evaluate the cisplatin response. Tumour sections were stained with anti-arginase 1 (M2 marker) to assess the number of M2 macrophages, and luciferase assay was used to evaluate Irf4 (M2 marker) as a direct target of miR-302b. Results and discussions Our results show that combination of miR-302b with cisplatin significantly impaired tumour growth in comparison with control cel-67. Gene expression profile identified ITGA6 as a regulatory target of miR-302b and cisplatin activity. Indeed, ITGA6 expression is down-modulated in mice treated with miR-302b plus cisplatin compared with control mice. Furthermore, TNBC cell lines increase their cisplatin sensitivity upon ITGA6 silencing. These data confirm the role of ITGA6 in cisplatin response mediated by miR-302b. Moreover, in xenograft tumours collected from the in vivo miR-302b delivery experiment, we observed a reduced number of M2 macrophages in the tumour microenvironment and gene expression confirm immune system modulation. Finally, luciferase assay validate Irf4, a key gene involved in M2 recruitment, as a direct target of miR-302b. Conclusion Our data demonstrate that miR-302b can be exploited as a new therapeutic tool to improve the response to chemotherapy, modulating ITGA6 expression in tumour cells and M2 recruitment in tumour microenvironment

CDCP1 is a novel marker of the most aggressive human triple-negative breast cancers

CDCP1, a transmembrane noncatalytic receptor, the expression of which has been associated with a poor prognosis in certain epithelial cancers, was found to be expressed in highly aggressive triple-negative breast cancer (TNBC) cell models, in which it promoted aggressive activities-ie, migration, invasion, anchorage-independent tumor growth, and the formation of vascular-like structures in vitro. By immunohistochemical (IHC) analysis of 100 human TNBC specimens, CDCP1 was overexpressed in 57% of samples, 38% of which exhibited a gain in CDCP1 copy number by fluorescence in situ hybridization (FISH). CDCP1 positivity was significantly associated between FISH and IHC. CDCP1 expression and gains in CDCP1 copy number synergized with nodal (N) status in determining disease-free and distant disease-free survival. The hazard ratios (HRs) of the synergies between CDCP1 positivity by IHC and FISH and lymph node positivity in predicting relapse did not differ significantly, indicating that CDCP1 overexpression in human primary TNBCs, regardless of being driven by gains in CDCP1, is for a critical factor in the progression of N-positive TNBCs. Thus, CDCP1 is a novel marker of the most aggressive N-positive TNBCs and a potential therapeutic target

The Usability of E-learning Platforms in Higher Education: A Systematic Mapping Study

The use of e-learning in higher education has increased significantly in recent years, which has led to several studies being conducted to investigate the usability of the platforms that support it. A variety of different usability evaluation methods and attributes have been used, and it has therefore become important to start reviewing this work in a systematic way to determine how the field has developed in the last 15 years. This paper describes a systematic mapping study that performed searches on five electronic libraries to identify usability issues and methods that have been used to evaluate e-learning platforms. Sixty-one papers were selected and analysed, with the majority of studies using a simple research design reliant on questionnaires. The usability attributes measured were mostly related to effectiveness, satisfaction, efficiency, and perceived ease of use. Furthermore, several research gaps have been identified and recommendations have been made for further work in the area of the usability of online learning

Ergonomic Quality in Green Building Protocols

The control of living conditions in built spaces is a key aspect of design in order to guarantee the final user to live in healthy and safe spaces. This importance is also recognized in green building rating systems that, in fact, present criteria on wellbeing with particular link to physical issues. In this context, the adoption of an ergonomic approach would be useful in order to address the interaction between user and built environment as a whole, considering both factors that affect physical wellbeing (i.e. thermo-hygrometric, acoustic, lighting, air purity), and those that complete the complex sphere of wellbeing, that are psychological and social too

Office workspace for an ageing workforce: A systematic review

BACKGROUND: With the ageing of the working population, it is becoming crucial empowering staff of all ages to perform at its best. To this end, organizations can act on the built environment, adapting the workspace to the changing characteristics of workers and using it as a tool for health promotion. OBJECTIVE: To provide an overview of office workspace requirements to optimise the wellbeing and productivity of older workers. METHODS: The search, by Scopus, Web of Science core collection and Medline, produced 290 records. The screening process, according to the Prisma method, reduced the records to 13 included in the review. RESULTS: The results showthe needs and preferences of the ageingworkforce, such as personal control over the environment in terms of both comfort and use of space, as well as negative opinions on specific solutions, such as the extensive use of open offices and the introduction of shared workstations. The included studies report mainly subjective data, derived from interviews and questionnaires. CONCLUSIONS: The review provides a first framework for acting on the office workspace to improve wellbeing and productivity of older workers. However, further studies, evidence-based and with subjective and objective measurements of specific solutions, are needed to develop guidelines for an inclusive workspace for all ages

Definition of an Environmental Performance Evaluation System

Department of Building National University of Singapor