The basal epithelial marker P-cadherin associates with breast cancer cell populations harboring a glycolytic and acid-resistant phenotype

"BMC Cancer 2014 14:734"BACKGROUND: Cancer stem cells are hypoxia-resistant and present a preponderant glycolytic metabolism. These characteristics are also found in basal-like breast carcinomas (BLBC), which show increased expression of cancer stem cell markers.Recently, we demonstrated that P-cadherin, a biomarker of BLBC and a poor prognostic factor in this disease, mediates stem-like properties and resistance to radiation therapy. Thus, the aim of the present study was to evaluate if P-cadherin expression was associated to breast cancer cell populations with an adapted phenotype to hypoxia. METHODS: Immunohistochemistry was performed to address the expression of P-cadherin, hypoxic, glycolytic and acid-resistance biomarkers in primary human breast carcinomas. In vitro studies were performed using basal-like breast cancer cell lines. qRT-PCR, FACS analysis, western blotting and confocal microscopy were used to assess the expression of P-cadherin after HIF-1a stabilization, achieved by CoCl2 treatment. siRNA-mediated knockdown was used to silence the expression of several targets and qRT-PCR was employed to evaluate the effects of P-cadherin on HIF-1a signaling. P-cadherin high and low breast cancer cell populations were sorted by FACS and levels of GLUT1 and CAIX were assessed by FACS and western blotting. Mammosphere forming efficiency was used to determine the stem cell activity after specific siRNA-mediated knockdown, further confirmed by western blotting. RESULTS: We demonstrated that P-cadherin overexpression was significantly associated with the expression of HIF-1a, GLUT1, CAIX, MCT1 and CD147 in human breast carcinomas. In vitro, we showed that HIF-1a stabilization was accompanied by increased membrane expression of P-cadherin and that P-cadherin silencing led to a decrease of the mRNA levels of GLUT1 and CAIX. We also found that the cell fractions harboring high levels of P-cadherin were the same exhibiting more GLUT1 and CAIX expression. Finally, we showed that P-cadherin silencing significantly decreases the mammosphere forming efficiency in the same range as the silencing of HIF-1a, CAIX or GLUT1, validating that all these markers are being expressed by the same breast cancer stem cell population. CONCLUSIONS: Our results establish a link between aberrant P-cadherin expression and hypoxic, glycolytic and acid-resistant breast cancer cells, suggesting a possible role for this marker in cancer cell metabolismo.This work was funded by FEDER funds through the COMPETE Program (Programa Operacional Factores de Competitividade) and by national funds through FCT (Portuguese Foundation for Science and Technology, Portugal), mainly in the context of the scientific project PTDC/SAU-GMG/120049/2010-FCOMP-01-0124-FEDER-021209, and partially by PTDC/SAU-FCF/104347/2008. FCT funded the research grants of BS (SFRH/BD/69353/2010), ASR (SFRH/BPD/75705/2011), ARN (grant from the project PTDC/SAU-GMG/120049/2010), CP (SFRH/BPD/69479/2010), AV (SFRH/BPD/90303/2012), as well as JP, with Programa Ciencia 2007 (Contratacao de Doutorados para o SCTN - financiamento pelo POPH - QREN - Tipologia 4.2 - Promocao do Emprego Cientifico, comparticipado pelo Fundo Social Europeu e por fundos nacionais do MCTES) and Programa IFCT (FCT Investigator). IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education and is partially supported by FCT

Theorising capitalist diversity: The uneven and combined development of labour forms

This article seeks to elaborate a framework for the study of diversity in forms of labour using Trotsky’s theory of uneven and combined development (UCD). It argues that labour markets are constituted by systemic processes of capital accumulation and uneven development in the global economy, but that these processes have highly differentiated outcomes in terms of the forms of labour that have historically emerged within and across national boundaries. Exploring some of the neglected elements of different forms of labour, including non-waged labour, the article demonstrates how we might conceptualise the way in which combinations of labour forms exist within any given space of the world economy. Using the examples of both internal and transnational migration, it argues that charting the social and spatial relations of production, and the labouring experiences and forms of worker politics associated with them, is an effective way of understanding the constitution and restructuring of different forms of labour

Machine Learning and Evolutionary Techniques in Interplanetary Trajectory Design

After providing a brief historical overview on the synergies between artificial intelligence research, in the areas of evolutionary computations and machine learning, and the optimal design of interplanetary trajectories, we propose and study the use of deep artificial neural networks to represent, on-board, the optimal guidance profile of an interplanetary mission. The results, limited to the chosen test case of an Earth–Mars orbital transfer, extend the findings made previously for landing scenarios and quadcopter dynamics, opening a new research area in interplanetary trajectory planning.</p

2020 international consensus on ANCA testing beyond systemic vasculitis

This document follows up on a 2017 revised international consensus on anti-neutrophil cytoplasm antibodies (ANCA) testing in granulomatosis with polyangiitis and microscopic polyangiitis and focuses on the clinical and diagnostic value of ANCA detection in patients with connective tissue diseases, idiopathic interstitial pneumonia, autoimmune liver diseases, inflammatory bowel diseases, anti-glomerular basement membrane (GBM) disease, infections, malignancy, and during drug treatment. Current evidence suggests that in certain settings beyond systemic vasculitis, ANCA may have clinical, pathogenic and/or diagnostic relevance. Antigen-specific ANCA targeting proteinase-3 and myeloperoxidase should be tested by solid phase immunoassays in any patient with clinical features suggesting ANCA-associated vasculitis and in all patients with anti-GBM disease, idiopathic interstitial pneumonia, and infective endocarditis associated with nephritis, whereas in patients with other aforementioned disorders routine ANCA testing is not recommended. Among patients with autoimmune liver diseases or inflammatory bowel diseases, ANCA testing may be justified in patients with suspected autoimmune hepatitis type 1 who do not have conventional autoantibodies or in case of diagnostic uncertainty to discriminate ulcerative colitis from Crohn’s disease. In these cases, ANCA should be tested by indirect immunofluorescence as the target antigens are not yet well characterized. Many questions concerning the optimal use of ANCA testing in patients without ANCA-associated vasculitis remain to be answered

AB0501 Three cases of vertebral arteritis identified on FDG-PET in patients with suspected GCA at University of College London Hospital (UCLH)

Background: Giant cell arteritis (GCA) may affect both cranial and extra-cranial vessels; where the latter occurs, it can be termed large-vessel GCA (LV-GCA). Large vessel involvement is common: histological evidence has been seen in 80% of autopsies of patients with known GCA, and imaging studies suggest large vessel involvement in over 80%1. LV-GCA is important to diagnose due to the risks of vascular complications such as occlusion and ischaemic stroke. The clinical diagnosis can be challenging, and the American College of Rheumatology (ACR) GCA classification criteria often underperform in cases of LV-GCA1. F-fluorodeoxyglucose positron emission tomography (FDG-PET) has been found to be useful in the detection of extra-cranial involvement to support the diagnosis of LV-GCA.2 Objectives: To appreciate the variability in presentation of cases of LV-GCA, and to further characterise a subgroup of patients with vertebral arteritis. To explore the use of FDG-PET imaging in GCA patients in addition to or in place of traditional diagnostic tools (temporal artery ultrasound / biopsy). Methods: Through evaluation of the new GCA fast-track pathway implemented at UCLH, a subgroup of patients diagnosed with vertebral arteritis was identified. The history and presentation of these patients were analysed. Results: Three patients were diagnosed with vertebral arteritis. All three were male, Caucasian and aged over 70. All were investigated for GCA due to a history of severe headache (frontal in one, occipital in one, bi-temporal in one) with associated red flag symptoms. Two had a history of jaw claudication and visual disturbances (unilateral visual loss in one, transient diplopia in the other). Both of these patients had positive temporal artery biopsies. The third patient had no ischaemic symptoms but a strong history of prominent polymyalgic features and a positive temporal artery ultrasound. Inflammatory markers were raised in two, and normal in one, of the patients. Only one had systemic symptoms (weight loss). All three proceeded to FDG-PET scans which showed vertebral arteritis and were commenced on immunosuppressive treatment. Conclusion: The cases discussed illustrate the heterogeneity of the presentation of LV-GCA, and the diagnostic challenge this poses. FDG-PET imaging is useful in confirming extra-cranial involvement and therefore guiding treatment

Ant-1, an active transposon from the fungus Aspergillus niger

A transposable element has been isolated from the industrially important fungus Aspergillus niger (strain N402). The element was identified as an insertion sequence within the coding region of the nitrate reductase gene. It had inserted at a TA site and appeared to have duplicated the target site upon insertion. The isolated element was found to be 4798 by in length and contained 37-bp inverted, imperfect, terminal repeats (ITRs). The sequence of the central region of the element revealed an open reading frame (designated ORF1) which showed similarity, at the amino acid level, to the transposase of the Tc1/mariner class of DNA transposons. Another sequence within the central region of the element showed similarity to the 3 coding and downstream untranslated region of the amyA gene of A. niger. Sequence homology and structural features indicate that this element, which has been named Ant1 (A. niger transposon 1), is related to the Tc1/mariner group of DNA transposons. Ant1 is apparently present as a single copy in strain N402 of A. niger