Differential expression and biochemical activity of the immune receptor Tim-3 in healthy and malignant human myeloid cells

The T cell immunoglobulin and mucin domain 3 (Tim-3) is a plasma membrane-associated receptor which is involved in a variety of biological responses in human immune cells. It is highly expressed in most acute myeloid leukaemia (AML) cells and therefore may serve as a possible target for AML therapy. However, its biochemical activities in primary human AML cells remain unclear. We therefore analysed the total expression and surface presence of the Tim-3 receptor in primary human AML blasts and healthy primary human leukocytes isolated from human blood. We found that Tim-3 expression was significantly higher in primary AML cells compared to primary healthy leukocytes. Tim-3 receptor molecules were distributed largely on the surface of primary AML cells, whereas in healthy leukocytes Tim-3 protein was mainly expressed intracellularly. In primary human AML blasts, both Tim-3 agonistic antibody and galectin-9 (a Tim-3 natural ligand) significantly upregulated mTOR pathway activity. This was in line with increased accumulation of hypoxia-inducible factor 1 alpha (HIF-1α) and secretion of VEGF and TNF-α. Similar results were obtained in primary human healthy leukocytes. Importantly, in both types of primary cells, Tim-3-mediated effects were compared with those induced by lipopolysaccharide (LPS) and stem cell factor (SCF). Tim-3 induced comparatively moderate responses in both AML cells and healthy leukocytes. However, Tim-3, like LPS, mediated the release of both TNF-α and VEGF, while SCF induced mostly VEGF secretion and did not upregulate TNF-α release

The role of national institutions and product architecture in joint decision-making in supply chains

info:eu-repo/semantics/publishedVersio

The Guiding Principles of the profession. A comparative study of Ethical Codes promoted by PR associations

Ethics has been central to the debate about what public relations is, what it does and how it should be practiced in contemporary times. Ethical codes are a moral reference regarding the duties and rights of a profession. In this paper we reflect about the main values that guide PR practice based on Schwartz’s theory of basic human values, which measures universal values that are recognized throughout all major cultures. We aim to ascertain which basic human values are portrayed on the codes of public relations associations worldwide and understand their similarities/discrepancies with the global code of ethics portrayed by the Global Alliance. A qualitative and quantitative content analysis was carried out of the codes of ethics of six national PR and communication associations (representative of the sector in Europe and Americas) and of the Global Alliance's code as an international reference institution. The codes analysed were DIRCOM, Spain; ABERJE, Brazil; APCE, Portugal; CIPR, the United Kingdom; CPRPA, Argentina; PRSA, United States; and the Global Alliance. The documents obtained were analysed according to Schwartz's "Theory of the Universal Structure of Human Values" (1999) to study the priorities of values contained in the ethical codes of the public relations associations analysed, and to highlight the motivational values that may be present in them. The researchers adapted the codes to the structure, based on the descriptions of Schwartz's typology of values, and classified them according to higher-order types and their dimensions.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Non-traditional students in higher education: barriers to learning and professional insertion

This article emerges from two research projects focused on non-traditional students in higher education. Our objectives aims to understand the barriers of learning and academic success, considering the perspectives of the several social actors in the academia; and to understand the barriers of the same students had in their transition to the work environment. The results show that a set of situational and institutional factors work as obstacles to these students. The results also show that age is a determinant factor regarding hiring and that the characteristics of the labour market today make hard the professional insertion of non-traditional undergraduates

Tim-3 as a signalling receptor expressed by leukaemia cells and potential target for highly specific drug delivery

Leukaemia is a blood/bone marrow cancer caused by malignant immature hematopoietic precursors, and quickly becomes a systematic malignancy. The most severe type of leukaemia that has the highest number of lethal outcomes is Acute Myeloid Leukaemia (AML) where malignant cells escape host immune surveillance by inactivating cytotoxic lymphoid cells. We discovered a fundamental biochemical mechanism in AML cells, which includes ligand dependent (probably FLRT3) activation of ectopically expressed latrophilin 1 and possible other G-protein coupled receptors, leading to upregulated translation and secretion of the immune receptor Tim-3 and its ligand galectin-9. This process involved protein kinase C and the mammalian target of rapamycin (mTOR). Tim-3 was observed to participate in galectin-9 secretion, and was also released in a free soluble form. Galectin-9 impaired the anti-cancer activities of cytotoxic lymphoid cells including natural killer (NK) cells and soluble Tim-3 prevented the secretion of interleukin-2 (IL-2), which was required for the activation of cytotoxic lymphoid cells. These results were validated in ex vivo experiments, using primary samples from AML patients. This fundamental pathway provides reliable targets for both highly specific diagnosis and immune therapy of AML. Furthermore, we demonstrated that the Tim-3/galectin-9 autocrine loop has intracellular functions and promotes cell growth and proliferation by directly upregulating translational pathway controlled by mTOR

Tim-3 as a signalling receptor expressed by leukaemia cells and potential target for highly specific drug delivery

Leukaemia is a blood/bone marrow cancer caused by malignant immature hematopoietic precursors, and quickly becomes a systematic malignancy. The most severe type of leukaemia that has the highest number of lethal outcomes is Acute Myeloid Leukaemia (AML) where malignant cells escape host immune surveillance by inactivating cytotoxic lymphoid cells. We discovered a fundamental biochemical mechanism in AML cells, which includes ligand dependent (probably FLRT3) activation of ectopically expressed latrophilin 1 and possible other G-protein coupled receptors, leading to upregulated translation and secretion of the immune receptor Tim-3 and its ligand galectin-9. This process involved protein kinase C and the mammalian target of rapamycin (mTOR). Tim-3 was observed to participate in galectin-9 secretion, and was also released in a free soluble form. Galectin-9 impaired the anti-cancer activities of cytotoxic lymphoid cells including natural killer (NK) cells and soluble Tim-3 prevented the secretion of interleukin-2 (IL-2), which was required for the activation of cytotoxic lymphoid cells. These results were validated in ex vivo experiments, using primary samples from AML patients. This fundamental pathway provides reliable targets for both highly specific diagnosis and immune therapy of AML. Furthermore, we demonstrated that the Tim-3/galectin-9 autocrine loop has intracellular functions and promotes cell growth and proliferation by directly upregulating translational pathway controlled by mTOR