PARP-1 regulates metastatic melanoma through modulation of vimentin-induced malignant transformation.

PARP inhibition can induce anti-neoplastic effects when used as monotherapy or in combination with chemo- or radiotherapy in various tumor settings; however, the basis for the anti-metastasic activities resulting from PARP inhibition remains unknown. PARP inhibitors may also act as modulators of tumor angiogenesis. Proteomic analysis of endothelial cells revealed that vimentin, an intermediary filament involved in angiogenesis and a specific hallmark of EndoMT (endothelial to mesenchymal transition) transformation, was down-regulated following loss of PARP-1 function in endothelial cells. VE-cadherin, an endothelial marker of vascular normalization, was up-regulated in HUVEC treated with PARP inhibitors or following PARP-1 silencing; vimentin over-expression was sufficient to drive to an EndoMT phenotype. In melanoma cells, PARP inhibition reduced pro-metastatic markers, including vasculogenic mimicry. We also demonstrated that vimentin expression was sufficient to induce increased mesenchymal/pro-metastasic phenotypic changes in melanoma cells, including ILK/GSK3-β-dependent E-cadherin down-regulation, Snail1 activation and increased cell motility and migration. In a murine model of metastatic melanoma, PARP inhibition counteracted the ability of melanoma cells to metastasize to the lung. These results suggest that inhibition of PARP interferes with key metastasis-promoting processes, leading to suppression of invasion and colonization of distal organs by aggressive metastatic cells.

Low transformation growth factor-β1 production and collagen synthesis correlate with the lack of hepatic periportal fibrosis development in undernourished mice infected with Schistosoma mansoni

Undernourished mice infected (UI) submitted to low and long-lasting infections by Schistosoma mansoni are unable to develop the hepatic periportal fibrosis that is equivalent to Symmers’ fibrosis in humans. In this report, the effects of the host’s nutritional status on parasite (worm load, egg viability and maturation) and host (growth curves, biology, collagen synthesis and characteristics of the immunological response) were studied and these are considered as interdependent factors influencing the amount and distribution of fibrous tissue in hepatic periovular granulomas and portal spaces. The nutritional status of the host influenced the low body weight and low parasite burden detected in UI mice as well as the number, viability and maturation of released eggs. The reduced oviposition and increased number of degenerated or dead eggs were associated with low protein synthesis detected in deficient hosts, which likely induced the observed decrease in transformation growth factor (TGF)-β1 and liver collagen. Despite the reduced number of mature eggs in UI mice, the activation of TGF-β1 and hepatic stellate cells occurred regardless of the unviability of most miracidia, due to stimulation by fibrogenic proteins and eggshell glycoproteins. However, changes in the repair mechanisms influenced by the nutritional status in deficient animals may account for the decreased liver collagen detected in the present study.

Agriculture, technological change and environmental sustainability: Looking for a win-win water policy strategy

This paper analyses the effects that technological changes in agriculture would have on environmental, social and economic indicators. Specifically, our study is focused on two alternative technological improvements: the modernization of water transportation systems versus the increase in the total factor productivity of agriculture. Using a computable general equilibrium model for the Catalan economy, our results suggest that a water policy that leads to greater economic efficiency is not necessarily optimal if we consider social or environmental criteria. Moreover, improving environmental sustainability depends less on the type of technological change than on the institutional framework in which technological change occurs. Keywords: agricultural technological changes, computable general equilibrium model, economic impact, water policy

Historical review of clinical vaccine studies at Oswaldo Cruz Institute and Oswaldo Cruz Foundation - technological development issues

This paper presents, from the perspective of technological development and production, the results of an investigation examining 61 clinical studies with vaccines conducted in Brazil between 1938-2013, with the participation of the Oswaldo Cruz Institute (IOC) and the Oswaldo Cruz Foundation (Fiocruz). These studies have been identified and reviewed according to criteria, such as the kind of vaccine (viral, bacterial, parasitic), their rationale, design and methodological strategies. The results indicate that IOC and Fiocruz have accumulated along this time significant knowledge and experience for the performance of studies in all clinical phases and are prepared for the development of new vaccines products and processes. We recommend national policy strategies to overcome existing regulatory and financing constraints.

Luteinizing hormone (LH) and prolactin-releasing pituitary tumor: possible malignant transformation of the LH cell line.

A pituitary tumor was diagnosed in a prepubertal 13-yr-old girl, who had elevated plasma LH (58 mIU/ml) and PRL (93 ng/ml) levels; decreased GH, ACTH, and FSH secretion; and diabetes insipidus. After surgery, plasma LH and PRL declined, but not to normal levels. Conventional external radiotherapy to the pituitary was immediately followed by a decrease in LH to prepubertal values (0.7 mIU/ml), while PRL levels became normal only after a long course of bromocriptine therapy. The pituitary tumor was composed of two distinct cell types: small polygonal cells, which were PRL positive by immunohistochemistry, and clusters of pleomorphic large frequently mitotic polynucleated cells, which were LH positive, some of them also being positive for the alpha-subunit or beta LH but not for beta FSH. Four years after surgery and radiotherapy, the patient deteriorated neurologically. Computed tomographic scan showed widespread frontal and periventricular tumor, which had the histological features of a poorly differentiated carcinoma. No PRL, LH, or alpha- or beta-subunits were detectable on immunocytochemistry. While the PRL-positive cells of the pituitary tumor displayed the histological and clinical features of PRL adenomas, the morphological characteristics of LH cells and the sharp decline of plasma LH levels after radiotherapy were suggestive of malignant transformation. In this context, the later brain tumor could have been the result of subependymal spread of the pituitary tumor after it lost its hormone-secreting capacity.

Technological convergence: a strategic perspective

The information and communication technologies (ICT) sectors are in a process of technological convergence. Determinant factors in this process are the liberalisation of the telecommunications markets and technological change. Many firms are engaged in a process of mergers and alliances to position themselves in this new framework. Technological and demand uncertainties are very important. Our objective in this paper is to study the economic determinants of the strategies of the firms. With this aim, we review some key technological and demand aspects. We shed some light on the strategic motivations of the firms by establishing a parallel with the evolution of the retailing sector

Legal europeanization as legal transformation : some insights from Swiss 'outer Europe'

The "Europeanization" of non-EU countries' laws is predominantly seen as an "export" of the EU acquis, especially in the case of so-called "quasi-member" states such as Switzerland. Based on an examination of the Swiss experience, this paper highlights the flaws of this conceptualization: the Europeanization of Swiss Law is a highly differentiated phenomenon, encompassing several forms of approximation to EU Law. All of these forms fall short of an "export" of norms, and result in the creation of something new: a "Europeanized law" that is similar to, but qualitatively different from, EU Law. Another drawback of the "export" metaphor is the emphasis it places on the isomorphism of positive legislation. Europeanization goes deeper than that. As shown in this paper, it is a process of transformation involving not only positive law, but also legal thinking. The Swiss case demonstrates how significant such deeper transformations can be: the Europeanization of positive law has induced an alteration of the traditional canon of legal interpretation. It also demonstrates how problematic such transformations can be: the above-mentioned alteration has not given rise to a new and universally accepted canon of interpretation. This reflects the tension between the need for clear "rules of reference" for EU legal materials - which are required in order to restore coherence and predictability to an extensively Europeanized legal system - and the reluctance to give a legal value to foreign legal materials - which is rooted in a traditional understanding of the concept of "law". Such tension, in turn, shows what deep and difficult transformations are required in order to establish a viable model of legal integration outside supranational structures.

Genetics for clinicians: from candidate genes to whole genome scans (technological advances).

Human genetics has progressed at an unprecedented pace during the past 10 years. DNA microarrays currently allow screening of the entire human genome with high level of coverage and we are now entering the era of high-throughput sequencing. These remarkable technical advances are influencing the way medical research is conducted and have boosted our understanding of the structure of the human genome as well as of disease biology. In this context, it is crucial for clinicians to understand the main concepts and limitations of modern genetics. This review will describe key concepts in genetics, including the different types of genetic markers in the human genome, review current methods to detect DNA variation, describe major online public databases in genetics, explain key concepts in statistical genetics and finally present commonly used study designs in clinical and epidemiological research. This review will therefore concentrate on human genetic variation analysis.

Cyclical Skill-Biased Technological Change

Over the past two decades, technological progress has been biased towards making skilled labor more productive. The evidence for this finding is based on the persistent parallel increase in the skill premium and the supply of skilled workers. What are the implications of skill-biased technological change for the business cycle? To answer this question, we use the CPS outgoing rotation groups to construct quarterly series for the price and quantity of skill. The unconditional correlation of the skill premium with the cycle is zero. However, using a structural VAR with long run restrictions, we find that technology shocks substantially increase the premium. Investment-specific technology shocks are not skill-biased and our findings suggest that capital and skill are (mildly) substitutable in aggregate production.

Angiopoietin 2 regulates the transformation and integrity of lymphatic endothelial cell junctions.

Primitive lymphatic vessels are remodeled into functionally specialized initial and collecting lymphatics during development. Lymphatic endothelial cell (LEC) junctions in initial lymphatics transform from a zipper-like to a button-like pattern during collecting vessel development, but what regulates this process is largely unknown. Angiopoietin 2 (Ang2) deficiency leads to abnormal lymphatic vessels. Here we found that an ANG2-blocking antibody inhibited embryonic lymphangiogenesis, whereas endothelium-specific ANG2 overexpression induced lymphatic hyperplasia. ANG2 inhibition blocked VE-cadherin phosphorylation at tyrosine residue 685 and the concomitant formation of button-like junctions in initial lymphatics. The defective junctions were associated with impaired lymph uptake. In collecting lymphatics, adherens junctions were disrupted, and the vessels leaked upon ANG2 blockade or gene deletion. ANG2 inhibition also suppressed the onset of lymphatic valve formation and subsequent valve maturation. These data identify ANG2 as the first essential regulator of the functionally important interendothelial cell-cell junctions that form during lymphatic development.

Participation of nurses in the execution of clinical research protocol about technological innovation

AbstractOBJECTIVETo report the nurse's experience of inclusion in interdisciplinary clinical study about technological innovation, involving people with spinal cord injury.METHODDescriptive experience report. The empirical support was based on notes about perspectives and practice of clinical research, with a multi-professional nursing, physical education, physiotherapy and engineering staff.RESULTThe qualification includes the elaboration of the document for the Ethics Committee, familiarization among the members of staff and with the studied topic, and also an immersion into English. The nurse's knowledge gave support to the uptake of participants and time adequacy for data collection, preparation and assistance of the participants during the intervention and after collection. Nursing theories and processes have contributed to reveal risky diagnoses and the plan of care. It was the nurse's role to monitor the risk of overlapping methodological strictness to the human aspect. The skills for the clinical research must be the object of learning, including students in multidisciplinary researches.CONCLUSIONTo qualify the nurse for clinical research and to potentialize its caregiver essence, some changes are needed in the educational system, professional behavior, attitude and educational assistance.