32 research outputs found
Next-Generation Sequencing: Application in Liver Cancer—Past, Present and Future?
No full textHepatocellular Carcinoma (HCC) is the third most deadly malignancy worldwide characterized by phenotypic and molecular heterogeneity. In the past two decades, advances in genomic analyses have formed a comprehensive understanding of different underlying pathobiological layers resulting in hepatocarcinogenesis. More recently, improvements of sophisticated next-generation sequencing (NGS) technologies have enabled complete and cost-efficient analyses of cancer genomes at a single nucleotide resolution and advanced into valuable tools in translational medicine. Although the use of NGS in human liver cancer is still in its infancy, great promise rests in the systematic integration of different molecular analyses obtained by these methodologies, i.e., genomics, transcriptomics and epigenomics. This strategy is likely to be helpful in identifying relevant and recurrent pathophysiological hallmarks thereby elucidating our limited understanding of liver cancer. Beside tumor heterogeneity, progress in translational oncology is challenged by the amount of biological information and considerable “noise” in the data obtained from different NGS platforms. Nevertheless, the following review aims to provide an overview of the current status of next-generation approaches in liver cancer, and outline the prospects of these technologies in diagnosis, patient classification, and prediction of outcome. Further, the potential of NGS to identify novel applications for concept clinical trials and to accelerate the development of new cancer therapies will be summarized
Critical competences in public organizations facing turbulent environments: the EUROCONTROL case
No full textThe analysis of the organization‘s strategic competitive advantages in networks is now a recurrent issue in resource-based theories, which proposes that sustained competitive advantages are more a function of organization resources than of industry structure (Amesse et al, 2006; Sanchez et al, 1997; Prahalad et al, 1990; Teece et al, 1997). When organizations face turbulent environments and the increasing complexity of the scientific and technological knowledge base, they focus the attention on activities fostering their competitive advantage against partners and competitors, and their position in the value chain. Viewing the organization as a stock of knowledge, the argument is developed that dynamic competences represent an important antecedent of superior performance in turbulent environments. Approaches referring to the management of knowledge assets and of competencies investigate the frontier between organizations, and the nature of interactions between stakeholders in networks.
Dynamic competences stand here for the variety-generating capability of knowledge. Even in the resource-based views, the diversity of approaches about competences makes it obvious that the very concept of ―competence‖ remains imprecise. The identification of key technological and organizational competences represents a challenge for any organization (SubbaNarasimha, 2001). What is their actual content? How are they supposed to evolve against turbulent environments? What are key competences to be maintained in-house, or conversely outsourced? What is the relationship between key competences at organization level and individual key competencies?
These questions not only apply to the industry, yet also to public bodies. To be mentioned among public actors are national states, public authorities and agencies in charge of R&D, procurement and technological innovation. The evolution of public agencies‘ roles and missions explain why they now inquire the nature and content of competences and the key knowledge assets to be maintained. This evolution has to account for the specificities of public missions and services, and also to the plasticity of organizations (which is their capacity to adapt efficiently to the turbulent environment).
This contribution focuses on agencies in charge of complex technological programs in relation with public missions. These organizations face the need of adapting to the evolution of their institutional and technological environment.
Numerous agencies face this type of challenge. They most often endorse specific responsibilities in R&D and technological policies. These agencies are in charge of making relevant technological choices in the framework of policy objectives assigned by political levels; they also need to make the
subsequent decisions and implement them at the level of technological programs. Numerous instances may be raised to illustrate such evolutions: agencies in charge of technological programs and procurement in the Defense domain (Merindol, 2009; Merindol & Versailles, 2010), or agencies in charge of space programs at national level (for instance CNES in France; cf. Belleval, 2006) or at European level (the European Space Agency, cf. Cohendet & Lebeau, 1987).
In this contribution, we will elaborate on a mission commissioned by EUROCONTROL, the European agency in charge of Air traffic management missions (ATM), which is also running a series of technological missions in order to ―produce‖ ATM-related technological programs.
The agencies‘ role remains very specific. They currently face institutional evolutions and confront turbulent environments: technologies, economic relations, and governance modalities are reshaped at the same time. The turbulent environment affects the nature of public-private relations and the stakeholders‘ respective responsibilities in the development of technologies. The evolution of technological and organizational key competences translates into new positions in the value chain associated to the conception of technological programs, and in the characterization of public service missions (safety, security, quality, neutrality of the agency, etc.). This characterizes all stakeholders, yet our contribution will only address EUROCONTROL‘s perspective over this new environment.
This contribution proposes an analysis of the evolution of EUROCONTROL‘s key competences in the domain of the Surveillance products and systems (SPS) which root at the kernel of the ATM mission.
This contribution in strategic management will aim at investigating EUROCONTROL SPS unit key competences, as an instance of public body in charge of the management of complex technological programs. This contribution identifies key organizational and technological competences, and characterizes ―values‖ and ―attributes‖ of the knowledge assets mobilized by EUROCONTROL SPS unit. We propose to refer to the depth and breadth of knowledge and capabilities. Depth and breadth are the result of the technological and cognitive complexity associated to the conception of SPS products, and at the same time the condition necessary for managing it (Prencipe, 2000; Wang and von Tunzelmann, 2000).
The interaction with EUROCONTROL SPS unit has led to appraise the level of depth and breadth of capabilities associated with several roles in the SPS product environment (i.e. the interaction between the Agency, its stakeholders, the SPS products end-users, and the industry). Evaluations have focused on EUROCONTROL SPS unit‘s capability to manage problem-solving, implement solutions, and facilitate interactions within the SPS network. We frame the investigation with several scenarios characterizing EUROCONTROL‘s roles and responsibilities, which correspond to specific positions in the value chain and to potential arrangements in the turbulent environment.
Following the perspective developed by Hitt (2005), this contribution stresses the relevance and specificities of the investigation of competences for public organizations in strategic management, which holds particularly when agencies are in charge of the management of complex programs.ou
In vivo expression of carbohydrate responsive element binding protein in lean and obese rats
No full textChREBP (Carbohydrate response element binding protein) is considered to mediate the stimulatory ChREBP (Carbohydrate response element binding protein) is considered to mediate the stimulatory effect of glucose on the expression of lipogenic genes. Its activity is stimulated by glucose. Less is known on the control of its expression. This expression could be controlled by nutritional (glucose, fatty acids) and hormonal (insulin) factors. We examined the in vivo nutritional control of ChREBP expression in liver and adipose tissue of Wistar rats. Compared respectively to the fed state and to a high carbohydrate diet, ChREBP mRNA concentrations were not modified by fasting or a high fat diet in rat liver and adipose tissue. FAS and ACC1 mRNA concentrations were on the contrary decreased as expected by fasting and high fat diets and these variations of FAS and ACC1 mRNA were positively related to those of SREBP-1c mRNA and protein, but not of ChREBP mRNA. Therefore i) ChREBP expression appears poorly responsive to modifications of nutritional condition, ii) modifications of the expression of ChREBP do not seem implicated in the physiological control of lipogenesis. To investigate the possible role of ChREBP in pathological situations we measured its mRNA concentrations in the liver and adipose tissue of obese Zucker rats. ChREBP expression was increased in the liver but not the adipose tissue of obese rats compared to their lean littermates. These results support a role of ChREBP in the development of hepatic steatosis and hypertriglyceridemia but not of obesity in this experimental model
Metabolism of lipids in human white adipocyte.
No full textInternational audienceAdipose tissue is considered as the body's largest storage organ for energy in the form of triacylglycerols, which are mobilized through lipolysis process, to provide fuel to other organs and to deliver substrates to liver for gluconeogenesis (glycerol) and lipoprotein synthesis (free fatty acids). The release of glycerol and free fatty acids from human adipose tissue is mainly dependent on hormone-sensitive lipase which is intensively regulated by hormones and agents, such as insulin (inhibition of lipolysis) and catecholamines (stimulation of lipolysis). A special attention is paid to the recently discovered perilipins which could regulate the activity of the lipase hormono-sensible. Most of the plasma triacylglycerols are provided by dietary lipids, secreted from the intestine in the form of chylomicron or from the liver in the form of VLDL. Released into circulation as non-esterified fatty acids by lipoprotein lipase, those are taken up by adipose tissue via specific plasma fatty acid transporters (CD36, FATP, FABPpm) and used for triacylglycerol synthesis. A small part of triacylglycerols is synthesized into adipocytes from carbohydrates (lipogenesis) but its regulation is still debated in human. Physiological factors such as dieting/fasting regulate all these metabolic pathways, which are also modified in pathological conditions e.g. obesity
In vivo expression of carbohydrate responsive element binding protein in lean and obese rats
No full textChREBP (Carbohydrate response element binding protein) is considered to mediate the stimulatory ChREBP (Carbohydrate response element binding protein) is considered to mediate the stimulatory effect of glucose on the expression of lipogenic genes. Its activity is stimulated by glucose. Less is known on the control of its expression. This expression could be controlled by nutritional (glucose, fatty acids) and hormonal (insulin) factors. We examined the in vivo nutritional control of ChREBP expression in liver and adipose tissue of Wistar rats. Compared respectively to the fed state and to a high carbohydrate diet, ChREBP mRNA concentrations were not modified by fasting or a high fat diet in rat liver and adipose tissue. FAS and ACC1 mRNA concentrations were on the contrary decreased as expected by fasting and high fat diets and these variations of FAS and ACC1 mRNA were positively related to those of SREBP-1c mRNA and protein, but not of ChREBP mRNA. Therefore i) ChREBP expression appears poorly responsive to modifications of nutritional condition, ii) modifications of the expression of ChREBP do not seem implicated in the physiological control of lipogenesis. To investigate the possible role of ChREBP in pathological situations we measured its mRNA concentrations in the liver and adipose tissue of obese Zucker rats. ChREBP expression was increased in the liver but not the adipose tissue of obese rats compared to their lean littermates. These results support a role of ChREBP in the development of hepatic steatosis and hypertriglyceridemia but not of obesity in this experimental model
Heavy hydrogen in the stratosphere
No full textWe report measurements of the deuterium content of molecular hydrogen (H2) obtained from a suite of air samples that were collected during a stratospheric balloon flight between 12 and 33 km at 40º N in October 2002. Strong deuterium enrichments of up to 400 permil versus Vienna Standard Mean Ocean Water (VSMOW) are observed, while the H2 mixing ratio remains virtually constant. Thus, as hydrogen is processed through the H2 reservoir in the stratosphere, deuterium is accumulated in H2 . Using box model calculations we investigated the effects of H2 sources and sinks on the stratospheric enrichments. Results show that considerable isotope enrichments in the production of H2 from CH4 must take place, i.e., deuterium is transferred preferentially to H2 during the CH4 oxidation sequence. This supports recent conclusions from tropospheric H2 isotope measurements which show that H2 produced photochemically from CH4 and non-methane hydrocarbons must be enriched in deuterium to balance the tropospheric hydrogen isotope budget. In the absence of further data on isotope fractionations in the individual reaction steps of the CH4 oxidation sequence, this effect cannot be investigated further at present. Our measurements imply that molecular hydrogen has to be taken into account when the hydrogen isotope budget in the stratosphere is investigated
Cold-acclimation-induced non-shivering thermogenesis in birds is associated with upregulation of avian UCP but not with innate uncoupling or altered ATP efficiency
No full textSUMMARY
Despite their lack of brown adipose tissue, some bird species develop regulatory non-shivering thermogenesis (NST) of skeletal muscle origin in response to cold acclimation. Mechanisms involved in avian NST are still unclear but may involve reduced energetic coupling in skeletal muscle mitochondria through the expression of an avian homologue of mammalian uncoupling proteins. The aim of this work was to investigate whether the expression of avian uncoupling protein (avUCP) would correlate with the capacity for cold-induced muscle NST. Various levels of cold acclimation were obtained by rearing 1-week-old ducklings (Cairina moschata) for 4 weeks at three different ambient temperatures (25°C, 11°C or 4°C). Muscle NST was measured by simultaneous recordings of metabolic rate and electromyographic activity (gastrocnemius muscle) at ambient temperatures (Ta) ranging from 27°C to −5°C. The expression of avUCP gene and mitochondrial bioenergetics were also determined in gastrocnemius muscle. Results showed that muscle NST capacity depends on the Ta at which ducklings were acclimated, i.e. the lower the rearing temperature, the higher the capacity for NST. This increased metabolic heat production occurred in parallel with an upregulation of avUCP, which was not associated with a change in mitochondrial membrane conductance. The intensity of mitochondrial oxidative phosphorylation also increased in proportion with the harshness of cold, while the efficiency of ATP generation was equally effective in all three acclimation temperatures. In the absence of mitochondrial uncoupling, these data indicate a clear link between avUCP expression and the capacity of ducklings to adjust their muscular aerobic activity to cold exposure.</jats:p
Time course of liver nitric oxide concentration in early septic shock by cecal ligation and puncture in rats
No full textInternational audienceAn overwhelming nitric oxide (NO) production is a crucial step in the circulatory events as well as in the cellular alterations taking place in septic shock. However, evidences of this role arise from studies assessing the NO production on an intermittent basis precluding any clear evaluation of temporal relationship between NO production and circulatory alterations. We evaluated this relationship by using a NO specific electrode allowing a continuous measurement of NO production. Septic shock was induced by a cecal ligation and puncture (CLP) in a first group of anesthetized rats. After the same CLP, a second group received a selective iNOS inhibitor (L-NIL). Control rats were sham operated or sham operated with LNILadministration. While NO concentration was measured every 2 min by a NO-sensitive electrode over 7 h following CLP, the liver microcirculation was recorded by a laser-Doppler flowmeter. CLP induced a severe septic shock with hypotension occurring at a mean time of 240 min after CLP. At the same time, an increase in liver NO concentration was observed, whereas a decrease in microvascular liver perfusion was noted. In the septic shock group, L-NIL administration induced an increase in arterial pressure whereas the liver NO concentration returned to baseline values. In addition, shock groups experienced an increase in iNOS mRNA. These data showed a close temporal relationship between the increase in liver NO concentration and the microvascular alteration taking place in the early period of septic shock induced by CLP. The iNOS isoform is involved in this NO increas
