Metabolomics for mitochondrial and cancer studies

AbstractMetabolomics, a high-throughput global metabolite analysis, is a burgeoning field, and in recent times has shown substantial evidence to support its emerging role in cancer diagnosis, cancer recurrence, and prognosis, as well as its impact in identifying novel cancer biomarkers and developing cancer therapeutics. Newly evolving advances in disease diagnostics and therapy will further facilitate future growth in the field of metabolomics, especially in cancer, where there is a dire need for sensitive and more affordable diagnostic tools and an urgency to develop effective therapies and identify reliable biomarkers to predict accurately the response to a therapy. Here, we review the application of metabolomics in cancer and mitochondrial studies and its role in enabling the understanding of altered metabolism and malignant transformation during cancer growth and metastasis. The recent developments in the area of metabolic flux analysis may help to close the gap between clinical metabolomics research and the development of cancer metabolome. In the era of personalized medicine with more and more patient specific targeted therapies being used, we need reliable, dynamic, faster, and yet sensitive biomarkers both to track the disease and to develop and evolve therapies during the course of treatment. Recent advances in metabolomics along with the novel strategies to analyze, understand, and construct the metabolic pathways opens this window of opportunity in a very cost-effective manner. This article is part of a Special Issue entitled: Bioenergetics of Cancer

Editorial: Altered expression of proteins in cancer: function and potential therapeutic targets, volume II

[no abstract available

Muscle histopathology in nebulin-related nemaline myopathy : ultrastrastructural findings correlated to disease severity and genotype

Peer reviewe

Enforcement of developmental lineage specificity by transcription factor Oct1

Embryonic stem cells co-express Oct4 and Oct1, a related protein with similar DNA-binding specificity. To study the role of Oct1 in ESC pluripotency and transcriptional control, we constructed germline and inducible-conditional Oct1-deficient ESC lines. ESCs lacking Oct1 show normal appearance, self-renewal and growth but manifest defects upon differentiation. They fail to form beating cardiomyocytes, generate neurons poorly, form small, poorly differentiated teratomas, and cannot generate chimeric mice. Upon RA-mediated differentiation, Oct1-deficient cells induce lineage-appropriate developmentally poised genes poorly while lineage-inappropriate genes, including extra-embryonic genes, are aberrantly expressed. In ESCs, Oct1 co-occupies a specific set of targets with Oct4, but does not occupy differentially expressed developmental targets. Instead, Oct1 occupies these targets as cells differentiate and Oct4 declines. These results identify a dynamic interplay between Oct1 and Oct4, in particular during the critical window immediately after loss of pluripotency when cells make the earliest developmental fate decisions

C. elegans ATAD-3 Is Essential for Mitochondrial Activity and Development

Contains fulltext : 80701.pdf (publisher's version ) (Open Access)BACKGROUND: Mammalian ATAD3 is a mitochondrial protein, which is thought to play an important role in nucleoid organization. However, its exact function is still unresolved. RESULTS: Here, we characterize the Caenorhabditis elegans (C. elegans) ATAD3 homologue (ATAD-3) and investigate its importance for mitochondrial function and development. We show that ATAD-3 is highly conserved among different species and RNA mediated interference against atad-3 causes severe defects, characterized by early larval arrest, gonadal dysfunction and embryonic lethality. Investigation of mitochondrial physiology revealed a disturbance in organellar structure while biogenesis and function, as indicated by complex I and citrate synthase activities, appeared to be unaltered according to the developmental stage. Nevertheless, we observed very low complex I and citrate synthase activities in L1 larvae populations in comparison to higher larval and adult stages. Our findings indicate that atad-3(RNAi) animals arrest at developmental stages with low mitochondrial activity. In addition, a reduced intestinal fat storage and low lysosomal content after depletion of ATAD-3 suggests a central role of this protein for metabolic activity. CONCLUSIONS: In summary, our data clearly indicate that ATAD-3 is essential for C. elegans development in vivo. Moreover, our results suggest that the protein is important for the upregulation of mitochondrial activity during the transition to higher larval stages

<em>Enterococcus faecalis</em> Infection Causes Inflammation, Intracellular Oxphos-Independent ROS Production, and DNA Damage in Human Gastric Cancer Cells

Background: Achlorhydria caused by e.g. atrophic gastritis allows for bacterial overgrowth, which induces chronic inflammation and damage to the mucosal cells of infected individuals driving gastric malignancies and cancer. Enterococcus faecalis (E. faecalis) can colonize achlohydric stomachs and we therefore wanted to study the impact of E. faecalis infection on inflammatory response, reactive oxygen species (ROS) formation, mitochondrial respiration, and mitochondrial genetic stability in gastric mucosal cells. Methods: To separate the changes induced by bacteria from those of the inflammatory cells we established an in vitro E. faecalis infection model system using the gastric carcinoma cell line MKN74. Total ROS and superoxide was measured by fluorescence microscopy. Cellular oxygen consumption was characterized non-invasively using XF24 microplate based respirometry. Gene expression was examined by microarray, and response pathways were identified by Gene Set Analysis (GSA). Selected gene transcripts were verified by quantitative real-time polymerase chain reaction (qRT-PCR). Mitochondrial mutations were determined by sequencing. Results: Infection of MKN74 cells with E. faecalis induced intracellular ROS production through a pathway independent of oxidative phosphorylation (oxphos). Furthermore, E. faecalis infection induced mitochondrial DNA instability. Following infection, genes coding for inflammatory response proteins were transcriptionally up-regulated while DNA damage repair and cell cycle control genes were down-regulated. Cell growth slowed down when infected with viable E. faecalis and responded in a dose dependent manner to E. faecalis lysate. Conclusions: Infection by E. faecalis induced an oxphos-independent intracellular ROS response and damaged the mitochondrial genome in gastric cell culture. Finally the bacteria induced an NF-kappa B inflammatory response as well as impaired DNA damage response and cell cycle control gene expression

Feeding mice with diets containing mercury-contaminated fish flesh from French Guiana: a model for the mercurial intoxication of the Wayana Amerindians

International audienc

Leveraging Natural History Data in One- and Two-Arm Hierarchical Bayesian Studies of Rare Disease Progression

peer reviewedThe small sample sizes inherent in rare and pediatric disease settings offer significant challenges for clinical trial design. In such settings, Bayesian adaptive trial methods can often pay dividends, allowing the sensible incorporation of auxiliary data and other relevant information to bolster that collected by the trial itself. Previous work has also included the use of one-arm trials augmented by the participants’ own natural history data, from which the future course of the disease in the absence of intervention can be predicted. Patient response can then be defined by the degree to which post-intervention observations are inconsistent with the predicted “natural” trajectory. While such trials offer obvious advantages in efficiency and ethical hazard (since they expose no new patients to a placebo, anathema to patients or their parents and caregivers), they can offer no protection against bias arising from the presence of any “placebo effect,” the tendency of patients to improve merely by being in the trial. In this paper, we investigate the impact of both static and transient placebo effects on one-arm responder studies of this type, as well as two-arm versions that incorporate a small concurrent placebo group but still borrow strength from the natural history data. We also propose more traditional Bayesian changepoint models that specify a parametric functional form for the patient’s post-intervention trajectory, which in turn allow quantification of the treatment benefit in terms of the model parameters, rather than semi-parametrically in terms of a response relative to some “null” model. We compare the operating characteristics of our designs in the context of an ongoing investigation of centronuclear myopathies (CNMs), a group of congenital neuromuscular diseases whose most common and severe form is X-linked, affecting approximately 1 in 50,000 newborn boys. Our results indicate our two-arm responder and changepoint methods can offer protection against placebo effects, improving power while protecting the trial’s Type I error rate. However, further research into innovative trial designs as well as ongoing dialog with regulatory authorities remain critically important in rare disease research

Academic "success" and Information competencies at University : issues and influences

La présente étude se propose d'approcher la notion de "réussite" à l'université dans une perspective critique et interdisciplinaire. Pour servir cette ambition, nous avons mobilisé un appareillage conceptuel issu de deux disciplines : les Sciences de l'Information et de la Communication (SIC) et les Sciences de l'Éducation (SED). Les objectifs de notre démarche sont triples, et visent à : ÉVALUER l'influence des pratiques informationnelles des étudiants sur la validation de la première année universitaire ; MESURER l’appropriation de la formation documentaire dispensée par les bibliothécaires auprès des étudiants formés (L1) ; QUESTIONNER, d’une part la relation entre bibliothécaires et enseignants, et d’autre part leurs actions respectives pour l’acquisition des compétences informationnelles chez les étudiants. Enfin, nous nous intéresserons à la représentation de la notion de "réussite" à l'université en interrogeant les trois groupes d'acteurs étudiés (étudiants, enseignants et bibliothécaires).This study aim to approach the notion of academic "success" to the university in a critical and interdisciplinary perspective. To serve this ambition, we mobilised a conceptual apparatus coming from two french's disciplines: Sciences of Information and of Communication (SIC) and Sciences of Education (SED). The purpose of this strcuture are triple : ASSESS the influence of informational practices of students on the validation of the first academic year; MEASURE the reception of the library-course dispense to the formed students ; QUESTION, on one hand relation between librarians and academics, and on the other hand their respective actions for the acquirement of information competencies by the students. Finally, we will be interested in the representation of academic "success" to the university by questioning the studied actors (students, academics and librarians)

Utilisation et appropriation de l\u27outil informatique

Thierry Bellance s\u27intéresse à l\u27usage de l\u27outil informatique par les étudiants de la bibliothèque du campus universitaire de Schoelcher. Une étude menée au rez-de chaussée de la bibliothèque. Il effectue ensuite une contextualisation du sujet avant de mettre l\u27accent sur la problématique autour de laquelle il s\u27articule. Une problématique prenant corps autour de trois axes : L\u27espace informatique comme scission vis-àvis de l\u27environnement qui l\u27abritel\u27outil informatique comme instrument orienté vers les divertissementsune appropriation tributaire du niveau d\u27étude