Yeast vacuoles fragment in an asymmetrical two-phase process with distinct protein requirements.

Yeast vacuoles fragment and fuse in response to environmental conditions, such as changes in osmotic conditions or nutrient availability. Here we analyze osmotically induced vacuole fragmentation by time-lapse microscopy. Small fragmentation products originate directly from the large central vacuole. This happens by asymmetrical scission rather than by consecutive equal divisions. Fragmentation occurs in two distinct phases. Initially, vacuoles shrink and generate deep invaginations that leave behind tubular structures in their vicinity. Already this invagination requires the dynamin-like GTPase Vps1p and the vacuolar proton gradient. Invaginations are stabilized by phosphatidylinositol 3-phosphate (PI(3)P) produced by the phosphoinositide 3-kinase complex II. Subsequently, vesicles pinch off from the tips of the tubular structures in a polarized manner, directly generating fragmentation products of the final size. This phase depends on the production of phosphatidylinositol-3,5-bisphosphate and the Fab1 complex. It is accelerated by the PI(3)P- and phosphatidylinositol 3,5-bisphosphate-binding protein Atg18p. Thus vacuoles fragment in two steps with distinct protein and lipid requirements.

Assimilation process in a psychotherapy with a client presenting schizoid personality disorder

The assimilation of problematic experiences has been studied as change processes in psychotherapies of different client populations. Several theory-building case studies using the assimilation model have shown how important a meaning bridge is in such change processes. In a client presenting schizoid personality disorder the creation of meaning as an affect-evoking process may be a particularly important stage in the change process. The present case study aims to apply the assimilation model to a psychotherapy process with a highly disturbed client and focuses on the creation of a meaning bridge in the process. Moreover, the assimilation analysis focuses on the effect of an external person, i.e. the partner or the therapist, when responding to the client's unassimilated problematic experiences. Their effects on the client's assimilation processes are discussed.

Use of the dried blood spot sampling process coupled with fast gas chromatography and negative-ion chemical ionization tandem mass spectrometry: application to fluoxetine, norfluoxetine, reboxetine, and paroxetine analysis.

The objective of this work was to combine the advantages of the dried blood spot (DBS) sampling process with the highly sensitive and selective negative-ion chemical ionization tandem mass spectrometry (NICI-MS-MS) to analyze for recent antidepressants including fluoxetine, norfluoxetine, reboxetine, and paroxetine from micro whole blood samples (i.e., 10 microL). Before analysis, DBS samples were punched out, and antidepressants were simultaneously extracted and derivatized in a single step by use of pentafluoropropionic acid anhydride and 0.02% triethylamine in butyl chloride for 30 min at 60 degrees C under ultrasonication. Derivatives were then separated on a gas chromatograph coupled with a triple-quadrupole mass spectrometer operating in negative selected reaction monitoring mode for a total run time of 5 min. To establish the validity of the method, trueness, precision, and selectivity were determined on the basis of the guidelines of the "Société Française des Sciences et des Techniques Pharmaceutiques" (SFSTP). The assay was found to be linear in the concentration ranges 1 to 500 ng mL(-1) for fluoxetine and norfluoxetine and 20 to 500 ng mL(-1) for reboxetine and paroxetine. Despite the small sampling volume, the limit of detection was estimated at 20 pg mL(-1) for all the analytes. The stability of DBS was also evaluated at -20 degrees C, 4 degrees C, 25 degrees C, and 40 degrees C for up to 30 days. Furthermore, the method was successfully applied to a pharmacokinetic investigation performed on a healthy volunteer after oral administration of a single 40-mg dose of fluoxetine. Thus, this validated DBS method combines an extractive-derivative single step with a fast and sensitive GC-NICI-MS-MS technique. Using microliter blood samples, this procedure offers a patient-friendly tool in many biomedical fields such as checking treatment adherence, therapeutic drug monitoring, toxicological analyses, or pharmacokinetic studies.

Modeling of in-situ crystallization processes in the Permian mafic layered intrusion of Mont Collon (Dent Blanche nappe, western Alps)

The Mont Collon mafic complex is one of the best preserved examples of the Early Permian magmatism in the Central Alps, related to the intra-continental collapse of the Variscan belt. It mostly consists (> 95 vol.%) of ol+hy-nonnative plagioclase-wehrlites, olivine- and cpx-gabbros with cumulitic structures, crosscut by acid dikes. Pegmatitic gabbros, troctolites and anorthosites outcrop locally. A well-preserved cumulative, sequence is exposed in the Dents de Bertol area (center of intrusion). PT-calculations indicate that this layered magma chamber emplaced at mid-crustal levels at about 0.5 GPa and 1100 degrees C. The Mont Collon cumulitic rocks record little magmatic differentiation, as illustrated by the restricted range of clinopyroxene mg-number (Mg#(cpx)=83-89). Whole-rock incompatible trace-element contents (e.g. Nb, Zr, Ba) vary largely and without correlation with major-element composition. These features are characteristic of an in-situ crystallization process with variable amounts of interstitial liquid L trapped between the cumulus mineral phases. LA-ICPMS measurements show that trace-element distribution in the latter is homogeneous, pointing to subsolidus re-equilibration between crystals and interstitial melts. A quantitative modeling based on Langmuir's in-situ crystallization equation successfully duplicated the REE concentrations in cumulitic minerals of all rock facies of the intrusion. The calculated amounts of interstitial liquid L vary between 0 and 35% for degrees of differentiation F of 0 to 20%, relative to the least evolved facies of the intrusion. L values are well correlated with the modal proportions of interstitial amphibole and whole-rock incompatible trace-element concentrations (e.g. Zr, Nb) of the tested samples. However, the in-situ crystallization model reaches its limitations with rock containing high modal content of REE-bearing minerals (i.e. zircon), such as pegmatitic gabbros. Dikes of anorthositic composition, locally crosscutting the layered lithologies, evidence that the Mont Collon rocks evolved in open system with mixing of intercumulus liquids of different origins and possibly contrasting compositions. The proposed model is not able to resolve these complex open systems, but migrating liquids could be partly responsible for the observed dispersion of points in some correlation diagrams. Absence of significant differentiation with recurrent lithologies in the cumulitic pile of Dents de Bertol points to an efficiently convective magma chamber, with possible periodic replenishment, (c) 2005 Elsevier B.V. All rights reserved.

Perinatal care at the limit of viability between 22 and 26 completed weeks of gestation in Switzerland.

Perinatal care of pregnant women at high risk for preterm delivery and of preterm infants born at the limit of viability (22-26 completed weeks of gestation) requires a multidisciplinary approach by an experienced perinatal team. Limited precision in the determination of both gestational age and foetal weight, as well as biological variability may significantly affect the course of action chosen in individual cases. The decisions that must be taken with the pregnant women and on behalf of the preterm infant in this context are complex and have far-reaching consequences. When counselling pregnant women and their partners, neonatologists and obstetricians should provide them with comprehensive information in a sensitive and supportive way to build a basis of trust. The decisions are developed in a continuing dialogue between all parties involved (physicians, midwives, nursing staff and parents) with the principal aim to find solutions that are in the infant's and pregnant woman's best interest. Knowledge of current gestational age-specific mortality and morbidity rates and how they are modified by prenatally known prognostic factors (estimated foetal weight, sex, exposure or nonexposure to antenatal corticosteroids, single or multiple births) as well as the application of accepted ethical principles form the basis for responsible decision-making. Communication between all parties involved plays a central role. The members of the interdisciplinary working group suggest that the care of preterm infants with a gestational age between 22 0/7 and 23 6/7 weeks should generally be limited to palliative care. Obstetric interventions for foetal indications such as Caesarean section delivery are usually not indicated. In selected cases, for example, after 23 weeks of pregnancy have been completed and several of the above mentioned prenatally known prognostic factors are favourable or well informed parents insist on the initiation of life-sustaining therapies, active obstetric interventions for foetal indications and provisional intensive care of the neonate may be reasonable. In preterm infants with a gestational age between 24 0/7 and 24 6/7 weeks, it can be difficult to determine whether the burden of obstetric interventions and neonatal intensive care is justified given the limited chances of success of such a therapy. In such cases, the individual constellation of prenatally known factors which impact on prognosis can be helpful in the decision making process with the parents. In preterm infants with a gestational age between 25 0/7 and 25 6/7 weeks, foetal surveillance, obstetric interventions for foetal indications and neonatal intensive care measures are generally indicated. However, if several prenatally known prognostic factors are unfavourable and the parents agree, primary non-intervention and neonatal palliative care can be considered. All pregnant women with threatening preterm delivery or premature rupture of membranes at the limit of viability must be transferred to a perinatal centre with a level III neonatal intensive care unit no later than 23 0/7 weeks of gestation, unless emergency delivery is indicated. An experienced neonatology team should be involved in all deliveries that take place after 23 0/7 weeks of gestation to help to decide together with the parents if the initiation of intensive care measures appears to be appropriate or if preference should be given to palliative care (i.e., primary non-intervention). In doubtful situations, it can be reasonable to initiate intensive care and to admit the preterm infant to a neonatal intensive care unit (i.e., provisional intensive care). The infant's clinical evolution and additional discussions with the parents will help to clarify whether the life-sustaining therapies should be continued or withdrawn. Life support is continued as long as there is reasonable hope for survival and the infant's burden of intensive care is acceptable. If, on the other hand, the health care team and the parents have to recognise that in the light of a very poor prognosis the burden of the currently used therapies has become disproportionate, intensive care measures are no longer justified and other aspects of care (e.g., relief of pain and suffering) are the new priorities (i.e., redirection of care). If a decision is made to withhold or withdraw life-sustaining therapies, the health care team should focus on comfort care for the dying infant and support for the parents.

Modulation of fructose metabolism by dietary factors

High fructose consumption is associated with obesity and characteristics of metabolic syndrome. This includes insulin resistance, dyslipidemia, type II diabetes and hepatic steatosis, the hepatic component of metabolic syndrome. Short term high fructose consumption in healthy humans is considered as a study model to increase intrahepatocellular lipids (IHCL). Protein supplementation added to a short term high fructose diet exerts a protective role on hepatic fat accumulation. Fructose disposal after an acute fructose load is well established. However, fructose disposal is usually studied when a high intake of fructose is ingested. Interaction of fructose with other macronutrients on fructose disposal is not clearly established. We wanted to assess how fructose disposal is modulated with nutritional factors. For the first study, we addressed the question of how would essential amino acid (EAA) supplemented to a high fructose diet have an impact on hepatic fat accumulation? We tried to distinguish which metabolic pathways were responsible for the increase in IHCL induced by high fructose intake and how those pathways would be modulated by EAA. After 6 days of hypercaloric high fructose diet, we observed, as expected an increase in IHCL modulated by an increase in VLDL-triglycerides and an increase in VLDL-13C-palmitate production. When adding a supplementation in EAA, we observed a decrease in IHCL but we could not define which mechanism was responsible for this process. With the second study, we were interested to observe fructose disposal after a test meal that contained lipid, protein and a physiologic dose of fructose co-ingested or not with glucose. When ingested with other macronutrients, hepatic fructose disposal is similar as when ingested as pure fructose. It induced oxidation, gluconeogenesis followed by glycogen synthesis, conversion into lactate and to a minor extent by de novo lipogenesis. When co- ingested with glucose decreased fructose oxidation as well as gluconeogenesis and an increased glycogen synthesis without affecting de novo lipogenesis or lactate. We were also able to observe induction of intestinal de novo lipogenesis with both fructose and fructose co- ingested with glucose. In summary, essential amino acids supplementation blunted increase in hepatic fat content induced by a short term chronic fructose overfeeding. However, EAA failed to improve other cardiovascular risk factors. Under isocaloric condition and in the frame of an acute test meal, physiologic dose of fructose associated with other macronutrients led to the same fructose disposal as when fructose is ingested alone. When co-ingested with glucose, we observed a decrease in fructose oxidation and gluconeogenesis as well as an increased in glycogen storage without affecting other metabolic pathways. - Une consommation élevée en fructose est associée à l'obésité et aux caractéristiques du syndrome métabolique. Ces dernières incluent une résistance à l'insuline, une dyslipidémie, un diabète de type II et la stéatose hépatique, composant hépatique du syndrome métabolique. À court terme une forte consommation en fructose chez l'homme sain est considérée comme un modèle d'étude pour augmenter la teneur en graisse hépatique. Une supplémentation en protéines ajoutée à une alimentation riche en fructose de courte durée a un effet protecteur sur l'accumulation des graisses au niveau du foie. Le métabolisme du fructose après une charge de fructose aiguë est bien établi. Toutefois, ce dernier est généralement étudié quand une consommation élevée de fructose est donnée. L'interaction du fructose avec d'autres macronutriments sur le métabolisme du fructose n'est pas connue. Nous voulions évaluer la modulation du métabolisme du fructose par des facteurs nutritionnels. Pour la première étude, nous avons abordé la question de savoir quel impact aurait une supplémentation en acides aminés essentiels (AEE) associé à une alimentation riche en fructose sur l'accumulation des graisses hépatiques. Nous avons essayé de distinguer les voies métaboliques responsables de l'augmentation des graisses hépatiques induite par l'alimentation riche en fructose et comment ces voies étaient modulées par les AEE. Après 6 jours d'une alimentation hypercalorique riche en fructose, nous avons observé, comme attendu, une augmentation des graisses hépatiques modulée par une augmentation des triglycérides-VLDL et une augmentation de la production de VLDL-13C-palmitate. Lors de la supplémentation en AEE, nous avons observé une diminution des graisses hépatiques mais les mécanismes responsables de ce processus n'ont pas pu être mis en évidence. Avec la seconde étude, nous nous sommes intéressés à observer le métabolisme du fructose après un repas test contenant des lipides, des protéines et une dose physiologique de fructose co-ingéré ou non avec du glucose. Lorsque le fructose était ingéré avec les autres macronutriments, le devenir hépatique du fructose était similaire à celui induit par du fructose pur. Il a induit une oxydation, suivie d'une néoglucogenèses, une synthèse de glycogène, une conversion en lactate et dans une moindre mesure une lipogenèse de novo. Lors de la co-ngestion avec du glucose, nous avons observé une diminution de l'oxydation du fructose et de la néoglucogenèse et une augmentation de la synthèse du glycogène, sans effet sur la lipogenèse de novo ni sur le lactate. Nous avons également pu mettre en évidence que le fructose et le fructose ingéré de façon conjointe avec du glucose ont induit une lipogenèse de novo au niveau de l'intestin. En résumé, la supplémentation en acides aminés essentiels a contrecarré l'augmentation de la teneur en graisse hépatique induite par une suralimentation en fructose sur le court terme. Cependant, la supplémentation en AEE a échoué à améliorer d'autres facteurs de risque cardiovasculaires. Dans la condition isocalorique et dans le cadre d'un repas test aiguë, la dose physiologique de fructose associée à d'autres macronutriments a conduit aux mêmes aboutissants du métabolisme du fructose que lorsque le fructose est ingéré seul. Lors de la co-ngestion avec le glucose, une diminution de l'oxydation du fructose est de la néoglucogenèse est observée en parallèle à une augmentation de la synthèse de glycogène sans affecter les autres voies métaboliques.

Microcrystals As Damps And Their Role In Joint Inflammation

The concept of danger signals as important triggers of inflammation and immune activation has passed from fanciful hypothesis to a widely accepted biological process with receptors, signalling cascades and mediators. Products of cell death or cell stress are prime examples of DAMPs. They interact with receptors on the cell surface such as TLRs as well as cytoplasmic proteins such as the NLRs to modulate cellular metabolism and activation. Recently, the identification of the inflammasomes and their role in processing IL-1b and IL18 provided further insights into how DAMPs provoke inflammation. A class of substances that are potent activators of the inflammasome is microcrystals. All three microcrystals associated with joint disease in man : urate, CPP and hydroxyapatite require the NLRP3 inflammasome to process and release IL-1b from leucocytes. This mechanism most probably explain the inflammatory phase of acute crystal arthritis. However, microcrystals can also induce apoptosis, cell death as well as cell activation, depending on the cell type they are in contact with. These different cellular effects could well explain the role crystals can play in degenerative joint diseases, where inflammation is not as prominent. Our understanding of the intracellular pathways linking microcrystals to inflammation and cell activation is currently still very sketchy, and we hope that the detailed analysis of these pathways may lead to better comprehension and treatment of microcrystal induced joint diseases.Disclosures : The author has declared no conflicts of interest.

Three essays on liquidity risk

Preface In this thesis we study several questions related to transaction data measured at an individual level. The questions are addressed in three essays that will constitute this thesis. In the first essay we use tick-by-tick data to estimate non-parametrically the jump process of 37 big stocks traded on the Paris Stock Exchange, and of the CAC 40 index. We separate the total daily returns in three components (trading continuous, trading jump, and overnight), and we characterize each one of them. We estimate at the individual and index levels the contribution of each return component to the total daily variability. For the index, the contribution of jumps is smaller and it is compensated by the larger contribution of overnight returns. We test formally that individual stocks jump more frequently than the index, and that they do not respond independently to the arrive of news. Finally, we find that daily jumps are larger when their arrival rates are larger. At the contemporaneous level there is a strong negative correlation between the jump frequency and the trading activity measures. The second essay study the general properties of the trade- and volume-duration processes for two stocks traded on the Paris Stock Exchange. These two stocks correspond to a very illiquid stock and to a relatively liquid stock. We estimate a class of autoregressive gamma process with conditional distribution from the family of non-central gamma (up to a scale factor). This process was introduced by Gouriéroux and Jasiak and it is known as Autoregressive gamma process. We also evaluate the ability of the process to fit the data. For this purpose we use the Diebold, Gunther and Tay (1998) test; and the capacity of the model to reproduce the moments of the observed data, and the empirical serial correlation and the partial serial correlation functions. We establish that the model describes correctly the trade duration process of illiquid stocks, but have problems to adjust correctly the trade duration process of liquid stocks which present long-memory characteristics. When the model is adjusted to volume duration, it successfully fit the data. In the third essay we study the economic relevance of optimal liquidation strategies by calibrating a recent and realistic microstructure model with data from the Paris Stock Exchange. We distinguish the case of parameters which are constant through the day from time-varying ones. An optimization problem incorporating this realistic microstructure model is presented and solved. Our model endogenizes the number of trades required before the position is liquidated. A comparative static exercise demonstrates the realism of our model. We find that a sell decision taken in the morning will be liquidated by the early afternoon. If price impacts increase over the day, the liquidation will take place more rapidly.

Literature review on advance care planning of nursing home residents

Aim: Conduct a search and analytic review of literature regarding attributes of Advance Care Planning (ACP) and Advance Directive in order to identify the experiences and the best care strategies for older adults resident in nursing homes or long term institutions. Methodology: An extensive electronic search was undertaken in the following databases: Pubmed (via Ovid search), Cumulative Index of Nursing and Allied Health (CINAHL, via EBHOST), psychINFO and Cochrane. After analyzing and eliminating duplicates and professional's point of view (19), 144 titles were considered relevant: 28 opinion papers, 94 descriptive/qualitative studies or predictive studies, 17 experimental and five systematic reviews. Most of them were produced in North America and only 10 were in French. Results: With regard to European experiences, studies are scarce and further research could benefit from North American evidence. Contrary to Europe, nurses in North America play a major role in the process of care planning. The major findings were related to the poor efficacy of the completion of Advance Directives, even in presence of a substantial variety of implementation strategies. The evidence supports interventions that conceptualize ACP as a process, with an emphasis on the ascertainment of patients' values and beliefs and the necessity to include the family or loved ones from the beginning of the process in order to favor the expression and sharing of one's life perspectives and priorities in care. The most relevant findings were associated with the conceptualization of the ACP as a change in health behaviors which needs an involvement in different stages to overcome a variety of barriers. Conclusion: Rigorous research in ACP for the older adults in Swiss nursing homes that promote respect and dignity in this frail population is needed. How to best achieve patients and families goals should be the focus of nursing intervention and research in this domain.

TNFα controls glutamatergic gliotransmission in the hippocampal dentate gyrus.

Glutamatergic gliotransmission provides a stimulatory input to excitatory synapses in the hippocampal dentate gyrus. Here, we show that tumor necrosis factor-alpha (TNFα) critically controls this process. With constitutive TNFα present, activation of astrocyte P2Y1 receptors induces localized [Ca(2+)](i) elevations followed by glutamate release and presynaptic NMDA receptor-dependent synaptic potentiation. In preparations lacking TNFα, astrocytes respond with identical [Ca(2+)](i) elevations but fail to induce neuromodulation. We find that TNFα specifically controls the glutamate release step of gliotransmission. In cultured astrocytes lacking TNFα glutamate exocytosis is dramatically slowed down due to altered vesicle docking. Addition of low picomolar TNFα promptly reconstitutes both normal exocytosis in culture and gliotransmission in situ. Alternatively, gliotransmission can be re-established without adding TNFα, by limiting glutamate uptake, which compensates slower release. These findings demonstrate that gliotransmission and its synaptic effects are controlled not only by astrocyte [Ca(2+)](i) elevations but also by permissive/homeostatic factors like TNFα. VIDEO ABSTRACT:

Essays on the treatment of cash flows under stochastic interest rates

Abstract This paper shows how to calculate recursively the moments of the accumulated and discounted value of cash flows when the instantaneous rates of return follow a conditional ARMA process with normally distributed innovations. We investigate various moment based approaches to approximate the distribution of the accumulated value of cash flows and we assess their performance through stochastic Monte-Carlo simulations. We discuss the potential use in insurance and especially in the context of Asset-Liability Management of pension funds.

IMRT credentialing for prospective trials using institutional virtual phantoms: results of a joint European Organization for the Research and Treatment of Cancer and Radiological Physics Center project.

BACKGROUND AND PURPOSE: Intensity-modulated radiotherapy (IMRT) credentialing for a EORTC study was performed using an anthropomorphic head phantom from the Radiological Physics Center (RPC; RPCPH). Institutions were retrospectively requested to irradiate their institutional phantom (INSTPH) using the same treatment plan in the framework of a Virtual Phantom Project (VPP) for IMRT credentialing. MATERIALS AND METHODS: CT data set of the institutional phantom and measured 2D dose matrices were requested from centers and sent to a dedicated secure EORTC uploader. Data from the RPCPH and INSTPH were thereafter centrally analyzed and inter-compared by the QA team using commercially available software (RIT; ver.5.2; Colorado Springs, USA). RESULTS: Eighteen institutions participated to the VPP. The measurements of 6 (33%) institutions could not be analyzed centrally. All other centers passed both the VPP and the RPC ±7%/4 mm credentialing criteria. At the 5%/5 mm gamma criteria (90% of pixels passing), 11(92%) as compared to 12 (100%) centers pass the credentialing process with RPCPH and INSTPH (p = 0.29), respectively. The corresponding pass rate for the 3%/3 mm gamma criteria (90% of pixels passing) was 2 (17%) and 9 (75%; p = 0.01), respectively. CONCLUSIONS: IMRT dosimetry gamma evaluations in a single plane for a H&N prospective trial using the INSTPH measurements showed agreement at the gamma index criteria of ±5%/5 mm (90% of pixels passing) for a small number of VPP measurements. Using more stringent, criteria, the RPCPH and INSTPH comparison showed disagreement. More data is warranted and urgently required within the framework of prospective studies.

Development of a pediatric eosinophilic esophagitis activity index (ped-EEsAI): International experts propose dysphagia, whitish exudates on endoscopy , and intraepithelial eosinophili count as major items related to EoE activity

Background and Aims: The international EEsAI study group aims to develop, validate and evaluate the first pediatric EoE activity index (ped-EEsAI). We report on results of phase 1, which aims to generate candidate items. Methods: This study involves 3 phases: (1) item generation, (2) index derivation and testing on a first patient cohort, and (3) validation in a second cohort. In phase 1, item generation, weighting and reduction are achieved through a Delphi process with an international EoE expert group. The experts proposed and ranked candidate items on a 7-point Likert scale (0 = no, 6 = perfect relationship with EoE activity). Results: 23 international EoE experts proposed and ranked 39 items (20 clinical, 6 endoscopic, 8 histologic, 5 laboratory items). Rank order for clinical items: dysphagia related to food consistencies (median 5, range 2-6), severity of dysphagia (5, 3-6), frequency of dysphagia episodes (5, 3-6), regurgitation and vomiting (4, 2-5), response to dietary restrictions (4, 1-6); endoscopic items: whitish exudates (5, 3-6), furrowing (4, 3-6), corrugated rings (4, 2-6), linear shearing (4, 2-6), strictures (3, 2-6); histologic items: intraepithelial eosinophil count (5, 4-6), lamina propria fibrosis (3, 2-6), basal layer enlargement (3, 1-5); laboratory items: % blood eosinophils (3, 0-5). Conclusions: These items will now be reduced in further Delphi rounds, tested on a cohort of 100 pediatric EoE patients and validated in a second independent cohort, resulting in a robust, broadly accepted disease activity index for use in clinical trials and daily care.

Interactions between cancer stem cells and their niche govern metastatic colonization.

Metastatic growth in distant organs is the major cause of cancer mortality. The development of metastasis is a multistage process with several rate-limiting steps. Although dissemination of tumour cells seems to be an early and frequent event, the successful initiation of metastatic growth, a process termed 'metastatic colonization', is inefficient for many cancer types and is accomplished only by a minority of cancer cells that reach distant sites. Prevalent target sites are characteristic of many tumour entities, suggesting that inadequate support by distant tissues contributes to the inefficiency of the metastatic process. Here we show that a small population of cancer stem cells is critical for metastatic colonization, that is, the initial expansion of cancer cells at the secondary site, and that stromal niche signals are crucial to this expansion process. We find that periostin (POSTN), a component of the extracellular matrix, is expressed by fibroblasts in the normal tissue and in the stroma of the primary tumour. Infiltrating tumour cells need to induce stromal POSTN expression in the secondary target organ (in this case lung) to initiate colonization. POSTN is required to allow cancer stem cell maintenance, and blocking its function prevents metastasis. POSTN recruits Wnt ligands and thereby increases Wnt signalling in cancer stem cells. We suggest that the education of stromal cells by infiltrating tumour cells is an important step in metastatic colonization and that preventing de novo niche formation may be a novel strategy for the treatment of metastatic disease.