Low income, community poverty and risk of end stage renal disease

BACKGROUND: The risk of end stage renal disease (ESRD) is increased among individuals with low income and in low income communities. However, few studies have examined the relation of both individual and community socioeconomic status (SES) with incident ESRD. METHODS: Among 23,314 U.S. adults in the population-based Reasons for Geographic and Racial Differences in Stroke study, we assessed participant differences across geospatially-linked categories of county poverty [outlier poverty, extremely high poverty, very high poverty, high poverty, neither (reference), high affluence and outlier affluence]. Multivariable Cox proportional hazards models were used to examine associations of annual household income and geospatially-linked county poverty measures with incident ESRD, while accounting for death as a competing event using the Fine and Gray method. RESULTS: There were 158 ESRD cases during follow-up. Incident ESRD rates were 178.8 per 100,000 person-years (105 py) in high poverty outlier counties and were 76.3 /105 py in affluent outlier counties, p trend = 0.06. In unadjusted competing risk models, persons residing in high poverty outlier counties had higher incidence of ESRD (which was not statistically significant) when compared to those persons residing in counties with neither high poverty nor affluence [hazard ratio (HR) 1.54, 95% Confidence Interval (CI) 0.75-3.20]. This association was markedly attenuated following adjustment for socio-demographic factors (age, sex, race, education, and income); HR 0.96, 95% CI 0.46-2.00. However, in the same adjusted model, income was independently associated with risk of ESRD [HR 3.75, 95% CI 1.62-8.64, comparing the < $20,000 income group to the > $75,000 group]. There were no statistically significant associations of county measures of poverty with incident ESRD, and no evidence of effect modification. CONCLUSIONS: In contrast to annual family income, geospatially-linked measures of county poverty have little relation with risk of ESRD. Efforts to mitigate socioeconomic disparities in kidney disease may be best appropriated at the individual level.

Cloning and characterization of Helicobacter pylori succinyl CoA:acetoacetate CoA-transferase, a novel prokaryotic member of the CoA-transferase family.

Sequencing of a fragment of Helicobacter pylori genome led to the identification of two open reading frames showing striking homology with Coenzyme A (CoA) transferases, enzymes catalyzing the reversible transfer of CoA from one carboxylic acid to another. The genes were present in all H. pylori strains tested by polymerase chain reaction or slot blotting but not in Campylobacter jejuni. Genes for the putative A and B subunits of H. pylori CoA-transferase were introduced into the bacterial expression vector pKK223-3 and expressed in Escherichia coli JM105 cells. Amino acid sequence comparisons, combined with measurements of enzyme activities using different CoA donors and acceptors, identified the H. pylori CoA-transferase as a succinyl CoA:acetoacetate CoA-transferase. This activity was consistently observed in different H. pylori strains. Antibodies raised against either recombinant A or B subunits recognized two distinct subunits of Mr approximately 26,000 and 24, 000 that are both necessary for H. pylori CoA-transferase function. The lack of alpha-ketoglutarate dehydrogenase and of succinyl CoA synthetase activities indicates that the generation of succinyl CoA is not mediated by the tricarboxylic acid cycle in H. pylori. We postulate the existence of an alternative pathway where the CoA-transferase is essential for energy metabolism.

La pré-configuration des débats publics : apports d'une approche multimodale et longitudinale des dispositifs de catégorisation

Most linguistic and interactional studies on public and media debates focus on the way talk-in- interaction is locally managed by the moderator. For example, they analyze the extent to which the questions asked are both sequentially and categorically relevant. The present paper aims at enriching these studies by discussing the profitability of a multimodal and longitudinal approach to membership categorization practices. The approach is multimodal in the sense that it does not focus exclusively on verbal features. The approach is also longitudinal by considering the extent to which a debate is pre- configured. To this end, particular attention is paid to the posters promoting the encounters and to the way the participants are positioned in physical space.

NS4B Self-Interaction through Conserved C-Terminal Elements Is Required for the Establishment of Functional Hepatitis C Virus Replication Complexes.

Hepatitis C virus (HCV) is an important human pathogen, persistently infecting more than 170 million individuals worldwide. Studies of the HCV life cycle have become possible with the development of cell culture systems supporting the replication of viral RNA and the production of infectious virus. However, the exact functions of individual proteins, especially of nonstructural protein 4B (NS4B), remain poorly understood. NS4B triggers the formation of specific, vesicular membrane rearrangements, referred to as membranous webs, which have been reported to represent sites of HCV RNA replication. However, the mechanism of vesicle induction is not known. In this study, a panel of 15 mutants carrying substitutions in the highly conserved NS4B C-terminal domain was generated. Five mutations had only a minor effect on replication, but two of them enhanced assembly and release of infectious virus. Ten mutants were replication defective and used for selection of pseudoreversions. Most of the pseudoreversions also localized to the highly conserved NS4B C-terminal domain and were found to restore replication competence upon insertion into the corresponding primary mutant. Importantly, pseudoreversions restoring replication competence also restored heterotypic NS4B self-interaction, which was disrupted by the primary mutation. Finally, electron microscopy analyses of membrane alterations induced by NS4B mutants revealed striking morphological abnormalities, which were restored to wild-type morphology by the corresponding pseudoreversion. These findings demonstrate the important role of the C-terminal domain in NS4B self-interaction and the formation of functional HCV replication complexes.

Surrogate decision making for patients with end-stage dementia.

OBJECTIVE: We aim to explore how health surrogates of patients with dementia proceed in decision making, which considerations are decisive, and whether family surrogates and professional guardians decide differently. METHODS: We conducted an experimental vignette study using think aloud protocol analysis. Thirty-two family surrogates and professional guardians were asked to decide on two hypothetical case vignettes, concerning a feeding tube placement and a cardiac pacemaker implantation in patients with end-stage dementia. They had to verbalize their thoughts while deciding. Verbalizations were audio-recorded, transcribed, and analyzed according to content analysis. By experimentally changing variables in the vignettes, the impact of these variables on the outcome of decision making was calculated. RESULTS: Although only 25% and 31% of the relatives gave their consent to the feeding tube and pacemaker placement, respectively, 56% and 81% of the professional guardians consented to these life-sustaining measures. Relatives decided intuitively, referred to their own preferences, and focused on the patient's age, state of wellbeing, and suffering. Professional guardians showed a deliberative approach, relied on medical and legal authorities, and emphasized patient autonomy. Situational variables such as the patient's current behavior and the views of health care professionals and family members had higher impacts on decisions than the patient's prior statements or life attitudes. CONCLUSIONS: Both the process and outcome of surrogate decision making depend heavily on whether the surrogate is a relative or not. These findings have implications for the physician-surrogate relationship and legal frameworks regarding surrogacy. Copyright © 2011 John Wiley & Sons, Ltd.

Assessing the assignation of public subsidies: Do the experts choose the most efficient R and D projects?

[spa] La implementación de un programa de subvenciones públicas a proyectos empresariales de I+D comporta establecer un sistema de selección de proyectos. Esta selección se enfrenta a problemas relevantes, como son la medición del posible rendimiento de los proyectos de I+D y la optimización del proceso de selección entre proyectos con múltiples y a veces incomparables medidas de resultados. Las agencias públicas utilizan mayoritariamente el método peer review que, aunque presenta ventajas, no está exento de críticas. En cambio, las empresas privadas con el objetivo de optimizar su inversión en I+D utilizan métodos más cuantitativos, como el Data Envelopment Análisis (DEA). En este trabajo se compara la actuación de los evaluadores de una agencia pública (peer review) con una metodología alternativa de selección de proyectos como es el DEA.

Assessing the assignation of public subsidies: Do the experts choose the most efficient R and D projects?

[spa] La implementación de un programa de subvenciones públicas a proyectos empresariales de I+D comporta establecer un sistema de selección de proyectos. Esta selección se enfrenta a problemas relevantes, como son la medición del posible rendimiento de los proyectos de I+D y la optimización del proceso de selección entre proyectos con múltiples y a veces incomparables medidas de resultados. Las agencias públicas utilizan mayoritariamente el método peer review que, aunque presenta ventajas, no está exento de críticas. En cambio, las empresas privadas con el objetivo de optimizar su inversión en I+D utilizan métodos más cuantitativos, como el Data Envelopment Análisis (DEA). En este trabajo se compara la actuación de los evaluadores de una agencia pública (peer review) con una metodología alternativa de selección de proyectos como es el DEA.

Non-constant discounting in finite horizon: The free terminal time case

This paper derives the HJB (Hamilton-Jacobi-Bellman) equation for sophisticated agents in a finite horizon dynamic optimization problem with non-constant discounting in a continuous setting, by using a dynamic programming approach. A simple example is used in order to illustrate the applicability of this HJB equation, by suggesting a method for constructing the subgame perfect equilibrium solution to the problem.Conditions for the observational equivalence with an associated problem with constantdiscounting are analyzed. Special attention is paid to the case of free terminal time. Strotz¿s model (an eating cake problem of a nonrenewable resource with non-constant discounting) is revisited.

The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition.

Peripheral inflammation induces persistent central sensitization characterized by mechanical allodynia and heat hyperalgesia that are mediated by distinct mechanisms. Compared to well-demonstrated mechanisms of heat hyperalgesia, mechanisms underlying the development of mechanical allodynia and contralateral pain are incompletely known. In this study, we investigated the distinct role of spinal JNK in heat hyperalgesia, mechanical allodynia, and contralateral pain in an inflammatory pain model. Intraplantar injection of complete Freund's adjuvant (CFA) induced bilateral mechanical allodynia but unilateral heat hyperalgesia. CFA also induced a bilateral activation (phosphorylation) of JNK in the spinal cord, and the phospho JNK1 (pJNK1) levels were much higher than that of pJNK2. Notably, both pJNK and JNK1 were expressed in GFAP-positive astrocytes. Intrathecal infusion of a selective peptide inhibitor of JNK, D-JNKI-1, starting before inflammation via an osmotic pump, reduced CFA-induced mechanical allodynia in the maintenance phase but had no effect on CFA-induced heat hyperalgesia. A bolus intrathecal injection of D-JNKI-1 or SP600126, a small molecule inhibitor of JNK also reversed mechanical allodynia bilaterally. In contrast, peripheral (intraplantar) administration of D-JNKI-1 reduced the induction of CFA-induced heat hyperalgesia but did not change mechanical allodynia. Finally, CFA-induced bilateral mechanical allodynia was attenuated in mice lacking JNK1 but not JNK2. Taken together, our data suggest that spinal JNK, in particular JNK1 plays an important role in the maintenance of persistent inflammatory pain. Our findings also reveal a unique role of JNK1 and astrocyte network in regulating tactile allodynia and contralateral pain.

Assessing the assignation of public subsidies: Do the experts choose the most efficient R and D projects?

[spa] La implementación de un programa de subvenciones públicas a proyectos empresariales de I+D comporta establecer un sistema de selección de proyectos. Esta selección se enfrenta a problemas relevantes, como son la medición del posible rendimiento de los proyectos de I+D y la optimización del proceso de selección entre proyectos con múltiples y a veces incomparables medidas de resultados. Las agencias públicas utilizan mayoritariamente el método peer review que, aunque presenta ventajas, no está exento de críticas. En cambio, las empresas privadas con el objetivo de optimizar su inversión en I+D utilizan métodos más cuantitativos, como el Data Envelopment Análisis (DEA). En este trabajo se compara la actuación de los evaluadores de una agencia pública (peer review) con una metodología alternativa de selección de proyectos como es el DEA.

c-Jun N-terminal kinase binding domain-dependent phosphorylation of mitogen-activated protein kinase kinase 4 and mitogen-activated protein kinase kinase 7 and balancing cross-talk between c-Jun N-terminal kinase and extracellular signal-regulated kinase pathways in cortical neurons

The c-Jun N-terminal kinase (JNK) is a mitogen-activated protein kinase (MAPK) activated by stress-signals and involved in many different diseases. Previous results proved the powerful effect of the cell permeable peptide inhibitor d-JNKI1 (d-retro-inverso form of c-Jun N-terminal kinase-inhibitor) against neuronal death in CNS diseases, but the precise features of this neuroprotection remain unclear. We here performed cell-free and in vitro experiments for a deeper characterization of d-JNKI1 features in physiological conditions. This peptide works by preventing JNK interaction with its c-Jun N-terminal kinase-binding domain (JBD) dependent targets. We here focused on the two JNK upstream MAPKKs, mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 7 (MKK7), because they contain a JBD homology domain. We proved that d-JNKI1 prevents MKK4 and MKK7 activity in cell-free and in vitro experiments: these MAPKK could be considered not only activators but also substrates of JNK. This means that d-JNKI1 can interrupt downstream but also upstream events along the JNK cascade, highlighting a new remarkable feature of this peptide. We also showed the lack of any direct effect of the peptide on p38, MEK1, and extracellular signal-regulated kinase (ERK) in cell free, while in rat primary cortical neurons JNK inhibition activates the MEK1-ERK-Ets1/c-Fos cascade. JNK inhibition induces a compensatory effect and leads to ERK activation via MEK1, resulting in an activation of the survival pathway-(MEK1/ERK) as a consequence of the death pathway-(JNK) inhibition. This study should hold as an important step to clarify the strong neuroprotective effect of d-JNKI1.

Evaluación económica de la determinación del propéptido natriurético cerebral N-terminal (NT-proBNP) en pacientes con disnea en los servicios de urgencias españoles

Introducción: Analizar la eficiencia de añadir la determinación NT-proBNP al examen clínico convencional (ECC) para el diagnóstico de insuficiencia cardíaca (IC) en pacientes con disnea que acuden a servicios de urgencias (SU) españoles. Material y métodos: Se desarrolló un árbol de decisión para evaluar los resultados clínicos y económicos de ambas alternativas durante 60 días de seguimiento desde la visita al SU en pacientes hospitalizados y no hospitalizados. Los parámetros clínicos fueron principalmente obtenidos del estudio PRIDE y validados por médicos de SU y cardiólogos. El punto de corte de la determinación NT-proBNP fue de 900 pg/mL (sensibilidad del 90% y especificidad del 85%). En base a datos espa noles publicados, se asumió que el 65% de pacientes con disnea sufrían IC. El uso de recursos fue identificado mediante opinión de expertos y evaluado desde la perspectiva del Sistema Nacional de Salud (SNS). El análisis comparó el diagnóstico final del paciente con el diagnóstico realizado en el SU. Se realizaron diversos análisis de sensibilidad para evaluar la incertidumbre del modelo. Resultados: El diagnóstico incorporando la determinación NT-proBNP fue correcto en el 91,96% de los pacientes (59,09% verdaderos positivos y 32,87% verdaderos negativos) frente al 85,53% mediante ECC (50,79% verdaderos positivos y 34,74% verdaderos negativos). La incorporación de la determinación NT-proBNP resultó tener un coste menor (3.720 versus 5.188 ). Los análisis de sensibilidad realizados confirmaron los resultados.

Disentangling the Hettangian carbon isotope record: Implications for the aftermath of the end-Triassic mass extinction

This study provides an organic carbon stable isotope (delta(13)C(org)) record calibrated with detailed ammonite biostratigraphy, following the end-Triassic biological crisis. Precise correlation between this crucial fossil group and the delta(13)C(org) record is key to understanding feedbacks between biological and environmental events following mass extinction. The latest Triassic and Hettangian delta(13)C(org) record shows several negative and positive excursions. The end-Triassic negative shift coinciding with the mass extinction interval is followed by a positive excursion in the earliest Hettangian Psiloceras spelae beds, which marks the onset of recovery in the marine ecosystem. This positive trend is interrupted by a second negative delta(13)C(org) excursion in the P. pacificum beds related to a minor ammonite extinction event. This pattern of the delta(13)C(org) curve culminates in the uppermost Hettangian Angulata Zone major positive excursion. This indicates that both the ecosystem and the carbon cycle remained in a state of perturbation for at least 2 Ma, although the recovery of some pelagic taxa already began at the base of Jurassic. The early and late Hettangian positive delta(13)C(org) excursions have been confused in several recent papers. Here, we show that during the Hettangian there are indeed two distinct positive delta(13)C(org) excursions. Phases of anoxia and further pulses of Central Atlantic Magmatic Province volcanism during the Hettangian might have inhibited the full recovery for that interval of time. The main Liasicus-Angulata organic positive CIE (carbon isotope excursion) during the Late Hettangian might be related to gradual decreasing of pCO(2) due to protracted high organic burial, and coincides with a second phase of recovery, as indicated by a pulse of ammonoid diversification.

Role of notch signalling in mammary gland

ÁBSTRACT : Mammary gland is composed of two main epithelial cell types, myoepithelial and luminal. The mechanisms involved in determination and maintenance of them remain poorly understood. Notch signaling is known to regulate cell fate determination in other tissues like skin and nervous system. It was also shown that it can act as tumor suppressor or oncogene depending on the tissue type. The mouse models overexpressing active Notch receptors indicated that Notch signaling is oncogenic in the mammary gland. This observation was followed by some descriptive and functional studies in human breast cancer and it was reported that Notch signaling activity or expression of its components are increased in some of the breast tumor samples compared to normal tissue. However, the physiological role of the Notch signaling and its downstream mechanisms in mammary gland is poorly defined. p63, a member of p53 family, has been implicated in the cell fate determination of keratinocytes. Knockout mouse models revealed that p63 is required for the formation of the mammary anlagen in embryo and its ΔN isoform is expressed exclusively in the myoepithelial layer of the adult breast. In order to understand its function in normal breast epithelial cells, I activated Notch signaling by expression of Notch1 intracellular domain (NICD) in normal primary human breast epithelial cells (HBECs). In this context, NICD reduced growth of HBECs and led to downmodulation of extracellular matrix-receptor interaction network (ECM) components as well as ΔNp63. Expression of ΔNp63 together with NICD partially rescued Notch induced growth reduction, which was correlated with an increase in ECM components. Moreover, silencing ΔNp63 in myoepithelial HBECs reduced growth similar to Notch activation and it led to downregulation of myoepithelial and upregulation of luminal markers. Complementing this observation, forced expression of ONp63 in luminal HBECs induced myoepithelial phenotype and decreased luminal markers. In vivo, by the analysis of a Notch reporter mouse strain, I showed that Notch is activated during puberty specifically at the sites of ductal morphogenesis, terminal end buds. FAGS analysis revealed that it can be detected in two different populations based on CD24 expression (low (lo) or high (high)): at lower levels in CD24lo, which includes stem/progenitor and myoepithelial cells and higher levels in CD24hi, which contains luminal cells. In parallel with in vitro results, the CD24lo mouse mammary epithelial cells displaying Notch activity have lower levels of p63 expression. Furthermore, deletion of RBPjk, the main mediator of Notch signaling, or the overexpression of ΔNp63 inhibited luminal cell lineage in vivo. Another important point revealed by Notch reporter mouse strain is the simultaneous activation of Notch with estrogen signaling during pubertal development. The expression of FOXA1, the mediator of estrogen receptor (ER) transcriptional activity, is correlated with Notch activation in vivo that it is lower in CD24lo than in CD24hi cells. Moreover, FOXA1 is regulated by NICD in vitro supporting the presence of a link between Notch and ER signaling. Taken together, I report that Notch signaling is involved in luminal cell fate determination and its effects are partially mediated through inhibition of ONp63. Besides, ΔNp63 is required for the maintenance and sufficient for the induction of myoepithelial phenotype in HBECs in vitro and is not compatible with luminal lineage in vivo. Based on these results, I propose a model for epithelial cell hierarchy in mammary gland, whereby there are two different types of luminal progenitors, early and late, displaying different levels of Notch activity. Notch signaling contributes to the determination of luminal cell lineage in these two progenitor steps: In "Early Luminal Progenitor" stage, it inhibits myoepithelial fate by decreasing p63 expression, and in "Late Luminal Progenitor" stage, Notch signaling is involved in induction of luminal lineage by acting on ER-FOXA1 axis. It has to be investigated further whether Notch signaling might behave as an oncogene or tumor suppressor depending on which cell type in the epithelial hierarchy it is modulated and which one is more likely to occur in different human breast cancer types. RÉSUMÉ : La glande mammaire est composée de deux types principaux de cellules: les cellules luminales, qui bordent le lumen et les cellules myoépithéliales, qui se trouvent entre la lame basale et les cellules luminales. Les mécanismes intervenant dans leur différenciation et leur maintenance demeurent encore mal compris. La protéine transmembranaire Notch est connue pour déterminer le destin des cellules dans plusieurs types de tissus comme la peau ou le système nerveux. Selon le type de tissu dans lequel se trouve Notch, il agira soit comme un suppresseur de tumeur soit comme un oncogène. A l'aide de modèles de souris surexprimant les récepteurs actifs de Notch, il a été démontré que la voie de signalisation de Notch est oncogénique au niveau de la glande mammaire. Des études descriptives et fonctionnelles dans le cadre du cancer du sein ont permis de mettre en évidence une augmentation de l'activité de Notch ou de l'expression de ces composants dans certains tissus cancéreux. Toutefois, le rôle physiologique de Notch et des mécanismes qu'il active restent méconnus. P63, une protéine membre de la famille p53, est impliquée dans la différenciation des kératinocytes. Le modèle issu de l'étude des souris p63 knockout a révélé que cette protéine est requise pour la formation des primordia mammaires chez l'embryon et que son isoforme ΔNp63 est exclusivement exprimée dans la couche myoépithéliale de la glande mammaire adulte. Dans le but de comprendre les fonctions physiologiques de Notch, je l'ai activé en exprimant le domaine intracellulaire de Notch 1 (NICD) dans des cellules épithéliales primaires de glande mammaire humaine (HBECs). Le NICD a alors réduit la croissance des HBECs et conduit à la régulation négative non seulement de p63 mais également des composants du réseau d'interaction des récepteurs de la matrice extracellulaire (ECM). En exprimant conjointement ΔNp63 et NICD, il est apparu que la réduction de croissance induite par Notch était partiellement compensée, et qu'il y avait également une augmentation des composants ECM. De plus, lorsque ΔNp63 a été inactivé dans les cellules HBECs myoépithéliales, une réduction de croissance cellulaire identique à celle provoquée par l'activation de Notch a pu être mise en évidence, de même qu'une régulation négative des marqueurs myoépithéliaux ainsi qu'une augmentation des marqueurs luminaux. Afin de compléter ces informations, l'expression de ΔNp63 a été forcée dans les HBECs luminales, ce qui a induit un phénotype myoépithélial et une diminution des marqueurs lumineux. In vivo, par l'analyse de souris ayant un gène rapporteur de l'activité de Notch, j'ai démontré que Notch est activé pendant la puberté au niveau des sites de la morphogenèse canalaire, à savoir les bourgeons terminaux. Les analyses par FACS (Fluorescence-activated cell sorting) basées sur l'expression de l'antigène CD24 ont révélé qu'il peut tre détecté dans deux populations différentes : une population qui l'exprime faiblement, qui regroupe les cellules souches/progéniteurs et les cellules myoépithéliales, et une population qui l'exprime fortement qui est composé des cellules luminales. Parallèlement aux résultats in vitro, j'ai mis en évidence un faible niveau d'expression de p63 dans les cellules épithéliales de la glande mammaire de souris, exprimant faiblement l'antigène CD24 et présentant une activité de Notch. De plus, la délétion de RBPjr~, médiateur principal de la signalisation de Notch, ainsi que la surexpression de ΔNp63 in vivo ont inhibé la lignée des cellules luminales. Un autre point important révélé par les souris rapporteur de l'activité de Notch a été l'activation simultanée de Notch et de la signalisation de l'oestrogène pendant le développement pubertaire. L'expression de FOXA1, médiateur de l'activité transcriptionnelle des récepteurs aux oestrogènes (ER), est en corrélation avec l'activation de Notch in vivo, plus basse dans les cellules avec une faible expression de l'antigène CD24 que dans celles avec une forte expression. De plus, FOXA1 est régulé par NICD in vitro confirmant la présence d'un lien entre Notch et la signalisation des ER. En résumé, la signalisation de Notch est impliquée dans la détermination du destin cellulaire des cellules luminales et ses effets sont partiellement modifiés par l'inhibition de ΔNp63. ΔNp63 est requis pour la maintenance et est suffisant pour l'induction du phénotype myoépithéliale dans les HBECs in vitro et ne peut donc pas se trouver dans les cellules luminales in vivo. Basé sur ces résultats, je propose un modèle de hiérarchisation des cellules épithéliales de la glande mammaire, dans lequel sont présents deux types de progéniteurs des cellules luminales exprimant des niveaux différents d'activité de Notch, les progéniteurs lumineux précoces et tardifs. La signalisation de Notch contribue à la différenciation de la lignée cellulaire luminale au niveau de ces deux progéniteurs : dans la forme précoce, il inhibe la différenciation des cellules myoépithéliales en réduisant l'expression de p63 et dans la forme tardive, Notch est impliqué dans l'induction de la lignée luminale en agissant sur l'axe ER-FOXA1. Il serait nécessaire d'investiguer plus loin si le fait que Notch agisse comme oncogène ou suppresseur de tumeur dépend du stade de différenciation de la cellule dans laquelle il est modulé et laquelle de ces deux fonctions il est le plus probable de rencontrer dans les différents types de cancer du sein.