Construction of the vertebrate nervous system begins with the decision of a group of ectoderm cells to take on a neural fate. Studies using Xenopus ectodermal explants, or with mouse ectoderm cells or embryonic stem (ES) cells, demonstrated that this process of neural determination occurred by default – the ectoderm cells became neural after the removal of inhibitory signals. Whether ectoderm or ES cells directly differentiate into bona fide neural stem cells is not clear. One model suggests that there is an intermediate stage where “primitive” neural stem cells (pNSC) emerge harbouring properties of both ES cells and neural stem cells. The goal of my research was to address this question by evaluating the role of growth factor signaling pathways and their impact on the function of the zinc-finger homeobox transcription factor, Zfhx1b, during mouse neural stem cell development. I tested whether FGF and Wnt signaling pathways could regulate Zfhx1b expression to control early neural stem cell development. Inhibition of FGF signaling at a time when the ectoderm is acquiring a neural fate resulted in the accumulation of too many pNSCs, at the expense of the definitive neural stem cells. Interestingly, over-expression of Zfhx1b was sufficient to rescue the transition from a pNSC to definitive NSC. These data suggested that definitive NSC fate specification in the mouse ectoderm was facilitated by FGF activation of Zfhx1b, whereas canonical Wnt signaling repressed Zfhx1b expression. Next I sought to determine whether Zfhx1b was similarly required during neural lineage development in ES cells. FGF and Wnt signaling modulated expression of Zfhx1b in ES cell cultures in manner resembling my observations from similar experiments using mouse ectoderm. Knockdown of Zfhx1b in ES cells using siRNA did not affect the initial transition of ES cells to pNSC fate, but did limit the ability of these neural cells to further develop into definitive NSCs. Thus, my findings using ES cells were congruent with evidence from mouse embryos and supported a model whereby intercellular signaling induced Zfhx1b, required for the development of definitive NSCs, subsequent to an initial neural specification event that was independent of this pathway.

Construction of the vertebrate nervous system begins with the decision of a group of ectoderm cells to take on a neural fate. Studies using Xenopus ectodermal explants, or with mouse ectoderm cells or embryonic stem (ES) cells, demonstrated that this process of neural determination occurred by default – the ectoderm cells became neural after the removal of inhibitory signals. Whether ectoderm or ES cells directly differentiate into bona fide neural stem cells is not clear. One model suggests that there is an intermediate stage where “primitive” neural stem cells (pNSC) emerge harbouring properties of both ES cells and neural stem cells. The goal of my research was to address this question by evaluating the role of growth factor signaling pathways and their impact on the function of the zinc-finger homeobox transcription factor, Zfhx1b, during mouse neural stem cell development. I tested whether FGF and Wnt signaling pathways could regulate Zfhx1b expression to control early neural stem cell development. Inhibition of FGF signaling at a time when the ectoderm is acquiring a neural fate resulted in the accumulation of too many pNSCs, at the expense of the definitive neural stem cells. Interestingly, over-expression of Zfhx1b was sufficient to rescue the transition from a pNSC to definitive NSC. These data suggested that definitive NSC fate specification in the mouse ectoderm was facilitated by FGF activation of Zfhx1b, whereas canonical Wnt signaling repressed Zfhx1b expression. Next I sought to determine whether Zfhx1b was similarly required during neural lineage development in ES cells. FGF and Wnt signaling modulated expression of Zfhx1b in ES cell cultures in manner resembling my observations from similar experiments using mouse ectoderm. Knockdown of Zfhx1b in ES cells using siRNA did not affect the initial transition of ES cells to pNSC fate, but did limit the ability of these neural cells to further develop into definitive NSCs. Thus, my findings using ES cells were congruent with evidence from mouse embryos and supported a model whereby intercellular signaling induced Zfhx1b, required for the development of definitive NSCs, subsequent to an initial neural specification event that was independent of this pathway.

El cicle cellular és el conjunt d'esdeveniments ordenats que permeten a la cèllula donar lloc a dues cèllules filles genèticament idèntiques. Diversos senyals externs i interns regulen aquest procés per a que la cèllula proliferi només en les condicions apropiades. Un punt de control important pel que fa a la coordinació de la proliferació amb el creixement cellular es troba en la fase G1 (punt de restricció), on la cèllula comprova que ha adquirit la massa i la maquinària necessària per la replicació del DNA. Les ciclines D són molècules que juguen un paper clau en la regulació de la fase G1. Les cèllules de mamífer contenen gens que codifiquen per 3 ciclines de tipus D altament homòlogues (D1, D2, D3), que s'expressen de manera específica de teixit i s'associen a Cdk4 o Cdk6 per formar una proteïna quinasa activa. D'aquestes tres ciclines la ciclina D1 és la més estudiada ja que es troba freqüentment superexpressada en molts càncers humans. L'expressió de ciclina D1 i la seva unió a Cdk4 representa un dels esdeveniments més importants, regulats per senyals mitogènics, necessaris per la progressió del cicle cellular a través del punt de restricció. Les cèllules inhibeixen l'entrada en cicle en la fase G1 principalment per dos mecanismes diferents: la disminució de l'expressió de ciclines D i l'augment de les proteïnes KIP que inhibeixen l'activitat residual del complex Cdk4/6ciclina D. Tot i discrepàncies d'origen metodològic, diferents estudis han observat l'acumulació de la ciclina D1 en el citoplasma de cèllules quiescents o diferenciades, suggerint l'existència d'altres mecanismes que podrien regular l'activitat dels complexes Cdk4ciclina D1 a nivell de la seva distribució nucleocitoplasmàtica. D'altra banda, en el nostre laboratori s'havia desvetllat un mecanisme de retenció citoplasmàtica de Cln3, l'homòleg funcional de ciclina D1 en llevat de gemmació, que regula l'entrada en cicle i juga un paper molt important en la coordinació entre creixement i proliferació. Aquests antecedents ens van conduir a plantejar com a hipòtesi de treball d'aquesta tesi doctoral l'existència d'un mecanisme de control de la localització de la ciclina D1 entre el nucli i el citoplasma, que podria tenir un paper especialment rellevant en situacions d'aturada de la proliferació cellular. En aquest treball hem demostrat que la ciclina D1 es localitza en el citoplasma de fibroblasts embrionaris de ratolí quiescents, i que això succeeix per un mecanisme independent de l'export mediat per Crm1. De la cerca d'interactors de ciclina D1 per dihíbrid i copurificació hem identificat la transloquina, una proteïna que havia estat descrita com a important en el procés d'import nuclear de FGF2. En observar durant el nostre treball que FGF2 és un potent estimulador de l'acumulació nuclear de ciclina D1, varem decidir analitzar en detall les seves implicacions funcionals. La superexpressió de transloquina inhibeix l'acumulació nuclear de ciclina D1 en cèllules proliferant. En canvi, la inhibició de l'expressió de transloquina causa l'efecte oposat, és a dir, indueix l'acumulació nuclear de ciclina D1 i la fosforilació de RB per Cdk4 en cèllules sotmeses a condicions de quiescència. En resum, en aquest treball de tesi doctoral hem desvetllat i descrit un mecanisme de retenció citoplasmàtica de la ciclina D1 en fibroblasts embrionaris de ratolí, on la transloquina hi juga un paper important per a mantenir l'estat de quiescència cellular. La transloquina i Cdk4 s'uneixen i competeixen pel mateix domini de ciclina D1 i, donat que cal la formació prèvia del complex Cdk4ciclina D1 per al seu import nuclear, aquest fet permet establir una base molecular senzilla pel propi mecanisme de retenció citoplasmàtica. / El ciclo celular es el conjunto de sucesos ordenados que permiten a la célula originar dos células hijas genéticamente idénticas. Distintas señales internas y externas regulan este proceso para que las células proliferen sólo en las condiciones más apropiadas. Uno de los puntos de control importantes, donde se coordina la proliferación con el crecimiento celular se encuentra en la fase G1 (punto de restricción). En este punto la célula comprueba que ha adquirido la masa y la maquinaria necesaria para la replicación del DNA. Las ciclinas D son moléculas que tienen un papel clave en la regulación de la fase G1. Las células de mamífero contienen genes que codifican para tres ciclina tipo D altamente homólogas (D1, D2, D3), que se expresan de forma específica de tejido y se asocian a Cdk4 o Cdk6 para formar una proteína quinasa activa. Entre las tres ciclinas, la ciclina D1 es la más estudiada, ya que se encuentra sobrexpresada en muchos cánceres humanos. La expresión de ciclina D1 y su unión con Cdk4 representa uno de los acontecimientos más importantes, regulados por señales mitogénicas, necesarios para la progresión del ciclo celular a través del punto de restricción. Las células inhiben la entrada en ciclo en la fase G1 principalmente por dos mecanismos distintos: la disminución de la expresión de ciclinas D y el aumento de las proteínas KIP que inhiben la actividad residual del complejo Cdk4/6ciclina D. A pesar de alguna inconsistencia de origen metodológico, distintos estudios han observado la acumulación de la ciclina D1 en el citoplasma de células quiescentes o diferenciadas, sugiriendo la existencia de otros mecanismos que podrían regular la actividad de los complejos Cdk4ciclina D1 a nivel de su localización núcleocitoplasmática. Por otro lado, en nuestro laboratorio se había descrito un mecanismo de retención citoplasmática de Cln3, el homólogo funcional de ciclina D1 en levadura de gemación, que regula la entrada en ciclo y juega un papel muy importante en la coordinación entre crecimiento y proliferación. Estos antecedentes nos llevaron a plantear, como hipótesis de trabajo de esta tesis doctoral, la existencia de un mecanismo de control de localización de ciclina D1 entre el núcleo y el citoplasma, que podría tener un papel relevante en situaciones de detención de la proliferación celular. En este trabajo hemos demostrado que la ciclina D1 se localiza en el citoplasma de fibroblastos embrionarios de ratón quiescentes, y que además sucede por un mecanismo independiente del exporte por Crm1. De la búsqueda de interactores de ciclina D1 por dihíbrido y copurificación hemos identificado la transloquina, una proteína cuya implicación ya se había descrito en el proceso de importe nuclear de FGF2. Además, durante nuestro trabajo observamos que FGF2 es un potente estimulador de la acumulación nuclear de ciclina D1. La sobreexpresión de transloquina inhibe la acumulación nuclear de ciclina D1 en células proliferando. En cambio, la inhibición de la expresión de transloquina causa un efecto opuesto, induce la acumulación nuclear de ciclina D1 y la fosforilación de RB por Cdk4 en células sometidas a condiciones de quiescencia. En resumen, en este trabajo de tesis doctoral hemos identificado un mecanismo de retención citoplasmática de la ciclina D1 en fibroblastos embrionarios de ratón, donde la transloquina juega un papel importante para mantener el estado de quiescencia celular. La transloquina y Cdk4 se unen y compiten por el mismo dominio de ciclina D1, y puesto que la formación del complejo Cdk4ciclina D1 es un requisito previo para el importe nuclear, este hecho permite establecer una base molecular sencilla para el propio mecanismo de retención citoplasmática. / The cell cycle is the series of events by which the cell duplicates its contents and divides into two daughter cells identical genetically. This process is regulated by different external and internal signals allowing the cell to proliferate under suitable conditions. Higher eukaryotes control proliferation and growth in late G1 at the restriction point, where they ensure that enough appropriate nutrients and extracellular mitogens are present to enter a new cell cycle and initiate DNA replication. Dtype cyclins are a key target in the regulation of G1 phase. Mammalian cells contain genes encoding three highly homologous Dtype cyclins (D1, D2, D3) that associate in a tissue specific manner with either Cdk4 or Cdk6 to form an active protein kinase. Among them, cyclin D1 is the most studied because its overexpression is frequently present in human tumors. Mitogendriven upregulation of cyclin D1 levels and assembly into active complexes with Cdk4/6 are key events for exit from quiescence and G1 progression in mammalian cells. Quiescent cells are thought to inhibit cell cycle entry mainly by two different mechanisms: downregulation of Dtype cyclin expression and upregulation of KIP proteins to inhibit residual Cdk4/6cyclin D activity. However, cytoplasmic accumulation of cyclin D1 in quiescent or differentiated cells has been observed in different instances, suggesting the existence of other mechanisms to control the nucleocytoplasmic distribution of cyclin D1 as a function of growth signals. On the other hand, we have previously characterized a cytoplasmic retention device that sequesters Cln3, the functional homologue of Dtype cyclins in budding yeast, to regulate G1 progression and cell size homeostasis. Thus, as the initial hypothesis of this doctoral thesis, we asked whether mammalian cells control the nucleocytoplasmic distribution of cyclin D1 as a function of growth signals. In this doctoral thesis we show that cyclin D1 is localized in the cytoplasm in quiescent mouse fibroblasts by a mechanism that does not involve the Crm1 exportin. We have screened for cyclin D1 interactors by twohybrid and coimmunopurification strategies and we have identified translokin, a protein that interacts with FGF2 and facilitates its nuclear import. We have also observed that FGF2 treatment of quiescent cells causes nuclear accumulation of cyclin D1. Overexpression of translokin prevents proper cyclin D1 accumulation in the nucleus of proliferating cells. On the other hand, downregulation of translokin levels results in nuclear accumulation of cyclin D1 and causes Cdk4dependent phosphorylation of RB in quiescent cells. In summary, in the present doctoral thesis we show that cyclin D1 is also subject to an analogous but different cytoplasmic retention mechanism in quiescent mouse fibroblasts. We have identified translokin as an interactor of cyclin D1 that plays an essential role to inhibit its accumulation in the nucleus under quiescence conditions. As translokin interacts with cyclin D1 domains also needed for Cdk4 binding and subsequent nuclear import, we propose that translokin is an essential component of a cytoplasmic retention mechanism of cyclin D1 that prevents cell cycle entry during cellular quiescence.

The regenerative capacity of mature mammalian CNS neurons after axonal injury is severely limited by a variety of mechanisms. Retrograde repression is the continuous inhibition of the expression of growth phenotypes by tonic signals produced by target tissues and transmitted to the neuron cell body via retrograde axonal transport. Loss of target contact through axonal injury is thought to interrupt this retrograde signal and allow the up-regulation of growth-associated proteins. Most CNS neurons, however, possess many widespread axon collaterals, such that retrograde repression is maintained by intact sustaining collaterals even if some axons are injured.<p>In this project we investigated whether or not retrograde repression plays a role in limiting the expression of GAP-43 in transcallosal neurons. Because TCNs possess local axon collaterals to nearby cortex and project distal axons to homologous areas of contralateral cortex, we hypothesized that the simultaneous interruption of retrograde repressive signals from both ipsilateral and contralateral cortex would result in an up-regulation of GAP-43 expression in at least some TCNs.<p>We found that a bilateral infusion of a function blocking antibody to FGF-2 into the parietal cortex of rats using implanted osmotic mini-pumps resulted in a significant increase in the level of expression of GAP-43 mRNA in TCNs identified by retrograde fluorescent labeling. In contrast, neither ipsilateral or contralateral antibody infusions alone increased GAP-43 expression significantly compared to controls. The level of expression of GAP-43 in TCNs did not significantly increase after stereotactic callosotomy alone, but callosotomized animals treated with an ipsilateral infusion of anti-FGF-2 had levels of increased GAP-43 expression equivalent to those seen in animals that had received bilateral antibody infusions.<p>We conclude that FGF-2 provides a retrograde repressive signal for at least some mature mammalian TCNs, and that the expression of growth-associated proteins can be up-regulated in CNS neurons by simultaneously blocking retrograde repressive signals from all existing axon collaterals. The ability to alter the gene expression of mature CNS neurons in both normal and injured states through the targeted infusion of a pharmacological agent may have potential clinical implications in the future.

<p>Chemotherapy remains the only available treatment for triple-negative (TN) breast cancer. Although some TN breast cancers respond initially to neoadjuvant chemotherapy, the majority of patients die within three years of treatment due to recurrent tumor growth. Developing ex vivo models for TN breast cancer recurrence and defining responsible molecules will be crucial to developing effective combination therapies for TN breast cancer patients. We have developed an in vitro model of TN breast cancer dormancy/recurrence. Short-term exposure of tumor cells to chemotherapy at clinically relevant doses enriches for a dormant tumor cell population. Several days after removing chemotherapy, dormant tumor cells regain proliferative ability and establish colonies, resembling tumor recurrence. Tumor cells from "recurrent" colonies exhibit increased chemotherapy resistance, resembling therapy resistance of recurrent tumors in patients. Furthermore, we identify a novel signaling axis [nuclear bFGF/DNA-dependent protein kinase (DNA-PK)] supported by chemotherapy-enriched dormant TN breast cancer cells. This signaling axis drives accelerated DNA repair in chemo-residual TN breast cancer cells. Targeting this axis with either with a bFGF shRNA or DNA-PK small molecule inhibitor blocks recurrent colony formation. Using the Oncomine gene expression database, we found that bFGF expression in tumor samples from TN breast cancer patients predicts five year tumor recurrence following neoadjuvant chemotherapy treatment. Finally, we demonstrate that recurrent tumor cells exhibit increased invasiveness, reflecting the aggressive behavior of recurrent tumors in patients. Collectively, these studies identify a novel signaling axis in TN breast cancer that likely contributes to tumor recurrence and provide molecular targets for developing future therapeutics against TN breast cancer.</p> / Dissertation

Durant ma thèse, j'ai participé à une étude fonctionnelle qui a démontré que p120-RasGAP, une protéine appartenant à la famille GAP (GTPase-activating protein), est le médiateur cytoplasmique de l'éphrine lors de l'atténuation d'ERK1/2. Pour confirmer cela, j'ai réalisé une expérience de co-immunoprécipitation et j'ai démontré que p120-RasGAP s'associe au récepteur de l'éphrine, Eph3, quand celui-ci est activé par un ligand éphrine. Ce résultat indique fortement que les signaux FGF et éphrine convergent au niveau de Ras et qu'ils contrôlent de manière antagoniste son activité. Dès lors, j'ai analysé les autres événements de spécification cellulaire impliquant l'antagonisme FGF/éphrine. Chez l'embryon d'ascidie, le signal FGF est décrit comme inducteur du destin neural dans les cellules ectodermiques qui, en absence du signal FGF, adoptent le destin épidermique. L'induction neurale des ascidies a lieu au stade 32 cellules et se traduit par la spécification de quatre précurseurs neuraux (ERK+) parmi les 16 cellules ectodermiques. J'ai démontré que le signal éphrine/Eph/RasGAP antagonise le signal FGF pour générer une activation d'ERK1/2 de type tout ou rien parmi les cellules ectodermiques. Enfin, en collaboration avec Philip Abitua, doctorant dans le laboratoire du Dr. Mike Levine (UC Berkeley), nous démontrons que l'antagonisme entre les signaux éphrine et FGF est impliqué dans la régionalisation antéro-postérieure de la plaque neurale

L'apparition de nouvelles structures telles que la crête neurale, les placodes et le mésoderme crânien a été essentielle pour l'émergence de la tête des vertébrées. Fait intéressant, le mésoderme de la tête des vertébrés n'est pas segmenté alors qu'il est supposé que le mésoderme de l'ancêtre de tous les chordés était totalement segmenté. De même le corps du le céphalochordé amphioxus est entièrement segmenté. Des travaux menés par l'équipe ont montré le rôle central du signal FGF dans la formation des somites les plus antérieures chez l'amphioxus. Afin de mieux comprendre le rôle de ce signal pour la formation de ces somites, nous avons réalisé une étude transcriptomique comparative par RNA-seq. Cette analyse a mis en évidence plusieurs gènes que sont impliqués dans la somitogenèse et la myogenèse et sous le contrôle du signal FGF. Nous avons pu montrer grâce à des analyses fonctionnelles que ER81/Erm/PEA3 et Six1/2 ont un rôle majeur dans la formation des somites les plus antérieures chez l'amphioxus. Inversement, Pax3/7 est impliqué dans la formation des somites postérieures. Cette cascade de régulation est semblable à celle observée lors de la somitogenèse pour les muscles du tronc chez les vertébrés, mais diverge de la cascade de gènes contrôlant la formation des muscles de la tête chez les vertébrés. Tous ces résultats supportent l'hypothèse selon laquelle le changement de fonction du signal FGF durant le développement précoce a été une étape clé pour la perte des somites antérieures, libérant ainsi les contraintes dans la partie antérieure de l'embryon et permettant dans un second temps l'acquisition des muscles de la tête chez l'ancêtre commun des vertébrés. / A central question in Evo-Devo is to understand the origin of the vertebrates’ head. The appearance of new structures such as the neural crest, placodes and a cranial mesoderm were essential for the appearance of the head in the vertebrates. Interestingly, it is supposed that the ancestor of all chordates was completely segmented. Remarkably, the cephalochordate amphioxus is completely segmented in the full length of its body as the hypothetical ancestor of all chordates. Moreover, it has been showed that the FGF signal plays a central role in the formation of the anterior-most somites of amphioxus. Thus, in order to understand the downstream signaling pathway under the control of the FGF signal for the formation of the anterior-most somites in amphioxus, we performed a comparative RNA-seq analysis. This analysis revealed several vertebrates orthologues genes playing roles in somitogenesis or myogenesis and under the control of the FGF signal. Furthermore, functional analysis revealed that ER81/Erm/PEA3 and Six1/2 plays majors roles in the formation of the anterior-most somites in amphioxus. Conversely, Pax3/7 is involved in the formation of the posterior somites. This regulatory cascade resembles that for the control of trunk somitogenesis in vertebrates and diverges from the gene cascades controlling the formation of the vertebrate head muscles. Altogether, our results strengthen the hypothesis that changes in the FGF function during early development were instrumental for the loss of anterior somites, releasing developmental constraints in the anterior part of the embryo and allowing a secondary acquisition of head muscles in the ancestor of vertebrates.

Abstract The embryonic urogenital system (UGS) generates the metanephric kidney, gonad and the adrenal gland. It is well known that the development of the UGS is regulated by sequential and reciprocal epithelial and mesenchymal tissue interactions but the secreted mediators involved are still poorly known. The action of such inductive signals is typically regulated by specific antagonists. The Sprouty (Spry) proteins compose one family of cytoplasmic regulators that typically repress the function of the receptor tyrosine kinase (RTK) signal transduction pathways. The DAN/Cerberus (Cer) family that encodes secreted proteins bind and antagonize the Bmp, Wnt and Nodal signals. In this study the roles of Spry and Cer1 was addressed during mouse UGS development by targeted expression of SPROUTY2 (SPRY2) and Cer1 in the ureteric bud and Wolffian duct under the Pax2 promoter. Changes induced in the UGS assembly process were analyzed in detail to reveal the normal developmental roles of these proteins. SPRY2 expression led to either complete lack of the kidney, reduction in the kidney size or formation of unilateral kidney with reduced size. The SPRY2 mediated reduction in kidney size was accompanied by inhibition of expression of genes that are known to regulate kidney development. The results indicated that the Spry may take part in kidney development by coordinating the reciprocal cell signaling between the ureteric bud, the mesenchymal cells and stromal cells. In addition to the kidney, the gain of SPRY2 function revealed an important role in the control of male gonadogenesis. SPRY2 over expression in the Wolffian duct malformed the Wolffian duct derivatives, diminished the number of seminiferous tubules and the amount of the interstitial tissue associated with reduced mesonephric cell migration to the testis. Exogenous FGF9 rescued mesonephric cell migration inhibited by SPRY2. It was concluded that Spry protein contribute to male sexual organogenesis by antagonizing Fgf9 signaling. When the Cer1 gene was over expressed in the ureteric bud this lead unexpectedly to increased kidney size. The Cer1 mediated promotion of kidney size was demonstrated to involve enhanced ureteric bud morphogenesis. At the molecular level Cer1 protein function lead to inhibition of Bmp4 gene expression and concurrent upregulation of Gdnf and Wnt11 expression. Notably, excess BMP4 reduced the Cer1 stimulated ureteric bud branching and downregulated normally expression of Gdnf and Wnt11 in the embryonic kidney. Based on the presented data it is proposed that the establishment of mammalian organ size is under the control of both systemic and the intrinsic factors. Together the work demonstrates significant roles for the proteins that typically inhibit growth factor signaling or signal transduction. Hence organogenesis is controlled by coordination between positive and negative growth factor regulator signals.

BACKGROUND Vascular calcification is a major risk factor for cardiovascular morbidity and mortality in patients with end stage renal disease (ESRD). In Western countries, Blacks with ESRD appear to have lesser degrees of vascular calcification compared to non-Blacks. However, there is no published data on the association of ethnic differences in vascular calcification and survival in ESRD from Sub-Saharan Africa. METHODS This study assessed the 5-year change in vascular calcification and mortality in a previously published cohort of patients with ESRD. Vascular calcification was assessed by abdominal aortic calcification score (lateral abdominal radiograph) and vascular stiffness by pulse wave velocity. RESULTS Sixty-six of the original 74 participants, studied a baseline, were identified. The median age was 46.6 years (37.6-59.2) and 57.6% were women. Abdominal aortic calcification showed no progression among Blacks [baseline range 0-5, follow up range 0-8 (p=1.00)], but a nonsignificant trend to progression among non-Blacks [baseline range 0-19, follow up range 0-22 (p=0.066)]. Black participants did not display a survival advantage (p=0.870). Overall, sepsis was the most common cause of mortality (64% of those with an identifiable cause of death). Non-Blacks had higher parathyroidectomy rates than Blacks with 9/30 cases compared to 2/36 (p=0.036). After adjustment for parathyroidectomy at follow up, the odds ratio of having abdominal vascular calcification score of ≥1 amongst non-Blacks was 8.6-fold greater compared to Blacks (p= 0.03). Central aortic systolic pressures (CASP) and pulse wave velocities (PWV) were higher in the study population than age matched normative values. At follow up, a positive correlation (r=0.3) was observed between PWV and abdominal aortic calcification (p=0.04). Elevated baseline coronary artery calcification score and FGF-23 level at baseline were not associated with a difference in mortality. CONCLUSION There was no significant progression in vascular calcification among Blacks. After adjusting for increased parathyroidectomy rates, there was a greater progression of vascular calcification amongst non-Blacks compared to Blacks highlighting possible ethnic differences in calcium phosphate metabolism in patients with ESRD. The lack of vascular calcification progression in Blacks was not however associated with improved survival, but the sample size was small.

No description available.