Latent KSHV Infection of Endothelial Cells Induces Integrin Beta3 to Activate Angiogenic Phenotypes

Kaposi's Sarcoma (KS), the most common tumor of AIDS patients, is a highly vascularized tumor supporting large amounts of angiogenesis. The main cell type of KS tumors is the spindle cell, a cell of endothelial origin, the primary cell type involved in angiogenesis. Kaposi's Sarcoma-associated herpesvirus (KSHV) is the etiologic agent of KS and is likely involved in both tumor formation and the induction of angiogenesis. Integrins, and specifically integrin αVβ3, have known roles in both tumor induction and angiogenesis. αVβ3 is also important for KSHV infection as it has been shown to be involved in KSHV entry into cells. We found that during latent infection of endothelial cells KSHV induces the expression of integrin β3 leading to increased surface levels of αVβ3. Signaling molecules downstream of integrins, including FAK and Src, are activated during viral latency. Integrin activation by KSHV is necessary for the KSHV-associated upregulation of a number of angiogenic phenotypes during latent infection including adhesion and motility. Additionally, KSHV-infected cells become more reliant on αVβ3 for capillary like formation in three dimensional culture. KSHV induction of integrin β3, leading to induction of angiogenic and cancer cell phenotypes during latency, is likely to be important for KS tumor formation and potentially provides a novel target for treating KS tumors

Characterization of the Endothelial Cell Cytoskeleton following HLA Class I Ligation

Vascular endothelial cells (ECs) are a target of antibody-mediated allograft rejection. In vitro, when the HLA class I molecules on the surface of ECs are ligated by anti-HLA class I antibodies, cell proliferation and survival pathways are activated and this is thought to contribute to the development of antibody-mediated rejection. Crosslinking of HLA class I molecules by anti-HLA antibodies also triggers reorganization of the cytoskeleton, which induces the formation of F-actin stress fibers. HLA class I induced stress fiber formation is not well understood.The present study examines the protein composition of the cytoskeleton fraction of ECs treated with HLA class I antibodies and compares it to other agonists known to induce alterations of the cytoskeleton in endothelial cells. Analysis by tandem mass spectrometry revealed unique cytoskeleton proteomes for each treatment group. Using annotation tools a candidate list was created that revealed 12 proteins, which were unique to the HLA class I stimulated group. Eleven of the candidate proteins were phosphoproteins and exploration of their predicted kinases provided clues as to how these proteins may contribute to the understanding of HLA class I induced antibody-mediated rejection. Three of the candidates, eukaryotic initiation factor 4A1 (eIF4A1), Tropomyosin alpha 4-chain (TPM4) and DDX3X, were further characterized by Western blot and found to be associated with the cytoskeleton. Confocal microscopy analysis showed that class I ligation stimulated increased eIF4A1 co-localization with F-actin and paxillin.Colocalization of eIF4A1 with F-actin and paxillin following HLA class I ligation suggests that this candidate protein could be a target for understanding the mechanism(s) of class I mediated antibody-mediated rejection. This proteomic approach for analyzing the cytoskeleton of ECs can be applied to other agonists and various cells types as a method for uncovering novel regulators of cytoskeleton changes

Cholinergic receptor pathways involved in apoptosis, cell proliferation and neuronal differentiation

Acetylcholine (ACh) has been shown to modulate neuronal differentiation during early development. Both muscarinic and nicotinic acetylcholine receptors (AChRs) regulate a wide variety of physiological responses, including apoptosis, cellular proliferation and neuronal differentiation. However, the intracellular mechanisms underlying these effects of AChR signaling are not fully understood. It is known that activation of AChRs increase cellular proliferation and neurogenesis and that regulation of intracellular calcium through AChRs may underlie the many functions of ACh. Intriguingly, activation of diverse signaling molecules such as Ras-mitogen-activated protein kinase, phosphatidylinositol 3-kinase-Akt, protein kinase C and c-Src is modulated by AChRs. Here we discuss the roles of ACh in neuronal differentiation, cell proliferation and apoptosis. We also discuss the pathways involved in these processes, as well as the effects of novel endogenous AChRs agonists and strategies to enhance neuronal-differentiation of stem and neural progenitor cells. Further understanding of the intracellular mechanisms underlying AChR signaling may provide insights for novel therapeutic strategies, as abnormal AChR activity is present in many diseases

Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination

Therapy-induced resistance remains a significant hurdle to achieve long-lasting responses and cures in cancer patients. We investigated the long-term consequences of genetically impaired angiogenesis by engineering multiple tumor models deprived of endoglin, a co-receptor for TGF-β in endothelial cells actively engaged in angiogenesis. Tumors from endoglin-deficient mice adapted to the weakened angiogenic response, and refractoriness to diminished endoglin signaling was accompanied by increased metastatic capability. Mechanistic studies in multiple mouse models of cancer revealed that deficiency for endoglin resulted in a tumor vasculature that displayed hallmarks of endothelial-to-mesenchymal transition, a process of previously unknown significance in cancer biology, but shown by us to be associated with a reduced capacity of the vasculature to avert tumor cell intra- and extravasation. Nevertheless, tumors deprived of endoglin exhibited a delayed onset of resistance to anti-VEGF (vascular endothelial growth factor) agents, illustrating the therapeutic utility of combinatorial targeting of multiple angiogenic pathways for the treatment of cancer

COMPLEXIDADE RACIAL: mitos e realidades em duas freguesias de Salvador em 1775

A partir da análise minuciosa dos dados do Censo de 1775 sobre duas freguesias de Salvador (São Pedro e Penha), são colocados em questão cinco mitos dominantes sobre a escravidão no imaginário nacional: (1) o domínio total do trabalho escravo na sociedade; (2) uma sociedade formada apenas por senhores e escravos; (3) uma sociedade constituída, por um lado, por um segmento de dominantes e exploradores e, por outro, por dominados e explorados; (4) uma sociedade urbana segregada; (5) uma sociedade patriarcal, em que as mulheres eram submissas e economicamente subordinadas. Os resultados do censo, portanto, levantam novas questões para o entendimento da complexidade do nosso passado, o que ajuda a entender a manutenção das extremas desigualdades atuais, além de evidenciar a existência de diferenciações espaciais na cidade. PALAVRAS-CHAVE: escravos, libertos, agregados, freguesias, Salvador.RACIAL COMPLEXITY: myth and reality in two Salvador freguesias in 1775 Pedro de Almeida Vasconcelos The meticulous analysis of data from the Census of 1775 on two freguesias of Salvador (São Pedro and Penha), bring doubt to five dominant myths on slavery in the national imaginary: (1) the exclusivity of slave work in the society; (2) a society just formed by slave owners and slaves; (3) a society where, on one side, live a segment of dominant exploiters and, on the other, dominated explored people; (4) a segregated urban society; (5) a patriarchal society, in which women were submissive and economically subordinates. The results of the census, therefore, bring new subjects to understanding the complexity of our past, what helps to understand the maintenance of the extreme current inequalities, besides showing the existence of space differentiations in the city. KEYWORDS: slaves, freed men, agregados, freguesias, Salvador.COMPLEXITÉ RACIALE: mythes et réalités dans deux paroisses de Salvador en 1775 Pedro de Almeida Vasconcelos A partir de l’analyse minutieuse des données du recensement de 1775 concernant deux paroisses de Salvador (São Pedro et Penha) sont remis en question cinq mythes dominants à propos de l’esclavage dans l’imaginaire national: (1) l’exclusivité du travail esclave dans la société; (2) une société formée uniquement de seigneurs et d’esclaves; (3) une société constituée d’une part par un segment de dominants et d’exploiteurs et d’autre part de dominés et d’exploités; (4) une société urbaine ségréguée; (5) une société patriarcale où les femmes étaient soumises et subordonnées économiquement. Les résultats de ce recensement soulèvent donc de nouvelles questions pour la compréhension de la complexité de notre passé, ceci permet de comprendre le maintien d’extrêmes inégalités actuelles et de mettre aussi en évidence l’existence de différenciations spatiales dans la ville. MOTS-CLÉS: esclaves, personnes libres, domestiques, paroisses, Salvador. Publicação Online do Caderno CRH: http://www.cadernocrh.ufba.b