Aurora A and B kinases are closely related kinases involved in regulating separate points in the cell cycle. This review highlights the rationale for Aurora kinases as cancer targets and examines the currently known Aurora kinase inhibitors in the patent and scientific literature. The known crystal structures of the Aurora kinases are described with relevance to bound ligand interactions and the prospect of the generation of drug-resistant mutant forms. The potential for selectivity versus primary cells will also be discussed. The status of the inhibitors in clinical development is described.

Kaposi sarcoma-associated herpesvirus (KSHV) is etiologically linked to Kaposi sarcoma (KS), a tumor genetically akin to lymphatic endothelial cells (LECs). IntroductionKaposi sarcoma (KS) lies at the interface of infection and malignancy. [1][2][3] It is a neoplasm common in para-Mediterranean populations, endemic in parts of sub-Saharan Africa, and frequently seen in patients with AIDS. 3 KS is a tumor of microvascular endothelium and gene-expression microarray (GEM) studies suggest that it belongs to the lymphatic endothelial lineage. 4 KS-associated herpesvirus (KSHV) is linked to the etiopathogenesis of KS 5,6 and certain lymphoproliferations, including primary effusion lymphoma (PEL) 7 and a plasmablastic variant of multicentric Castleman disease (MCD). 8 The risk of developing KS, PEL, and MCD is significantly higher during acquired or iatrogenic immunosuppression. 3,9 Moreover, posttransplantation KS can resolve when immunosuppressive therapy is reduced, 9 and the introduction of effective antiretroviral therapy for HIV infection has led to a decline in KS incidence. 3 These observations indicate that disruption of host-pathogen equilibrium promotes the precipitation of these neoplasms.Herpesviruses have evolved elaborate mechanisms to modulate host immune responses. 10 EBV is the prototype of a cancerinducing human herpesvirus. [11][12][13] EBV modulates cellular antiviral responses in various ways, including down-regulation of major histocompatibility complex (MHC) proteins 14 and blocking proteasomal degradation and antigen synthesis. 15,16 However, EBV also enhances antiviral immune responses by way of its latent membrane protein 1 (LMP1), which up-regulates MHC-I. 17,18 This leads to cytotoxic T-cell (CTL)-mediated elimination of EBV latency III cells, promoting the transition to latency I-infected B cells. As with KSHV, immunosuppression disturbs the host-virus equilibrium leading to an increased incidence of EBV-associated tumors. 12 Several KSHV proteins regulate host innate or adaptive immune responses. 19 Among these there are 5 viral proteins that block the innate antiviral interferon (IFN) response, including orf45, 20 viral , 21 viral interferon regulatory factors (vIRFs) 1 and 2, [22][23][24][25][26][27] and the transactivator of the lytic cycle, RTA. 28 Furthermore 2 viral modulators of immune response (vMIRs) act as E3 ubiquitin ligases and down-regulate MHC-I. 29,30 vMIR2 also down-regulates ICAM-1 and CD86 by enhancing endocytosis, lysosomal targeting, and proteasome-mediated degradation 31,32 and increases endocytosis of CD1d, leading to the escape of infected cells from NKT cells. 33 The majority of these viral mechanisms are used during the lytic viral cycle, when most of these proteins are expressed and a vigorous host response occurs to curtail viral dissemination.Immune regulation during KSHV latency remains insufficiently characterized. However, the KSHV lytic and latent gene profiles are not mutually exclusive. Some lytic proteins, such as RTA and vMIR2, are expressed during the...

Summary. Dendritic cells (DCs) are the most potent antigenpresenting cells described to date. In human peripheral blood, both myeloid and lymphoid subsets of DCs have been identified. In contrast, cord blood (CB) DCs have recently been described as being exclusively of the immature CD11c 2 lymphoid DC subset. Using an alternative method of enrichment, based on a negative selection system, both lymphoid (HLA-DR 1 CD123 111 CD11c 2 CD33 2 ) and myeloid (HLA-DR 11 CD123 1 CD11c 1 CD33 1 ) DCs were identified in CB. Although the majority of CB DCs showed a lymphoid phenotype, a significant number of CD11c 1 myeloid DCs (25´6%^14´5%, n 13) were also present.Other markers, such as CD80 and CD83, were negative in both subsets. Analyses of the allostimulatory capacity of both subsets showed that freshly isolated CB lymphoid DCs failed to induce a potent allostimulation of naive CB T cells. These features are therefore consistent with previous work reporting an immature phenotype for lymphoid DCs in adult blood. The significance of the inverted CD11c 1 /CD11c 2 ratio observed in CB DCs (1:3) with respect to adult blood DCs (3:1) remains to be explained.

No abstract