Aggressive forms of cancer are often defined by recurrent chromosomal alterations, yet in most cases, the causal or contributing genetic components remain poorly understood. Here, we utilized microarray informatics to identify candidate oncogenes potentially contributing to aggressive breast cancer behavior. We identified the Rab-coupling protein RCP (also known as RAB11FIP1), which is located at a chromosomal region frequently amplified in breast cancer (8p11-12) as a potential candidate. Overexpression of RCP in MCF10A normal human mammary epithelial cells resulted in acquisition of tumorigenic properties such as loss of contact inhibition, growth-factor independence, and anchorage-independent growth. Conversely, knockdown of RCP in human breast cancer cell lines inhibited colony formation, invasion, and migration in vitro and markedly reduced tumor formation and metastasis in mouse xenograft models. Overexpression of RCP enhanced ERK phosphorylation and increased Ras activation in vitro. As these results indicate that RCP is a multifunctional gene frequently amplified in breast cancer that encodes a protein with Ras-activating function, we suggest it has potential importance as a therapeutic target. Furthermore, these studies provide new insight into the emerging role of the Rab family of small G proteins and their interacting partners in carcinogenesis.

Triple-negative breast cancer (TNBC) is characterized by unique aggressive behavior and lack of targeted therapies. Among the various molecular subtypes of breast cancer, it was observed that TNBCs express elevated levels of sphingosine kinase 1 (SPHK1) compared to other breast tumor subtypes. High levels of SPHK1 gene expression correlated with poor overall and progression- free survival, as well as poor response to Doxorubicin-based treatment. Inhibition of SPHK1 was found to attenuate ERK1/2 and AKT signaling and reduce growth of TNBC cells in vitro and in a xenograft SCID mouse model. Moreover, SPHK1 inhibition by siRNA knockdown or treatment with SKI-5C sensitizes TNBCs to chemotherapeutic drugs. Our findings suggest that SPHK1 inhibition, which effectively counteracts oncogenic signaling through ERK1/2 and AKT pathways, is a potentially important anti-tumor strategy in TNBC. A combination of SPHK1 inhibitors with chemotherapeutic agents may be effective against this aggressive subtype of breast cancer.

The type I IFN family includes 14 closely related antiviral cytokines that are produced in response to viral infections. They bind to a common receptor, and have qualitatively similar biological activities. The physiological relevance of this redundancy is still unclear. In this study, we analyzed and compared the effects of two potent antiviral type I IFNs, IFN-α2 and IFN-α8, on the motility of various populations of human T lymphocytes in vitro. In this study, we show that IFN-α2 induces chemokinesis of both CD4+ and CD8+ T cells at various stages of differentiation, and induces functional changes that result in enhanced T cell motility, including up-regulation of the integrins LFA-1 and VLA-4, and subsequently, increased ICAM-1- and fibronectin-dependent migration. In contrast, IFN-α8 did not affect T cell motility, despite having similar antiviral properties and similar effects on the induction of the antiviral protein MxA. However, transcription of other IFN-stimulated genes showed that transcription of these genes is selectively activated by IFN-α2, but not IFN-α8, in T cells. Finally, while the antiviral activity of the two subtypes is inhibited by Abs against the two subunits of the IFN-α receptor, the chemokinetic effect of IFN-α2 is selectively blocked by Abs against the A1 receptor subunit. These observations are consistent with the possibility that subtype-specific intracellular signaling pathways are activated by type I IFNs in T lymphocytes.

A large number of etiological factors and the complexity of breast cancers present challenges for prevention and treatment. Recently, the emergence of microRNAs (miRNAs) as cancer biomarkers has added an extra dimension to the 'molecular signatures' of breast cancer. Bioinformatic analyses indicate that each miRNA can regulate hundreds of target genes and could serve functionally as 'oncogenes' or 'tumour suppressor' genes, and co-ordinate multiple cellular processes relevant to cancer progression. A number of studies have shown that miRNAs play important roles in breast tumorigenesis, metastasis, proliferation and differentiation of breast cancer cells. This review provides a comprehensive overview of miRNAs with established functional relevance in breast cancer, their established target genes and resulting cellular phenotype. The role and application of circulating miRNAs in breast cancer is also discussed. Furthermore, we summarize the role of miRNAs in the hallmarks of breast cancer, as well as the possibility of using miRNAs as potential biomarkers for detection of breast cancer.

In cancer cells, a vital cellular process during metastasis is the transformation of epithelial cells towards motile mesenchymal cells called the epithelial to mesenchymal transition (EMT). The cytoskeleton is an active network of three intracellular filaments: actin cytoskeleton, microtubules, and intermediate filaments. These filaments play a central role in the structural design and cell behavior and are necessary for EMT. During EMT, epithelial cells undergo a cellular transformation as manifested by cell elongation, migration, and invasion, coordinated by actin cytoskeleton reorganization. The actin cytoskeleton is an extremely dynamic structure, controlled by a balance of assembly and disassembly of actin filaments. Actin-binding proteins regulate the process of actin polymerization and depolymerization. Microtubule reorganization also plays an important role in cell migration and polarization. Intermediate filaments are rearranged, switching to a vimentin-rich network, and this protein is used as a marker for a mesenchymal cell. Hence, targeting EMT by regulating the activities of their key components may be a potential solution to metastasis. This review summarizes the research done on the physiological functions of the cytoskeleton, its role in the EMT process, and its effect on multidrug-resistant (MDR) cancer cells—highlight some future perspectives in cancer therapy by targeting cytoskeleton.

Due to their ability to inhibit antigeninduced T-cell activation in vitro and in vivo, anergic T cells can be considered part of the spectrum of immunoregulatory T lymphocytes. Here we report that both murine and human anergic T cells can impair the ability of parenchymal cells (including endothelial and epithelial cells) to establish cell-cell interactions necessary to sustain leukocyte migration in vitro and tissue infiltration in vivo. The inhibition is reversible and cell-contact dependent but does not require cognate recognition of the parenchymal cells to occur. Instrumental to this effect is the increased cell surface expression and enzymatic activity of molecules such as CD26 (dipeptidyl-peptidase IV), which may act by metabolizing chemoattractants bound to the endothelial/epithelial cell surface. These results describe a previously unknown antigen-independent antiinflammatory activity by locally generated anergic T cells and define a novel mechanism for the long-known immunoregulatory properties of these cells. IntroductionT-cell anergy has been defined as a "cellular state in which a lymphocyte is alive but fails to display certain functional responses (including cell division and interleukin 2 [IL-2] production) when optimally stimulated through both its antigen-specific receptor and any other receptor that is normally required for full activation." 1 Anergic T cells can be generated in vitro and in vivo by various mechanisms, 1,2 all involving partial or inappropriate stimulation. While losing their proliferative and effector potential, anergic T cells have long been known to be able to exert immunoregulation. The potential for anergic T cells to act as suppressor cells came first from a superantigen in vivo model in which anergic T cells acted as efficient suppressor cells in an antigen-nonspecific manner. 3 More recently, murine anergic T cells either generated in vivo or rendered anergic in vitro with immobilized anti-CD3 and adoptively transferred have been shown to prolong skin allograft survival in an antigen-specific manner. 4,5 In the human system, anergic CD4 ϩ T cells were shown to exert contact-dependent and antigen-specific suppression in vitro. 6,7 The mechanism by which anergic T cells exert their immunoregulatory properties appears to be indirect by altering the antigen presenting cells (APCs) immunogenicity 8,9 in a cell-cell contactdependent manner. The molecular basis for this effect is still unknown and it has been hypothesized to involve the induction of "regulatory" molecules on the anergic T cells, capable of delivering negative signals to the APC. 2 It has recently become clear that the initial stages of T-cell activation are mediated by antigen-independent interactions, which establish areas of focal contact between T cells and APCs. 10,11 Such interactions are initiated by chemoattractant-induced cell polarization and subsequent redistribution of adhesion molecules on the T-cell surface. These, in turn, allow T-cell receptor (TCR) interactions with the major histocompatibili...

This paper presents the results on the use of short columns (3-5 cm long) with small particle size (1.8 µm) for high performance liquid chromatographic separation of individual lanthanides and uranium from plutonium as well as uranium from thorium to achieve rapid separations i.e. separation time as short as 3.6 min for individual lanthanides, 1 min for thorium-uranium and 4.2 min for uranium from plutonium. These advantages can be exploited to significantly reduce analysis time, liquid waste generation as well as dose to operator when radioactive samples are analysed e.g. burn-up determination.In the present work, a dynamic ion-exchange chromatographic separation technique was employed using camphor-10-sulfonic acid (CSA) as the ion-pairing reagent and α-hydroxy isobutyric acid (α-HIBA) as the complexing reagent for the isolation of individual lanthanides as well as the separation of uranium from thorium.Uranium was separated from Pu(III) as well as Pu(IV) by reverse phase HPLC technique. The reverse phase HPLC was also investigated for the isolation and quantitative determination of uranium from thorium as well as lanthanide group from uranium.The dynamic ion-exchange technique using small particle support was demonstrated for measuring the concentrations of lanthanide fission products such as La, Ce, Pr, Nd and Sm in the dissolver solution of fast reactor fuel. Similarly, the assay of uranium in the dissolver solution of fast reactor was carried out using reverse phase HPLC technique. The rapid separation technique using reverse phase HPLC was also demonstrated for separation of lanthanides as a group from uranium matrix; samples of LiCl-KCl eutectic salt containing chlorides of lanthanides in uranium matrix (typically 1 : 2000) were analysed.

Objectives:Sphingosine kinase 1 (SphK1) phosphorylates the membrane sphingolipid, sphingosine, to sphingosine-1-phosphate (S1P), an oncogenic mediator, which drives tumor cell growth and survival. Although SphK1 has gained increasing prominence as an oncogenic determinant in several cancers, its potential as a therapeutic target in colon cancer remains uncertain. We investigated the clinical relevance of SphK1 expression in colon cancer as well as its inhibitory effects in vitro.Methods:SphK1 expression in human colon tumor tissues was determined by immunohistochemistry and its clinicopathological significance was ascertained in 303 colon cancer cases. The effects of SphK1 inhibition on colon cancer cell viability and the phosphoinositide 3-kinase (PI3K)/Akt cell survival pathway were investigated using a SphK1-selective inhibitor—compound 5c (5c). The cytotoxicity of a novel combination using SphK1 inhibition with the chemotherapeutic drug, 5-fluorouracil (5-FU), was also determined.Results:High SphK1 expression correlated with advanced tumor stages (AJCC classification). Using a competing risk analysis model to take into account disease recurrence, we found that SphK1 is a significant independent predictor for mortality in colon cancer patients. In vitro, the inhibition of SphK1 induced cell death in colon cancer cell lines and attenuated the serum-dependent PI3K/Akt signaling. Inhibition of SphK1 also enhanced the sensitivity of colon cancer cells to 5-FU.Conclusion:Our findings highlight the impact of SphK1 in colon cancer progression and patient survival, and provide evidence supportive of further development in combination strategies that incorporate SphK1 inhibition with current chemotherapeutic agents to improve colon cancer outcomes.