Dual role of SnoN in mammalian tumorigenesis

SnoN is an important negative regulator of transforming growth factor beta signaling through its ability to interact with and repress the activity of Smad proteins. It was originally identified as an oncoprotein based on its ability to induce anchorage-independent growth in chicken embryo fibroblasts. However, the roles of SnoN in mammalian epithelial carcinogenesis have not been well defined. Here we show for the first time that SnoN plays an important but complex role in human cancer. SnoN expression is highly elevated in many human cancer cell lines, and this high level of SnoN promotes mitogenic transformation of breast and lung cancer cell lines in vitro and tumor growth in vivo, consistent with its proposed pro-oncogenic role. However, this high level of SnoN expression also inhibits epithelial-to-mesenchymal transdifferentiation. Breast and lung cancer cells expressing the shRNA for SnoN exhibited an increase in cell motility, actin stress fiber formation, metalloprotease activity, and extracellular matrix production as well as a reduction in adherens junction proteins. Supporting this observation, in an in vivo breast cancer metastasis model, reducing SnoN expression was found to moderately enhance metastasis of human breast cancer cells to bone and lung. Thus, SnoN plays both pro-tumorigenic and antitumorigenic roles at different stages of mammalian malignant progression. The growth-promoting activity of SnoN appears to require its ability to bind to and repress the Smad proteins, while the antitumorigenic activity can be mediated by both Smad-dependent and Smad-independent pathways and requires the activity of small GTPase RhoA. Our study has established the importance of SnoN in mammalian epithelial carcinogenesis and revealed a novel aspect of SnoN function in malignant progression.     

Comparative analysis of differential expression of sialic acids and adhesion molecules on mononuclear cells of bone marrow and peripheral blood in childhood acute lymphoblastic leukaemia at diagnosis and clinical remission

Childhood acute lymphoblastic leukaemia (ALL) is characterized by the neoplasm of immature haematopoietic precursor cells (HPCs). We report significant differences between the expression of sialoglycoproteins and adhesion molecules on mononuclear cells (MNCs) of bone marrow (BM) and peripheral blood (PB) from individual children at diagnosis of the disease. Lymphoblasts in PB predominantly expressed 9-O-acetylated sialoglycoproteins (Neu5,9Ac2-GPs), sialic acid, alpha2-3 linked sialic acid, L- and P-selectins and vascular cell adhesion molecule -1 (VCAM-1) on their surface compared to BM, as determined with selective lectins and monoclonal antibodies (mAbs) by flow cytometric analysis. CD34+CD38+ cells present either in diagnostic PB or BM always showed enhanced expression of both alpha2-3 and alpha2-6 linked sialic acids, Neu5,9Ac2-GPs, L- and P-selectins and VCAM-1, compared to CD34+CD38- population, as confirmed by higher mean fluorescence intensity (MFI). Expression of ICAM-1 was reverse. However, MFI of Neu5,9Ac2-GPs was always higher both in CD34+CD38+ and CD34+CD38- population in PB compared to BM. Diverse trend of these cell surface macromolecules was observed during clinical remission. This is the first comparative study between PB and BM, where significant differential distribution of sialylated macromolecules and adhesion molecules was observed. Hence, supervising these cell surface macromolecules at various stages of treatment might help in minimal residual disease detection, identifying mobilization factor(s) and in isolation of normal HPCs for autologous BM transplantation.     

An energy-based population-balance approach to model granule growth and breakage in high-shear wet granulation processes

A mathematical model of high shear wet granulation is proposed, where granule breakage, and not growth, is the dominant process. The energy required for granule breakage is assumed to be provided by the impact of granules between themselves and the granulator parts, and the extent of granule breakage determined by the balance between the impactenergy and the work of adhesion between the agglomerating particles. A specific volume of dry powder per unit crack surface area was allowed to reattach to the surface of broken granules to account for granule growth. To verify proposed model conditions, lactose monohydrate was granulated with a relatively low amount (6%) of the binder phase, polyvinyl-pyrrolidone and water, and was added to the powder before granulation. The trend in granule size distribution during the experiment closely follwed the predicted model with an initial increase in the weight fraction of the larger granules. This increase was possibly due to extensive breakage of weaker granules and less extensive breakage, as if by attrition, of stronger granules, accompanied by the attachment of dry powder to the cracked surfaces. Eventually, larger granules experience increased impact energy and break. When excess binder is added and, higher volumes of powder reattach to the crack surface, more large granules form leading to granule overgrowth. This model highlights the importance of the probability of impact per unit time interval (ie, the rate of impact), the strength of the granules and the volume of powder that could attach to the cracked surface in high shear granulation processes where significant granule breakage is encountered. Published: August 10, 2007     

ADSBET2: Automated Determination of Salt-Bridge Energy-Terms version 2

AvailabilityADSBET2 is freely available at http://sourceforge.net/projects/ADSBET2/ for all users.     

Synthesis and bio-evaluation of aryl hydrazono esters for oviposition responses in Aedes albopictus

A novel series of aryl hydrazono esters (AHE) (1-13) were synthesized (yield 76-98%) to study the oviposition responses in Aedes albopictus (Skuse) mosquitoes for the first time. At a concentration of 10 μg ml⁻¹ in dual choice experiment, among the screened compounds, AHE-12 showed remarkable oviposition attractant activity with an oviposition activity index (OAI) of +0.299 (greater than 95% confidence limit) comparable to p-cresol (OAI +0.320) which is well-reported oviposition attractant for Aedes aegypti. Conversely, AHE-10 exhibited highest oviposition deterrent activity with OAI −0.247. The possible utilization of these compounds will be in integrated vector management strategies.     

A biologically inspired measure for coexpression analysis

Two genes are said to be coexpressed if their expression levels have a similar spatial or temporal pattern. Ever since the profiling of gene microarrays has been in progress, computational modeling of coexpression has acquired a major focus. As a result, several similarity/distance measures have evolved over time to quantify coexpression similarity/dissimilarity between gene pairs. Of these, correlation coefficient has been established to be a suitable quantifier of pairwise coexpression. In general, correlation coefficient is good for symbolizing linear dependence, but not for nonlinear dependence. In spite of this drawback, it outperforms many other existing measures in modeling the dependency in biological data. In this paper, for the first time, we point out a significant weakness of the existing similarity/distance measures, including the standard correlation coefficient, in modeling pairwise coexpression of genes. A novel measure, called BioSim, which assumes values between -1 and +1 corresponding to negative and positive dependency and 0 for independency, is introduced. The computation of BioSim is based on the aggregation of stepwise relative angular deviation of the expression vectors considered. The proposed measure is analytically suitable for modeling coexpression as it accounts for the features of expression similarity, expression deviation and also the relative dependence. It is demonstrated how the proposed measure is better able to capture the degree of coexpression between a pair of genes as compared to several other existing ones. The efficacy of the measure is statistically analyzed by integrating it with several module-finding algorithms based on coexpression values and then applying it on synthetic and biological data. The annotation results of the coexpressed genes as obtained from gene ontology establish the significance of the introduced measure. By further extending the BioSim measure, it has been shown that one can effectively identify the variability in the expression patterns over multiple phenotypes. We have also extended BioSim to figure out pairwise differential expression pattern and coexpression dynamics. The significance of these studies is shown based on the analysis over several real-life data sets. The computation of the measure by focusing on stepwise time points also makes it effective to identify partially coexpressed genes. On the whole, we put forward a complete framework for coexpression analysis based on the BioSim measure.     

Against expectation: a short sequence with high signal elucidates cone snail phylogeny

A short (259 nucleotide) conserved intronic sequence (CIS) is surprisingly informative for delineating deep phylogenetic relationships in cone snails. Conus species previously have been assigned to clades based on the evidence from mitochondrial 12S and 16S rRNA gene sequences (1129 bp). Despite their length, these genes lack the phylogenetic information necessary to resolve the relationships among the clades. Here we show that the relationships can be inferred from just 46 sites in the very short CIS sequence (a portion of "intron 9" of the γ-glutamyl carboxylase gene). This is counterintuitive because in short sequences sampling error (noise) often drowns out phylogenetic signal. The intron 9 CIS is rich in synapomorphies that define the divergence patterns among eight clades of worm- and fish-hunting Conus, and it contains almost no homoplasy. Parsimony, maximum likelihood and Bayesian analyses of the combined sequences (mt rRNA+CIS) confirm most of the relationships among 23 Conus sequences. This phylogeny implies that fish-hunting behavior evolved at least twice during the history of Conus-once among New World species and independently in the Indo-Pacific clades.     

Glut-1 Expression Correlates with Basal-like Breast Cancer

INTRODUCTION: Glucose transporter 1 (Glut-1) is a facilitative glucose transporter expressed in many cancers including breast cancer. Basal-like breast cancer (BLBC) is a high-risk disease associated with poor prognosis and lacks the benefit of targeted therapy. The aim of this study was to characterize the immunohistochemical (IHC) expression of Glut-1 in patients with BLBC compared with non-BLBC. MATERIALS AND METHODS: We identified 523 cases of invasive breast carcinoma from our database. The clinicopathologic findings and the biologic markers including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2) status were reviewed. IHC stains for cytokeratin 5/6 (CK5/6), epidermal growth factor receptor (EGFR), p53, and Glut-1 were performed on tissue microarray using standard procedures. BLBC was defined as ER-,PR-, Her2-, and CK5/6+ and/or EGFR+. RESULTS: Of informative cases, 14.7% were categorized as BLBC versus 85.3% as non-BLBC. Glut-1 was expressed in 42 (76.4%) of 55 BLBCs, whereas only 55 (23.8%) of 231 non-BLBCs showed immunostaining for Glut-1 (P < .001). Overall, Glut-1 expression was significantly associated with high histologic grade, ER negativity, PR negativity, CK5/6 positivity, EGFR expression, and high p53 expression (P < .001). However, there was no correlation between Glut-1 immunostaining and patient's outcome. CONCLUSIONS: Our results show that Glut-1 is significantly associated with BLBC and might be a potential therapeutic target for this aggressive subgroup of breast cancer, and this warrants further investigations.