Lung cancer tumorigenicity and drug resistance are maintained through ALDH(hi)CD44(hi) tumor initiating cells

published_or_final_versio

Supertwistor space for 6D maximal super Yang-Mills

6D maximal super Yang-Mills on-shell amplitudes are formulated in superspace using 6 dimensional twistors. The 3,4,5-point tree amplitudes are obtained by supersymmetrizing their bosonic counterparts and confirmed through the BCFW construction. In contrast to 4D this superspace is non-chiral, reflecting the fact that one cannot differentiate MHV from $\bar{{\rm MHV}}$ in 6D. Combined with unitarity methods, this superspace should be useful for the study of multi-loop D dimensional maximal super Yang-Mills and gravity amplitudes. Furthermore, the non-chiral nature gives a natural framework for an off-shell construction. We show this by matching our result with off-shell D=4 N=4 super Yang-Mills amplitudes, expressed in projective superspace.Comment: 6 figures 28 pages. with better sign

Emerging strengths in Asia Pacific bioinformatics

The 2008 annual conference of the Asia Pacific Bioinformatics Network (APBioNet), Asia's oldest bioinformatics organisation set up in 1998, was organized as the 7th International Conference on Bioinformatics (InCoB), jointly with the Bioinformatics and Systems Biology in Taiwan (BIT 2008) Conference, Oct. 20–23, 2008 at Taipei, Taiwan. Besides bringing together scientists from the field of bioinformatics in this region, InCoB is actively involving researchers from the area of systems biology, to facilitate greater synergy between these two groups. Marking the 10th Anniversary of APBioNet, this InCoB 2008 meeting followed on from a series of successful annual events in Bangkok (Thailand), Penang (Malaysia), Auckland (New Zealand), Busan (South Korea), New Delhi (India) and Hong Kong. Additionally, tutorials and the Workshop on Education in Bioinformatics and Computational Biology (WEBCB) immediately prior to the 20th Federation of Asian and Oceanian Biochemists and Molecular Biologists (FAOBMB) Taipei Conference provided ample opportunity for inducting mainstream biochemists and molecular biologists from the region into a greater level of awareness of the importance of bioinformatics in their craft. In this editorial, we provide a brief overview of the peer-reviewed manuscripts accepted for publication herein, grouped into thematic areas. As the regional research expertise in bioinformatics matures, the papers fall into thematic areas, illustrating the specific contributions made by APBioNet to global bioinformatics efforts

Classification of Dengue Fever Patients Based on Gene Expression Data Using Support Vector Machines

Background: Symptomatic infection by dengue virus (DENV) can range from dengue fever (DF) to dengue haemorrhagic fever (DHF), however, the determinants of DF or DHF progression are not completely understood. It is hypothesised that host innate immune response factors are involved in modulating the disease outcome and the expression levels of genes involved in this response could be used as early prognostic markers for disease severity. Methodology/Principal Findings: mRNA expression levels of genes involved in DENV innate immune responses were measured using quantitative real time PCR (qPCR). Here, we present a novel application of the support vector machines (SVM) algorithm to analyze the expression pattern of 12 genes in peripheral blood mononuclear cells (PBMCs) of 28 dengue patients (13 DHF and 15 DF) during acute viral infection. The SVM model was trained using gene expression data of these genes and achieved the highest accuracy of ,85% with leave-one-out cross-validation. Through selective removal of gene expression data from the SVM model, we have identified seven genes (MYD88, TLR7, TLR3, MDA5, IRF3, IFN-a and CLEC5A) that may be central in differentiating DF patients from DHF, with MYD88 and TLR7 observed to be the most important. Though the individual removal of expression data of five other genes had no impact on the overall accuracy, a significant combined role was observed when the SVM model of the two main genes (MYD88 and TLR7) was re-trained to include the five genes, increasing the overall accuracy to ,96%. Conclusions/Significance: Here, we present a novel use of the SVM algorithm to classify DF and DHF patients, as well as to elucidate the significance of the various genes involved. It was observed that seven genes are critical in classifying DF and DHF patients: TLR3, MDA5, IRF3, IFN-a, CLEC5A, and the two most important MYD88 and TLR7. While these preliminary results are promising, further experimental investigation is necessary to validate their specific roles in dengue disease

The role of NFATc2 in regulating tumor initiating cell phenotype in non-small cell lung cancer

Conference Theme: Harnessing Breakthroughs - Targeting Cure

Calcium/calmodulin-dependent protein kinase II alpha (CaMK2A) regulates the tumor initiating cell phenotype through SOX2 expression and modulates treatment response to anti-cancer drugs in lung adenocarcinoma

This journal suppl. entitled: Proceedings of the 107th Annual Meeting of the American Association for Cancer ResearchLung cancer is the most lethal of all cancers world-wide and the majority of patients require chemotherapy or targeted therapy at presentation. Survival is compromised by drug resistance through multiple mechanisms such as by-pass mutations, micro-environment activation of survival programs and induction of tumor initiating cells (TIC). Induction of TIC phenotypes could be accompanied by upregulation of embryonic or developmental pathways but molecular mechanisms are incompletely understood. Calcium/calmodulin-dependent protein kinase II alpha (CaMK2A) is a multifunctional serine/threonine kinase involved in growth and stress signals integration. A tumor-supportive role has been reported in leukaemia and thyroid cancer but reports on its involvement in TIC regulation are limited. We investigated the role and molecular mechanism of CaMK2A in lung cancer TIC regulation using in vitro and in vivo models. The results showed CaMK2A was overexpressed in lung cancer cell lines and human lung adenocarcinomas compared to normal lung. In cancer cells with stable CaMK2A-knockdown, in vitro reduction in tumor spheres formation, anchorage independent growth and increased reactive oxygen species, as well as in vivo reduction of xenograft tumorigenicity were observed. The opposite effects were observed in cancer cells with stable CaMK2A over-expression. Further, specific pharmacological inhibition of CaMK2A by KN93 led to significantly reduced IC50 for gefitinib in lung cancer cells harboring activating EGFR mutation (HCC827) and in HCC827 exogenously induced for gefitinib resistance. In contrast, IC50 of cisplatin treatment was increased in cancer cells with genetically-induced CaMK2A over-expression. Moreover, CaMK2A knockdown led to reduced mRNA expressions of pluripotency genes (SOX2, NANOG, OCT4) and TIC markers (ALDH, CD166). These results suggested CaMK2A is involved in lung tumorigenicity through TIC regulation. To further investigate the molecular mechanism, we showed tumorigenicity was restored in xenografts with CaMK2A knockdown rescued with SOX2 over-expression. In CaMK2A knockdown cells, reduced SOX2 expression was associated with increased H3K27me3 repressive histone mark, which has not been reported in the literature. Taken together, we have shown CaMK2A plays a role in lung adenocarcinoma and TIC maintenance through histone modification and regulation of SOX2 expression. Targeting TIC through CaMK2A modulation might be useful for overcoming drug resistance and improving long term lung cancer survival

SRC kinase promotes survival and invasion of non-small cell lung cancer cells with epidermal growth factor receptor abnormalities and is a potential candidate for combination targeted therapy

Epidermal growth factor receptor (EGFR) mutations are common in female non-smoking non-small cell lung cancer (NSCLC) patients in Hong Kong. Tyrosine kinase inhibitor (TKI) against EGFR is an effective therapy for tumors with EGFR activating mutations. However, drug resistance due to second EGFR mutations or unknown mechanisms is frequently observed. Although Src is a mutual activator of EGFR, the effect of Src kinase inhibition on NSCLC is not fully known. To study the potential usefulness of Src kinase inhibition in treating NSCLC, we examined the effects of a specific Src inhibitor 4-(4’-Phenoxyanilino)-6,7-dimethoxyquinazolinee (SKI-1), alone or combined with TKI treatment, on apoptosis and invasion as well as the activation profiles of Src, EGFR and their downstream mediators in NSCLC cells harboring different EGFR abnormalities. SKI-1 specificity was validated by Src siRNA knockdown. Phosphorylation studies showed higher basal Src activities (pY416) in mutant (MT)-EGFR NSCLC cells (exon 19 deletion in HCC827; L858R substitution in FA31; L858R+T790M double substitution in H1975; amplification in H1819) than wild-type (WT) cells (H358 and HKULC2). The results suggest that NSCLC cells harboring MT-EGFR are more sensitive to SKI due to enhancement of basal Src kinase activation by MT-EGFR. Immunohistochemical study of clinical cancers showed correlation of Src activation and EGFR expression. Analysis using Hoechst 33258 staining, TUNEL, flow cytometry and PARP cleavage showed SKI-1 significantly induced apoptosis in H1819 and HCC827 but not H358 cells in a dose dependent manner. Co-treatment with SKI-1 and gefitinib (Iressa) synergistically enhanced apoptosis in FA31 and H1819 cells, suggesting a new combination treatment regime for NSCLC. Furthermore, SKI-1 significantly inhibited invasion and migration in cells with EGFR alterations in a dose dependent manner using Matrigel chamber and wound healing assays. The inhibition-profile of EGFR phosphorylation implicates that induction of apoptosis and sensitivity of HCC827 and H1819 to SKI treatment is in part related to EGFR downstream targets including Stat 3/5, ERK1/2 and Akt pathways. Phosphorylation of FAK and p130Cas is involved in Src-mediated invasion in SKI-1 sensitive cells, suggesting the involvement of Src in lung cancer metastasis. Overall, the findings indicate that Src kinase pathway could be a useful target for combination molecular treatment of NSCLC. We further suggest EGFR DNA sequence alterations are not the only factors that determine SKI sensitivity; other forms of abnormalities in EGFR may also be important determinants