2,003 research outputs found
Understanding the response to EGFR targeting therapy in non-small-cell lung cancer using -omics approach
NSCLC is the leading cause of cancer-related death worldwide. EGFR targeted therapy is
used to inhibit the progress of NSCLC, but patients inevitably develop resistance to EGFRTKIs.
The work presented in this thesis aimed at better understanding response and resistance
mechanisms to EGFR-TKIs in NSCLC and to find novel biomarkers as well as drug targets
or combination therapies for NSCLC.
Paper I suggested a group of miRNAs with AAGUGC motif as oncomotif-miRNAs. Through
the control of their target tumor suppressors, the oncomotif-miRNAs are part of the
oncogenic signaling network that regulates NSCLC’s and other types of cancer’s cell
proliferation.
Paper II identified that BCL6, FGFR2, and JAK3 were upregulated after EGFR-TKI
treatment. Moreover, BCL6 together with EGFR were confirmed to contribute to treatment
escape. Dual targeting of BCL6 and EGFR could therefore be a potential combination
therapy for treating NSCLC.
Paper III reported that CDKN2A loss is associated with EGFR-TKIs sensitivity in EGFRwt
NSCLC, and that BCL2L1 (encoding for BCL-xL) overexpression existed before EGFR-TKI
treatment in a subset of EGFR-TKI responding cell lines. Additionally, EGFRwt/KRASwt,
CDKN2A deleted NSCLC is sensitive to BCL-xL and EGFR dual inhibition, which could be
a potential combination therapy for patients with this profile. These findings suggest that
CDKN2A deletion can be used as a biomarker to select EGFRwt KRASwt patients for EGFRTKI
based combination therapy.
Paper IV identified the upregulation of AXL and GAS6, EMT, MAPK pathway reactivation,
and AXL dependent CDK1 phosphorylation as potential resistance mechanisms of the thirdgeneration
EGFR-TKIs.
The work summarized in this thesis add new knowledge to understand the EGFR-TKI
response and resistance mechanisms in NSCLC. From our work CDKN2A and oncomotifmiRNA
have been identified as interesting candidates that can be investigated for use as
biomarkers in NSCLC. Moreover, we propose that BCL6 or BCL-xL inhibitors together with
EGFR-TKIs should be further investigated as a combination therapy
DEqMS : A Method for Accurate Variance Estimation in Differential Protein Expression Analysis
Quantitative proteomics by mass spectrometry is widely used in biomarker research and basic biology research for investigation of phenotype level cellular events. Despite the wide application, the methodology for statistical analysis of differentially expressed proteins has not been unified. Various methods such as t test, linear model and mixed effect models are used to define changes in proteomics experiments. However, none of these methods consider the specific structure of MS-data. Choices between methods, often originally developed for other types of data, are based on compromises between features such as statistical power, general applicability and user friendliness. Furthermore, whether to include proteins identified with one peptide in statistical analysis of differential protein expression varies between studies. Here we present DEqMS, a robust statistical method developed specifically for differential protein expression analysis in mass spectrometry data. In all data sets investigated there is a clear dependence of variance on the number of PSMs or peptides used for protein quantification. DEqMS takes this feature into account when assessing differential protein expression. This allows for a more accurate data-dependent estimation of protein variance and inclusion of single peptide identifications without increasing false discoveries. The method was tested in several data sets including E. coli proteome spike-in data, using both label-free and TMT-labeled quantification. Compared with previous statistical methods used in quantitative proteomics, DEqMS showed consistently better accuracy in detecting altered protein levels compared with other statistical methods in both label-free and labeled quantitative proteomics data. DEqMS is available as an R package in Bioconductor.Peer reviewe
First-principles calculation of topological invariants Z2 within the FP-LAPW formalism
In this paper, we report the implementation of first-principles calculations
of topological invariants Z2 within the full-potential linearized augmented
plane-wave (FP-LAPW) formalism. In systems with both time-reversal and spatial
inversion symmetry (centrosymmetric), one can use the parity analysis of Bloch
functions at time-reversal invariant momenta to determine the Z2 invariants. In
systems without spatial inversion symmetry (noncentrosymmetric), however, a
more complex and systematic method in terms of the Berry gauge potential and
the Berry curvature is required to identify the band topology. We show in
detail how both methods are implemented in FP-LAPW formalism and applied to
several classes of materials including centrosymmetric compounds Bi2Se3 and
Sb2Se3 and noncentrosymmetric compounds LuPtBi, AuTlS2 and CdSnAs2. Our work
provides an accurate and effective implementation of first-principles
calculations to speed up the search of new topological insulators
Computing Optical Properties of Ultra-thin Crystals
An overview is given of recent advances in experimental and theoretical
understanding of optical properties of ultra-thin crystal structures (graphene,
phosphorene, silicene, MoS2, MoSe2 , WS2 , WSe2 , h-AlN, h-BN, fluorographene,
graphane). Ultra-thin crystals are atomically-thick layered crystals that have
unique properties which differ from their 3D counterpart. Because of the
difficulties in the synthesis of few-atom-thick crystal structures, which are
thought to be the main building blocks of future nanotechnology, reliable
theoretical predictions of their electronic, vibrational and optical properties
are of great importance. Recent studies revealed the reliable predictive power
of existing theoretical approaches based on density functional theory (DFT)
Origination of New Immunological Functions in the Costimulatory Molecule B7-H3: The Role of Exon Duplication in Evolution of the Immune System
B7-H3, a recently identified B7 family member, has different isoforms in human and mouse. Mouse B7-H3 gene has only one isoform (2IgB7-H3) with two Ig-like domains, whereas human B7-H3 has two isoforms (2IgB7-H3 and 4IgB7-H3). In this study a systematic genomic survey across various species from teleost fishes to mammals revealed that 4IgB7-H3 isoform also appeared in pigs, guinea pigs, cows, dogs, African elephants, pandas, megabats and higher primate animals, which resulted from tandem exon duplication. Further sequence analysis indicated that this duplication generated a new conserved region in the first IgC domain, which might disable 4IgB7-H3 from releasing soluble form, while 2IgB7-H3 presented both membrane and soluble forms. Through three-dimensional (3D) structure modeling and fusion-protein binding assays, we discovered that the duplicated isoform had a different structure and might bind to another potential receptor on activated T cells. In T cell proliferation assay, human 2IgB7-H3 (h2IgB7-H3) and mouse B7-H3 (mB7-H3) both increased T cell proliferation and IL-2, IFN-γ production, whereas human 4IgB7-H3 (h4IgB7-H3) reduced cytokine production and T cell proliferation compared to control. Furthermore, both h2IgB7-H3 and mB7-H3 upregulated the function of lipopolysacharide (LPS)-activated monocyte in vitro. Taken together, our data implied that during the evolution of vertebrates, B7-H3 exon duplication contributed to the generation of a new 4IgB7-H3 isoform in many mammalian species, which have carried out distinct functions in the immune responses
Operon prediction in Pyrococcus furiosus
Identification of operons in the hyperthermophilic archaeon Pyrococcus furiosus represents an important step to understanding the regulatory mechanisms that enable the organism to adapt and thrive in extreme environments. We have predicted operons in P.furiosus by combining the results from three existing algorithms using a neural network (NN). These algorithms use intergenic distances, phylogenetic profiles, functional categories and gene-order conservation in their operon prediction. Our method takes as inputs the confidence scores of the three programs, and outputs a prediction of whether adjacent genes on the same strand belong to the same operon. In addition, we have applied Gene Ontology (GO) and KEGG pathway information to improve the accuracy of our algorithm. The parameters of this NN predictor are trained on a subset of all experimentally verified operon gene pairs of Bacillus subtilis. It subsequently achieved 86.5% prediction accuracy when applied to a subset of gene pairs for Escherichia coli, which is substantially better than any of the three prediction programs. Using this new algorithm, we predicted 470 operons in the P.furiosus genome. Of these, 349 were validated using DNA microarray data
Comparative Analysis of PvPAP Gene Family and Their Functions in Response to Phosphorus Deficiency in Common Bean
BACKGROUND: Purple acid phosphatases (PAPs) play a vital role in adaptive strategies of plants to phosphorus (P) deficiency. However, their functions in relation to P efficiency are fragmentary in common bean. PRINCIPAL FINDINGS: Five PvPAPs were isolated and sequenced in common bean. Phylogenetic analysis showed that PvPAPs could be classified into two groups, including a small group with low molecular mass, and a large group with high molecular mass. Among them, PvPAP3, PvPAP4 and PvPAP5 belong to the small group, while the other two belong to the large group. Transient expression of 35S:PvPAPs-GFP on onion epidermal cells verified the variations of subcellular localization among PvPAPs, suggesting functional diversities of PvPAPs in common bean. Quantitative PCR results showed that most PvPAPs were up-regulated by phosphate (Pi) starvation. Among them, the expression of the small group PvPAPs responded more to Pi starvation, especially in the roots of G19833, the P-efficient genotype. However, only overexpressing PvPAP1 and PvPAP3 could result in significantly increased utilization of extracellular dNTPs in the transgenic bean hairy roots. Furthermore, overexpressing PvPAP3 in Arabidopsis enhanced both plant growth and total P content when dNTPs were supplied as the sole external P source. CONCLUSIONS: The results suggest that PvPAPs in bean varied in protein structure, response to P deficiency and subcellular localization. Among them, both PvPAP1 and PvPAP3 might function as utilization of extracellular dNTPs
Small Interfering RNA Targeting M2 Gene Induces Effective and Long Term Inhibition of Influenza A Virus Replication
RNA interference (RNAi) provides a powerful new means to inhibit viral infection specifically. However, the selection of siRNA-resistant viruses is a major concern in the use of RNAi as antiviral therapeutics. In this study, we conducted a lentiviral vector with a H1-short hairpin RNA (shRNA) expression cassette to deliver small interfering RNAs (siRNAs) into mammalian cells. Using this vector that also expresses enhanced green fluorescence protein (EGFP) as surrogate marker, stable shRNA-expressing cell lines were successfully established and the inhibition efficiencies of rationally designed siRNAs targeting to conserved regions of influenza A virus genome were assessed. The results showed that a siRNA targeting influenza M2 gene (siM2) potently inhibited viral replication. The siM2 was not only effective for H1N1 virus but also for highly pathogenic avian influenza virus H5N1. In addition to its M2 inhibition, the siM2 also inhibited NP mRNA accumulation and protein expression. A long term inhibition effect of the siM2 was demonstrated and the emergence of siRNA-resistant mutants in influenza quasispecies was not observed. Taken together, our study suggested that M2 gene might be an optimal RNAi target for antiviral therapy. These findings provide useful information for the development of RNAi-based prophylaxis and therapy for human influenza virus infection
Winter Refuge for Aedes aegypti and Ae. albopictus Mosquitoes in Hanoi during Winter
Dengue occurs throughout the year in Hanoi, Vietnam, despite winter low temperatures 14°C, exceeding the developmental zero point of Ae. aegypti. Although jars, drums and concrete tanks were the dominant containers previously (1994-97) in Hanoi, currently the percentage of residences with concrete tanks was still high while jars and drums were quite low. Our study showed that concrete tanks with broken lids allowing mosquitoes access were important winter refuge for Ae. aegypti. We also indicate a concern about concrete tanks serving as foci for Ae. aegypti to expand their distribution in cooler regions
Sustained proliferation in cancer: mechanisms and novel therapeutic targets
Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression
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