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author:("Gao, qing")
1.  DIFFERENCES IN THE TRANSCRIPTIONAL RESPONSE TO FULVESTRANT AND OESTROGEN DEPRIVATION IN ER-POSITIVE BREAST CANCER 
Purpose
Endocrine therapies include aromatase inhibitors and the selective oestrogen receptor (ER) down-regulator fulvestrant. This study aimed to determine if the reported efficacy of fulvestrant over anastrozole, and high- over low-dose fulvestrant, reflect distinct transcriptional responses.
Experimental design
Global gene expression profiles from ERα-positive breast carcinomas before and during pre-surgical treatment with fulvestrant (n=22) or anastrozole (n=81), and corresponding in vitro models, were compared. Transcripts responding differently to fulvestrant and oestrogen (E) deprivation were identified and integrated using gene ontology (GO), pathway and network analyses to evaluate their potential significance.
Results
The overall transcriptional response to fulvestrant and E-deprivation was correlated (r=0.61 in pre-surgical studies, r=0.87 in vitro), involving down-regulation of E-regulated and proliferation-associated genes. The transcriptional response to fulvestrant was of greater magnitude than E-deprivation (slope=0.62 in pre-surgical studies, slope=0.63 in vitro). Comparative analyses identified 28 genes and 40 GO categories affected specifically by fulvestrant. Seventeen fulvestrant-specific genes, including CAV1/2, SNAI2 and NRP1, associated with ERα, androgen receptor (AR) and TP53, in a network regulating cell cycle, death, survival, and tumour morphology. Eighteen genes responding differently to fulvestrant specifically predicted anti-proliferative response to fulvestrant, but not anastrozole. Transcriptional effects of low-dose fulvestrant correlated with high-dose treatment, but were of lower magnitude (ratio=0.29).
Conclusions
The transcriptional response to fulvestrant has much in common with E-deprivation, but is stronger with distinctions potentially attributable to arrest of E-independent ERα activity and involvement of AR signalling. Genes responding differently to fulvestrant may have predictive utility. These data are consistent with the clinical efficacy of fulvestrant versus anastrozole and higher dosing regimens.
doi:10.1158/1078-0432.CCR-13-1378
PMCID: PMC4119788  PMID: 24916694
Breast cancer; oestrogen; estrogen; oestrogen receptor; estrogen receptor; oestrogen deprivation; aromatase inhibitor; fulvestrant
2.  Discerning Fragmentation Dynamics of Tropical Forest and Wetland during Reforestation, Urban Sprawl, and Policy Shifts 
PLoS ONE  2014;9(11):e113140.
Despite the overall trend of worldwide deforestation over recent decades, reforestation has also been found and is expected in developing countries undergoing fast urbanization and agriculture abandonment. The consequences of reforestation on landscape patterns are seldom addressed in the literature, despite their importance in evaluating biodiversity and ecosystem functions. By analyzing long-term land cover changes in Puerto Rico, a rapidly reforested (6 to 42% during 1940–2000) and urbanized tropical island, we detected significantly different patterns of fragmentation and underlying mechanisms among forests, urban areas, and wetlands. Forest fragmentation is often associated with deforestation. However, we also found significant fragmentation during reforestation. Urban sprawl and suburb development have a dominant impact on forest fragmentation. Reforestation mostly occurs along forest edges, while significant deforestation occurs in forest interiors. The deforestation process has a much stronger impact on forest fragmentation than the reforestation process due to their different spatial configurations. In contrast, despite the strong interference of coastal urbanization, wetland aggregation has occurred due to the effective implementation of laws/regulations for wetland protection. The peak forest fragmentation shifted toward rural areas, indicating progressively more fragmentation in forest interiors. This shift is synchronous with the accelerated urban sprawl as indicated by the accelerated shift of the peak fragmentation index of urban cover toward rural areas, i.e., 1.37% yr−1 in 1977–1991 versus 2.17% yr−1 in 1991–2000. Based on the expected global urbanization and the regional forest transition from deforested to reforested, the fragmented forests and aggregated wetlands in this study highlight possible forest fragmentation processes during reforestation in an assessment of biodiversity and functions and suggest effective laws/regulations in land planning to reduce future fragmentation.
doi:10.1371/journal.pone.0113140
PMCID: PMC4237398  PMID: 25409016
3.  Identification of chemokine receptors as potential modulators of endocrine resistance in oestrogen receptor–positive breast cancers 
Introduction
Endocrine therapies target oestrogenic stimulation of breast cancer (BC) growth, but resistance remains problematic. Our aims in this study were (1) to identify genes most strongly associated with resistance to endocrine therapy by intersecting global gene transcription data from patients treated presurgically with the aromatase inhibitor anastrazole with those from MCF7 cells adapted to long-term oestrogen deprivation (LTED) (2) to assess the clinical value of selected genes in public clinical data sets and (3) to determine the impact of targeting these genes with novel agents.
Methods
Gene expression and Ki67 data were available from 69 postmenopausal women with oestrogen receptor–positive (ER+) early BC, at baseline and 2 weeks after anastrazole treatment, and from cell lines adapted to LTED. The functional consequences of target genes on proliferation, ER-mediated transcription and downstream cell signalling were assessed.
Results
By intersecting genes predictive of a poor change in Ki67 with those upregulated in LTED cells, we identified 32 genes strongly correlated with poor antiproliferative response that were associated with inflammation and/or immunity. In a panel of LTED cell lines, C-X-C chemokine receptor type 7 (CXCR7) and CXCR4 were upregulated compared to their wild types (wt), and CXCR7, but not CXCR4, was associated with reduced relapse-free survival in patients with ER+ BC. The CXCR4 small interfering RNA variant (siCXCR4) had no specific effect on the proliferation of wt-SUM44, wt-MCF7 and their LTED derivatives. In contrast, siCXCR7, as well as CCX733, a CXCR7 antagonist, specifically suppressed the proliferation of MCF7-LTED cells. siCXCR7 suppressed proteins associated with G1/S transition and inhibited ER transactivation in MCF7-LTED, but not wt-MCF7, by impeding association between ER and proline-, glutamic acid– and leucine-rich protein 1, an ER coactivator.
Conclusions
These data highlight CXCR7 as a potential therapeutic target warranting clinical investigation in endocrine-resistant BC.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0447-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-014-0447-1
PMCID: PMC4303127  PMID: 25358600
4.  A TRP Channel in the Lysosome Regulates Large Particle Phagocytosis via Focal Exocytosis 
Developmental cell  2013;26(5):511-524.
Summary
Phagocytosis of large extracellular particles such as apoptotic bodies requires delivery of the intracellular endosomal and lysosomal membranes to form plasmalemmal pseudopods. Here we identified Mucolipin TRP channel 1 (TRPML1) as the key lysosomal Ca2+ channel regulating focal exocytosis and phagosome biogenesis. Both particle ingestion and lysosomal exocytosis are inhibited by synthetic TRPML1 blockers, and are defective in macrophages isolated from TRPML1 knockout mice. Furthermore, TRPML1 overexpression and TRPML1 agonists facilitate both lysosomal exocytosis and particle uptake. Using time-lapse confocal imaging and direct patch-clamping of phagosomal membranes, we found that particle binding induces lysosomal PI(3,5)P2 elevation to trigger TRPML1-mediated lysosomal Ca2+ release specifically at the site of uptake, rapidly delivering TRPML1-resident lysosomal membranes to nascent phagosomes via lysosomal exocytosis. Thus phagocytic ingestion of large particles activates a phosphoinositide- and Ca2+- dependent exocytosis pathway to provide membranes necessary for pseudopod extension, leading to clearance of senescent and apoptotic cells in vivo.
doi:10.1016/j.devcel.2013.08.003
PMCID: PMC3794471  PMID: 23993788
Lysosomal exocytosis; Phagocytosis; Phagosome; Membrane trafficking; Ca2+ release
5.  Relationship of PIK3CA mutation and pathway activity with antiproliferative response to aromatase inhibition 
Introduction
PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α) somatic mutations are the most common genetic alteration in breast cancer (BC). Their prognostic value and that of the phosphatidylinositol 3-kinase (PI3K) pathway in BC remains only partly defined. The effect of PIK3CA mutations and alterations of the PI3K pathway on the antiproliferative response to aromatase inhibitor treatment was determined.
Methods
The Sequenom MassARRAY System was used to determine the presence of 20 somatic mutations across the PIK3CA gene in 85 oestrogen receptor–positive (ER+) BC patients treated with 2 weeks of anastrozole before surgery. Whole-genome expression profiles were used to interrogate gene signatures (GSs) associated with the PI3K pathway. Antiproliferative activity was assessed by the change in Ki67 staining between baseline and surgery. Three GSs representing the PI3K pathway were assessed (PIK3CA-GS (Loi), PI3K-GS (Creighton) and PTEN-loss-GS (Saal)).
Results
In our study sample, 29% of tumours presented with either a hotspot (HS, 71%) or a nonhotspot (non-HS, 29%) PIK3CA mutation. Mutations were associated with markers of good prognosis such as progesterone receptor positivity (PgR+) (P = 0.006), low grade (P = 0.028) and luminal A subtype (P = 0.039), with a trend towards significance with degree of ER positivity (P = 0.051) and low levels of Ki67 (P = 0.051). Non-HS mutations were associated with higher PgR (P = 0.014) and ER (P < 0.001) expression than both wild-type (WT) and HS-mutated samples, whereas neither biomarker differed significantly between WT and HS mutations or between HS and non-HS mutations. An inverse correlation was found between the Loi signature and both the Creighton and Saal signatures, and a positive correlation was found between the latter signatures. Lower pretreatment Ki67 levels were observed in mutation compared with WT samples (P = 0.051), which was confirmed in an independent data set. Mutation status did not predict change in Ki67 in response to 2 weeks of anastrozole treatment; there was no significant difference between HS and non-HS mutations in this regard.
Conclusions
PIK3CA mutations are associated with classical markers of good prognosis and signatures of PI3K pathway activity. The presence of a PIK3CA mutation does not preclude a response to neoadjuvant anastrozole treatment.
doi:10.1186/bcr3683
PMCID: PMC4227109  PMID: 24981670
6.  Downregulation of the transcription factor, FoxD3, is associated with lymph node metastases in invasive ductal carcinomas of the breast 
FoxD3 is a transcription factor of the forkhead gene family. We investigated its expression in invasive ductal carcinomas (IDC) of the breast and its association with metastasis. The expression of FoxD3, human epidermal growth factor receptor-2 (HER-2), estrogen receptor (ER), progesterone receptor (PR) and Ki67 was examined by immunohistochemistry in samples from 121 patients with IDC. Non-tumorous breast adenosis tissues served as controls. HER2 expression was confirmed by fluorescence in situ hybridization (FISH). The expression levels of FoxD3 in IDC tissues and the breast cancer cell lines MCF-7 and MDA-MB-231 were additionally measured by western blotting. A greater percentage of total IDC patients and patients with lymph node metastases showed reduced FoxD3 expression compared to adenosis controls (p<0.05). Overall, FoxD3 was associated with metastatic status of IDC but not with age, pathological or clinical staging, or status of HER-2, ER, or PR. In particular, FoxD3 protein expression was down-regulated in the tumor epithelia of IDC samples from patients with metastases. Furthermore, FoxD3 protein expression was decreased in the metastatic MDA-MB-231 breast cancer cell line relative to the non-metastatic cell line, MCF-7. A greater number of patients with invasive, triple-negative breast cancer were also negative for FoxD3 expression than in other, non-triple-negative tumor types. These results suggest an inverse relationship between FoxD3 expression and tumor metastasis and warrants further investigation.
PMCID: PMC3925912  PMID: 24551288
Breast cancer; invasive ductal carcinomas; FoxD3; HER-2
7.  Detecting the Differences in Responses of Stomatal Conductance to Moisture Stresses between Deciduous Shrubs and Artemisia Subshrubs 
PLoS ONE  2013;8(12):e84200.
Shrubs and subshrubs can tolerate wider ranges of moisture stresses in both soil and air than other plant life forms, and thus represent greater nonlinearity and uncertainty in ecosystem physiology. The objectives of this paper are to model shrub/subshrub stomatal conductance by synthesizing the field leaf gas exchanges data of 24 species in China, in order to detect the differences between deciduous shrubs and Artemisia subshrubs in their responses of stomatal conductance to changes in the moisture stresses. We revised a model of stomatal conductance by incorporating the tradeoff between xylem hydraulic efficiency and cavitation loss risk. We then fit the model at the three hierarchical levels: global (pooling all data as a single group), three functional groups (deciduous non-legume shrubs, deciduous legume shrubs, and subshrubs in Artemisia genus), and individual observations (species × sites). Bayesian inference with Markov Chain Monte Carlo method was applied to obtain the model parameters at the three levels. We found that the model at the level of functional groups is a significant improvement over that at the global level, indicating the significant differences in the stomatal behavior among the three functional groups. The differences in tolerance and sensitivities to changes in moisture stresses are the most evident between the shrubs and the subshrubs: The two shrub groups can tolerate much higher soil water stress than the subshrubs. The analysis at the observation level is also a significant improvement over that at the functional group level, indicating great variations within each group. Our analysis offered a clue for the equivocal issue of shrub encroachment into grasslands: While the invasion by the shrubs may be irreversible, the dominance of subshrubs, due to their lower resistance and tolerance to moisture stresses, may be put down by appropriate grassland management.
doi:10.1371/journal.pone.0084200
PMCID: PMC3875489  PMID: 24386351
8.  GDNF-RET signaling in ER-positive breast cancers is a key determinant of response and resistance to aromatase inhibitors 
Cancer research  2013;73(12):3783-3795.
Most breast cancers at diagnosis are estrogen receptor (ER)-positive and depend on estrogen for growth and survival. Blocking estrogen biosynthesis by aromatase inhibitors (AI) has therefore become a first-line endocrine therapy for post-menopausal women with ER-positive breast cancers. Despite providing substantial improvements in patient outcome, AI resistance remains a major clinical challenge. The receptor tyrosine kinase RET and its co-receptor GFRα1 are upregulated in a subset of ER-positive breast cancers, and the RET ligand, glial-derived neurotrophic factor (GDNF) is upregulated by inflammatory cytokines. Here we report the findings of a multidisciplinary strategy to address the impact of GDNF-RET signaling in the response to AI treatment. In breast cancer cells in 2D and 3D culture, GDNF-mediated RET signaling is enhanced in a model of AI resistance. Further, GDNF-RET signaling promoted the survival of AI-resistant cells and elicited resistance in AI-sensitive cells. Both these effects were selectively reverted by the RET kinase inhibitor NVP-BBT594. Gene expression profiling in ER-positive cancers defined a proliferation-independent GDNF-response signature that prognosed poor patient outcome and, more importantly, predicted poor response to AI treatment with the development of resistance. We validated these findings by demonstrating increased RET protein expression levels in an independent cohort of AI-resistant patient specimens. Together, our results establish GDNF-RET signaling as a rational therapeutic target to combat or delay the onset of AI resistance in breast cancer.
doi:10.1158/0008-5472.CAN-12-4265
PMCID: PMC3686594  PMID: 23650283
aromatase inhibitor; breast cancer; GDNF; resistance; RET
9.  Interaction of Carbamazepine with Herbs, Dietary Supplements, and Food: A Systematic Review 
Background. Carbamazepine (CBZ) is a first-line antiepileptic drug which may be prone to drug interactions. Systematic review of herb- and food-drug interactions on CBZ is warranted to provide guidance for medical professionals when prescribing CBZ. Method. A systematic review was conducted on six English databases and four Chinese databases. Results. 196 out of 3179 articles fulfilled inclusion criteria, of which 74 articles were reviewed and 33 herbal products/dietary supplement/food interacting with CBZ were identified. No fatal or severe interactions were documented. The majority of the interactions were pharmacokinetic-based (80%). Traditional Chinese medicine accounted for most of the interactions (n = 17), followed by food (n = 10), dietary supplements (n = 3), and other herbs/botanicals (n = 3). Coadministration of 11 and 12 of the studied herbal products/dietary supplement/food significantly decreased or increased the plasma concentrations of CBZ. Regarding pharmacodynamic interaction, Xiao-yao-san, melatonin, and alcohol increased the side effects of CBZ while caffeine lowered the antiepileptic efficacy of CBZ. Conclusion. This review provides a comprehensive summary of the documented interactions between CBZ and herbal products/food/dietary supplements which assists healthcare professionals to identify potential herb-drug and food-drug interactions, thereby preventing potential adverse events and improving patients' therapeutic outcomes when prescribing CBZ.
doi:10.1155/2013/898261
PMCID: PMC3760091  PMID: 24023584
11.  A Polymorphism in a Gene Encoding Perilipin 4 Is Associated with Height but not with Bone Measures in Individuals from the Framingham Osteoporosis Study 
Calcified tissue international  2011;90(2):96-107.
There is increasing interest in identifying new pathways and candidate genes that confer susceptibility to osteoporosis. There is evidence that adipogenesis and osteogenesis may be related, including a common bone marrow progenitor cell for both adipocytes and osteoblasts. Perilipin 1 (PLIN1) and Perilipin 4 (PLIN4) are members of the PATS family of genes and are involved in lipolysis of intracellular lipid deposits. A previous study reported gender-specific associations between one polymorphism of PLIN1 and bone mineral density (BMD) in a Japanese population. We hypothesized that polymorphisms in PLIN1 and PLIN4 would be associated with bone measures in adult Caucasian participants of the Framingham Osteoporosis Study (FOS). We genotyped 1,206 male and 1,445 female participants of the FOS for four single-nucleotide polymorphism (SNPs) in PLIN1 and seven SNPs in PLIN4 and tested for associations with measures of BMD, bone ultrasound, hip geometry, and height. We found several gender-specific significant associations with the measured traits. The association of PLIN4 SNP rs8887, G>A with height in females trended toward significance after simulation testing (adjusted P = 0.07) and remained significant after simulation testing in the combined-sex model (adjusted P = 0.033). In a large study sample of men and women, we found a significant association between one SNP in PLIN4 and height but not with bone traits, suggesting that PATS family genes are not important in the regulation of bone. Identification of genes that influence human height may lead to a better understanding of the processes involved in growth and development.
doi:10.1007/s00223-011-9552-7
PMCID: PMC3628693  PMID: 22210160
Perilipin 1; Perilipin 4; Bone mineral density; Bone geometry; Framingham Osteoporosis Study
12.  Embryonic mammary signature subsets are activated in Brca1-/- and basal-like breast cancers 
Introduction
Cancer is often suggested to result from development gone awry. Links between normal embryonic development and cancer biology have been postulated, but no defined genetic basis has been established. We recently published the first transcriptomic analysis of embryonic mammary cell populations. Embryonic mammary epithelial cells are an immature progenitor cell population, lacking differentiation markers, which is reflected in their very distinct genetic profiles when compared with those of their postnatal descendents.
Methods
We defined an embryonic mammary epithelial signature that incorporates the most highly expressed genes from embryonic mammary epithelium when compared with the postnatal mammary epithelial cells. We looked for activation of the embryonic mammary epithelial signature in mouse mammary tumors that formed in mice in which Brca1 had been conditionally deleted from the mammary epithelium and in human breast cancers to determine whether any genetic links exist between embryonic mammary cells and breast cancers.
Results
Small subsets of the embryonic mammary epithelial signature were consistently activated in mouse Brca1-/- tumors and human basal-like breast cancers, which encoded predominantly transcriptional regulators, cell-cycle, and actin cytoskeleton components. Other embryonic gene subsets were found activated in non-basal-like tumor subtypes and repressed in basal-like tumors, including regulators of neuronal differentiation, transcription, and cell biosynthesis. Several embryonic genes showed significant upregulation in estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and/or grade 3 breast cancers. Among them, the transcription factor, SOX11, a progenitor cell and lineage regulator of nonmammary cell types, is found highly expressed in some Brca1-/- mammary tumors. By using RNA interference to silence SOX11 expression in breast cancer cells, we found evidence that SOX11 regulates breast cancer cell proliferation and cell survival.
Conclusions
Specific subsets of embryonic mammary genes, rather than the entire embryonic development transcriptomic program, are activated in tumorigenesis. Genes involved in embryonic mammary development are consistently upregulated in some breast cancers and warrant further investigation, potentially in drug-discovery research endeavors.
doi:10.1186/bcr3403
PMCID: PMC3672751  PMID: 23506684
13.  miR-141 Contributes to Fetal Growth Restriction by Regulating PLAG1 Expression 
PLoS ONE  2013;8(3):e58737.
Background
Fetal growth restriction (FGR) is an important but poorly understood condition of pregnancy, which results in significant fetal, neonatal and long-term morbidity and mortality. Novel research has suggested that altered miRNA expression in the plasma and placenta is associated with adverse pregnancy. We hypothesized that aberrant expression of microRNA-141 (miR-141) in the placenta is associated with FGR. Additionally, expression levels of predicted target genes of miR-141 were also analyzed in placental tissues of FGR and normal controls.
Methodology/Principal Findings
Using quantitative real time PCR, we analyzed the expression level of miR-141 and its target genes in placentas of FGR pregnancies (n = 21) and normal controls (n = 34). Western blot was used to detect the protein expression level of the target genes of miR-141. MiR-141 showed significant up regulation in FGR and significant down regulation of its targets, i.e. E2F transcription factor 3 (E2F3) protein, pleiomorphic adenoma gene 1 (PLAG1) mRNA and protein. Moreover, a positive correlation was found between PLAG1 and insulin-like growth factor 2 (IGF2) expression levels (Spearman r = 0.56, p<0.0001). MiR-141 yields an AUC of 0.83 with 88.5% sensitivity and 71.7% specificity for separating FGR from normal controls. This study indicates that miR-141 may be diagnostically important in FGR.
Conclusions/Significance
Our results indicate that aberrant high expression level of miR-141 might play important roles in the pathogenesis of FGR by suppressing E2F3 and PLAG1. We propose that miR-141 may participate in a miR-141-PLAG1-IGF2 network relating to FGR development. These findings may provide new targets via miR-141 in diagnosis and therapy of FGR in the future.
doi:10.1371/journal.pone.0058737
PMCID: PMC3598866  PMID: 23554918
14.  Leaf-traits and growth allometry explain competition and differences in response to climatic change in a temperate forest landscape: a simulation study 
Annals of Botany  2011;108(5):885-894.
Background and Aims
The ability to simulate plant competition accurately is essential for plant functional type (PFT)-based models used in climate-change studies, yet gaps and uncertainties remain in our understanding of the details of the competition mechanisms and in ecosystem responses at a landscape level. This study examines secondary succession in a temperate deciduous forest in eastern China with the aim of determining if competition between tree types can be explained by differences in leaf ecophysiological traits and growth allometry, and whether ecophysiological traits and habitat spatial configurations among PFTs differentiate their responses to climate change.
Methods
A temperate deciduous broadleaved forest in eastern China was studied, containing two major vegetation types dominated by Quercus liaotungensis (OAK) and by birch/poplar (Betula platyphylla and Populus davidiana; BIP), respectively. The Terrestrial Ecosystem Simulator (TESim) suite of models was used to examine carbon and water dynamics using parameters measured at the site, and the model was evaluated against long-term data collected at the site.
Key Results
Simulations indicated that a higher assimilation rate for the BIP vegetation than OAK led to the former's dominance during early successional stages with relatively low competition. In middle/late succession with intensive competition for below-ground resources, BIP, with its lower drought tolerance/resistance and smaller allocation to leaves/roots, gave way to OAK. At landscape scale, predictions with increased temperature extrapolated from existing weather records resulted in increased average net primary productivity (NPP; +19 %), heterotrophic respiration (+23 %) and net ecosystem carbon balance (+17 %). The BIP vegetation in higher and cooler habitats showed 14 % greater sensitivity to increased temperature than the OAK at lower and warmer locations.
Conclusions
Drought tolerance/resistance and morphology-related allocation strategy (i.e. more allocation to leaves/roots) played key roles in the competition between the vegetation types. The overall site-average impacts of increased temperature on NPP and carbon stored in plants were found to be positive, despite negative effects of increased respiration and soil water stress, with such impacts being more significant for BIP located in higher and cooler habitats.
doi:10.1093/aob/mcr218
PMCID: PMC3177688  PMID: 21835816
Succession; watershed; ecophysiological trait; landscape carbon dynamics; temperate forests; competition; simulation; Quercus liaotungensis; Betula platyphylla; Populus davidiana
15.  The PLIN4 Variant rs8887 Modulates Obesity Related Phenotypes in Humans through Creation of a Novel miR-522 Seed Site 
PLoS ONE  2011;6(4):e17944.
PLIN4 is a member of the PAT family of lipid storage droplet (LSD) proteins. Associations between seven single nucleotide polymorphisms (SNPs) at human PLIN4 with obesity related phenotypes were investigated using meta-analysis followed by a determination if these phenotypes are modulated by interactions between PLIN4 SNPs and dietary PUFA. Samples consisted of subjects from two populations of European ancestry. We demonstrated association of rs8887 with anthropometrics. Meta-analysis demonstrated significant interactions between the rs8887 minor allele with PUFA n3 modulating anthropometrics. rs884164 showed interaction with both n3 and n6 PUFA modulating anthropometric and lipid phenotypes. In silico analysis of the PLIN4 3′UTR sequence surrounding the rs8887 minor A allele predicted a seed site for the human microRNA-522 (miR-522), suggesting a functional mechanism. Our data showed that a PLIN4 3′UTR luciferase reporter carrying the A allele of rs8887 was reduced in response to miR-522 mimics compared to the G allele. These results suggest variation at the PLIN4 locus, and its interaction with PUFA as a modulator of obesity related phenotypes, acts in part through creation of a miR-522 regulatory site.
doi:10.1371/journal.pone.0017944
PMCID: PMC3080366  PMID: 21533135
16.  The FLIGHT Drosophila RNAi database 
Fly  2010;4(4):344-348.
FLIGHT (http://flight.icr.ac.uk/) is an online resource compiling data from high-throughput Drosophila in vivo and in vitro RNAi screens. FLIGHT includes details of RNAi reagents and their predicted off-target effects, alongside RNAi screen hits, scores and phenotypes, including images from high-content screens. The latest release of FLIGHT is designed to enable users to upload, analyze, integrate and share their own RNAi screens. Users can perform multiple normalizations, view quality control plots, detect and assign screen hits and compare hits from multiple screens using a variety of methods including hierarchical clustering. FLIGHT integrates RNAi screen data with microarray gene expression as well as genomic annotations and genetic/physical interaction datasets to provide a single interface for RNAi screen analysis and datamining in Drosophila.
doi:10.4161/fly.4.4.13303
PMCID: PMC3174485  PMID: 20855970
RNAi; database; integration; bioinformatics; phenotype
17.  O,O′-Diethyl {(Z)-[(2-chloro­phen­yl)(cyano)methyl­ene]amino­oxy}thio­phospho­nate 
The title mol­ecule, C12H14ClN2O3PS, has a cis configuration with respect to the C=N bond. Inter­molecular C—H⋯O inter­actions inter­connect the mol­ecules into chains along the c axis. The chains are further connected into a two-dimensional network parallel to the bc plane by weak π–π inter­actions between adjacent aromatic rings (centroid–centroid distance = 3.772Å).
doi:10.1107/S160053680900693X
PMCID: PMC2969034  PMID: 21582417
18.  MoKCa database—mutations of kinases in cancer 
Nucleic Acids Research  2008;37(Database issue):D824-D831.
Members of the protein kinase family are amongst the most commonly mutated genes in human cancer, and both mutated and activated protein kinases have proved to be tractable targets for the development of new anticancer therapies The MoKCa database (Mutations of Kinases in Cancer, http://strubiol.icr.ac.uk/extra/mokca) has been developed to structurally and functionally annotate, and where possible predict, the phenotypic consequences of mutations in protein kinases implicated in cancer. Somatic mutation data from tumours and tumour cell lines have been mapped onto the crystal structures of the affected protein domains. Positions of the mutated amino-acids are highlighted on a sequence-based domain pictogram, as well as a 3D-image of the protein structure, and in a molecular graphics package, integrated for interactive viewing. The data associated with each mutation is presented in the Web interface, along with expert annotation of the detailed molecular functional implications of the mutation. Proteins are linked to functional annotation resources and are annotated with structural and functional features such as domains and phosphorylation sites. MoKCa aims to provide assessments available from multiple sources and algorithms for each potential cancer-associated mutation, and present these together in a consistent and coherent fashion to facilitate authoritative annotation by cancer biologists and structural biologists, directly involved in the generation and analysis of new mutational data.
doi:10.1093/nar/gkn832
PMCID: PMC2686448  PMID: 18986996
19.  pSTIING: a ‘systems’ approach towards integrating signalling pathways, interaction and transcriptional regulatory networks in inflammation and cancer 
Nucleic Acids Research  2005;34(Database issue):D527-D534.
pSTIING () is a new publicly accessible web-based application and knowledgebase featuring 65 228 distinct molecular associations (comprising protein–protein, protein–lipid, protein–small molecule interactions and transcriptional regulatory associations), ligand–receptor–cell type information and signal transduction modules. It has a particular major focus on regulatory networks relevant to chronic inflammation, cell migration and cancer. The web application and interface provide graphical representations of networks allowing users to combine and extend transcriptional regulatory and signalling modules, infer molecular interactions across species and explore networks via protein domains/motifs, gene ontology annotations and human diseases. pSTIING also supports the direct cross-correlation of experimental results with interaction information in the knowledgebase via the CLADIST tool associated with pSTIING, which currently analyses and clusters gene expression, proteomic and phenotypic datasets. This allows the contextual projection of co-expression patterns onto prior network information, facilitating the identification of functional modules in physiologically relevant systems.
doi:10.1093/nar/gkj044
PMCID: PMC1347407  PMID: 16381926
20.  FLIGHT: database and tools for the integration and cross-correlation of large-scale RNAi phenotypic datasets 
Nucleic Acids Research  2005;34(Database issue):D479-D483.
FLIGHT () is a new database designed to help researchers browse and cross-correlate data from large-scale RNAi studies. To date, the majority of these functional genomic screens have been carried out using Drosophila cell lines. These RNAi screens follow 100 years of classical Drosophila genetics, but have already revealed their potential by ascribing an impressive number of functions to known and novel genes. This has in turn given rise to a pressing need for tools to simplify the analysis of the large amount of phenotypic information generated. FLIGHT aims to do this by providing users with a gene-centric view of screen results and by making it possible to cluster phenotypic data to identify genes with related functions. Additionally, FLIGHT provides microarray expression data for many of the Drosophila cell lines commonly used in RNAi screens. This, together with information about cell lines, protocols and dsRNA primer sequences, is intended to help researchers design their own cell-based screens. Finally, although the current focus of FLIGHT is Drosophila, the database has been designed to facilitate the comparison of functional data across species and to help researchers working with other systems navigate their way through the fly genome.
doi:10.1093/nar/gkj038
PMCID: PMC1347401  PMID: 16381916

Results 1-20 (20)