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Sample records for cancer revealed fragile

  1. Analysis of the molecular networks in androgen dependent and independent prostate cancer revealed fragile and robust subsystems.

    Directory of Open Access Journals (Sweden)

    Ryan Tasseff

    Full Text Available Androgen ablation therapy is currently the primary treatment for metastatic prostate cancer. Unfortunately, in nearly all cases, androgen ablation fails to permanently arrest cancer progression. As androgens like testosterone are withdrawn, prostate cancer cells lose their androgen sensitivity and begin to proliferate without hormone growth factors. In this study, we constructed and analyzed a mathematical model of the integration between hormone growth factor signaling, androgen receptor activation, and the expression of cyclin D and Prostate-Specific Antigen in human LNCaP prostate adenocarcinoma cells. The objective of the study was to investigate which signaling systems were important in the loss of androgen dependence. The model was formulated as a set of ordinary differential equations which described 212 species and 384 interactions, including both the mRNA and protein levels for key species. An ensemble approach was chosen to constrain model parameters and to estimate the impact of parametric uncertainty on model predictions. Model parameters were identified using 14 steady-state and dynamic LNCaP data sets taken from literature sources. Alterations in the rate of Prostatic Acid Phosphatase expression was sufficient to capture varying levels of androgen dependence. Analysis of the model provided insight into the importance of network components as a function of androgen dependence. The importance of androgen receptor availability and the MAPK/Akt signaling axes was independent of androgen status. Interestingly, androgen receptor availability was important even in androgen-independent LNCaP cells. Translation became progressively more important in androgen-independent LNCaP cells. Further analysis suggested a positive synergy between the MAPK and Akt signaling axes and the translation of key proliferative markers like cyclin D in androgen-independent cells. Taken together, the results support the targeting of both the Akt and MAPK

  2. Disabled-1 is a large common fragile site gene, inactivated in multiple cancers.

    Science.gov (United States)

    McAvoy, Sarah; Zhu, Yu; Perez, Damon S; James, C David; Smith, David I

    2008-02-01

    Common fragile sites (CFS) are large, genomically unstable regions, which are hot-spots for deletions and other alterations, especially in cancer cells. Several have been shown to contain genes that span large genomic regions, such as FHIT (1.5 Mb), WWOX (1.0 Mb), GRID2 (1.36 Mb), PARK2 (1.3 Mb), and RORA (730 kb). These genes are frequently inactivated in multiple different cancers, and FHIT and WWOX are shown to function as tumor suppressors. The disabled-1 gene (DAB1) is one of the human homologs of the Drosophila disabled locus, which in mammals is involved in neuronal migration and lamination in the developing cerebral cortex. Mice DAB1 inactivation results in the neurological mutant Scrambler, having similarities to mice with the inactivation of PARK2 (Quaker), GRID2 (Lurcher), and RORA (Staggerer). We were interested in whether DAB1 was another large CFS gene that could have cancer development importance. We demonstrated here that the human DAB1 gene (spanning 1.25 Mb) mapped within FRA1B CFS region on chromosomal band 1p32.2. Real-time RT-PCR analysis revealed that the expression level of DAB1 was decreased in many human cancer samples, including primary tumor tissues and cancer-derived cell lines, from several different cancers, especially in brain and endometrial cancer. Additionally, the introduction of an over-expression DAB1 plasmid into two different cell lines, having insignificant endogenous DAB1 expression, resulted in decreased cell growth. In summary, DAB1 is another gene that resides within an unstable CFS region and might play a role in human tumorigenesis. These data may provide further linkage between neurological development and cancer. PMID:18008369

  3. The Fragile X Protein binds mRNAs involved in cancer progression and modulates metastasis formation

    OpenAIRE

    Lucá, Rossella; Averna, Michele; Zalfa, Francesca; Vecchi, Manuela; Bianchi, Fabrizio; Fata, Giorgio La; Del Nonno, Franca; Nardacci, Roberta; Bianchi, Marco; Nuciforo, Paolo; Munck, Sebastian; Parrella, Paola; Moura, Rute; Signori, Emanuela; Alston, Robert

    2013-01-01

    The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS wh...

  4. The fragile X protein binds mRNAs involved in cancer progression and modulates metastasis formation.

    Science.gov (United States)

    Lucá, Rossella; Averna, Michele; Zalfa, Francesca; Vecchi, Manuela; Bianchi, Fabrizio; La Fata, Giorgio; Del Nonno, Franca; Nardacci, Roberta; Bianchi, Marco; Nuciforo, Paolo; Munck, Sebastian; Parrella, Paola; Moura, Rute; Signori, Emanuela; Alston, Robert; Kuchnio, Anna; Farace, Maria Giulia; Fazio, Vito Michele; Piacentini, Mauro; De Strooper, Bart; Achsel, Tilmann; Neri, Giovanni; Neven, Patrick; Evans, D Gareth; Carmeliet, Peter; Mazzone, Massimiliano; Bagni, Claudia

    2013-10-01

    The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS while a patient-case with FXS showed an unusual decrease of tumour brain invasiveness. However, a role for FMRP in regulating cancer biology, if any, remains unknown. We show here that FMRP and FMR1 mRNA levels correlate with prognostic indicators of aggressive breast cancer, lung metastases probability and triple negative breast cancer (TNBC). We establish that FMRP overexpression in murine breast primary tumours enhances lung metastasis while its reduction has the opposite effect regulating cell spreading and invasion. FMRP binds mRNAs involved in epithelial mesenchymal transition (EMT) and invasion including E-cadherin and Vimentin mRNAs, hallmarks of EMT and cancer progression. PMID:24092663

  5. Comprehensive analysis of ultrasonic vocalizations in a mouse model of fragile X syndrome reveals limited, call type specific deficits.

    Directory of Open Access Journals (Sweden)

    Snigdha Roy

    Full Text Available Fragile X syndrome (FXS is a well-recognized form of inherited mental retardation, caused by a mutation in the fragile X mental retardation 1 (Fmr1 gene. The gene is located on the long arm of the X chromosome and encodes fragile X mental retardation protein (FMRP. Absence of FMRP in fragile X patients as well as in Fmr1 knockout (KO mice results, among other changes, in abnormal dendritic spine formation and altered synaptic plasticity in the neocortex and hippocampus. Clinical features of FXS include cognitive impairment, anxiety, abnormal social interaction, mental retardation, motor coordination and speech articulation deficits. Mouse pups generate ultrasonic vocalizations (USVs when isolated from their mothers. Whether those social ultrasonic vocalizations are deficient in mouse models of FXS is unknown. Here we compared isolation-induced USVs generated by pups of Fmr1-KO mice with those of their wild type (WT littermates. Though the total number of calls was not significantly different between genotypes, a detailed analysis of 10 different categories of calls revealed that loss of Fmr1 expression in mice causes limited and call-type specific deficits in ultrasonic vocalization: the carrier frequency of flat calls was higher, the percentage of downward calls was lower and that the frequency range of complex calls was wider in Fmr1-KO mice compared to their WT littermates.

  6. Revealing the role of molecular rigidity on the fragility evolution of glass-forming liquids

    Science.gov (United States)

    Yildirim, C.; Raty, J.-Y.; Micoulaut, M.

    2016-03-01

    If quenched fast enough, a liquid is able to avoid crystallization and will remain in a metastable supercooled state down to the glass transition, with an important increase in viscosity upon further cooling. There are important differences in the way liquids relax as they approach the glass transition, rapid or slow variation in dynamic quantities under moderate temperature changes, and a simple means to quantify such variations is provided by the concept of fragility. Here, we report molecular dynamics simulations of a typical network-forming glass, Ge-Se, and find that the relaxation behaviour of the supercooled liquid is strongly correlated to the variation of rigidity with temperature and the spatial distribution of the corresponding topological constraints, which ultimately connect to the fragility minima. This permits extending the fragility concept to aspects of topology/rigidity, and to the degree of homogeneity of the atomic-scale interactions for a variety of structural glasses.

  7. Targeting fragile X

    OpenAIRE

    Gantois, Ilse; Kooy, R. Frank

    2002-01-01

    Ten years after the identification of the gene responsible for fragile X syndrome, recent studies have revealed a list of mRNAs bound by the fragile X gene product and have identified specific sequences required for the interaction between the fragile X protein and its targets. These results are a breakthrough in understanding why absence of the fragile X protein leads to mental retardation.

  8. Preferential integration of a transfected marker gene into spontaneously expressed fragile sites of a breast cancer cell line.

    Science.gov (United States)

    Matzner, Isabel; Savelyeva, Larissa; Schwab, Manfred

    2003-01-28

    Common fragile sites are non-randomly distributed unstable chromosomal regions thought to be hot spots for recombination. They appear as gaps, breaks and triradial figures when cells are cultured under conditions that inhibit replication or repair of DNA. The removal of replication-inhibitory challenges is followed by repair activation to restore the DNA damage at the fragile site. The breast cancer cell line MDA-MB-436 has a spontaneous and non-random expression pattern of fragile sites that appear to be related to the complex pattern of chromosomal rearrangements. The high frequency of which fragile sites are spontaneously activated should make MDA-MB-436 cells a powerful tool to study in greater detail the DNA sequences of a multiplicity of fragile sites. Here, we have explored if the DNA at spontaneously activated fragile sites in MDA-MB-436 cells can be genetically tagged by the repair-mediated insertion of an exogenously supplied drug resistance gene. The cells were transfected with pSV2Neo, stably transfected clones were selected with neomycin, and the sites of pSV2Neo integration were determined by fluorescent in situ hybridization. Eighty-eight of 100 isolated clones had a non-random distribution of a total of 112 pSV2Neo integrations. Of these, 95 integrations (85%) coincide with the position at which non-random gaps and breaks appear in the MDA-MB-436 cells. Forty-nine (44%) of the 112 integrations appeared to be at position of known fragile sites, 46 (41%) were at the non-random chromosomal sites not previously described as "true" fragile sites. It is possible, however, that these non-random instabilities signal of genomic regions equivalent to fragile sites, that either have not previously been detected due to low level expression or that are activated in a tissue- or cell-type-specific manner. Collectively, our results show a preferential integration of exogenous DNA into fragile sites and other non-random regions of high genomic instability in MDA

  9. miR-155 drives telomere fragility in human breast cancer by targeting TRF1.

    Science.gov (United States)

    Dinami, Roberto; Ercolani, Cristiana; Petti, Eleonora; Piazza, Silvano; Ciani, Yari; Sestito, Rosanna; Sacconi, Andrea; Biagioni, Francesca; le Sage, Carlos; Agami, Reuven; Benetti, Roberta; Mottolese, Marcella; Schneider, Claudio; Blandino, Giovanni; Schoeftner, Stefan

    2014-08-01

    Telomeres consist of DNA tandem repeats that recruit the multiprotein complex shelterin to build a chromatin structure that protects chromosome ends. Although cancer formation is linked to alterations in telomere homeostasis, there is little understanding of how shelterin function is limited in cancer cells. Using a small-scale screening approach, we identified miR-155 as a key regulator in breast cancer cell expression of the shelterin component TERF1 (TRF1). miR-155 targeted a conserved sequence motif in the 3'UTR of TRF1, resulting in its translational repression. miR-155 was upregulated commonly in breast cancer specimens, as associated with reduced TRF1 protein expression, metastasis-free survival, and relapse-free survival in estrogen receptor-positive cases. Modulating miR-155 expression in cells altered TRF1 levels and TRF1 abundance at telomeres. Compromising TRF1 expression by elevating miR-155 increased telomere fragility and altered the structure of metaphase chromosomes. In contrast, reducing miR-155 levels improved telomere function and genomic stability. These results implied that miR-155 upregulation antagonizes telomere integrity in breast cancer cells, increasing genomic instability linked to poor clinical outcome in estrogen receptor-positive disease. Our work argued that miRNA-dependent regulation of shelterin function has a clinically significant impact on telomere function, suggesting the existence of "telo-miRNAs" that have an impact on cancer and aging. PMID:24876105

  10. Characteristics of seismic and tsunami fragility of industries, revealed by the 2011 Tohoku-oki earthquake

    Science.gov (United States)

    Kuwahara, Y.; Hasegawa, I.; Yoshimi, M.; Namegaya, Y.; Horikawa, H.; Nakai, M.; Masuda, S.

    2013-12-01

    We have developed seismic and tsunami fragility curves of industries by using damage data of industrial companies, estimated strong motions and estimated tsunami heights of the 2011 Tohoku-oki earthquake. The damage data were obtained from 7,019 industrial companies, which responded to an inquiry survey to 30,000 companies carried out by the Regional Innovation Research Center of Tohoku University. As a damage level indicator for each company, we introduced a ratio of an economical damage of physical fixed assets excluding lands to previous balance of the physical fixed assets. The estimated strong motions of the 2011 Tohoku-oki earthquake at all the sites of the companies were from the database of the so-called QuiQuake system (Quick estimation system for earthquake maps triggered by observation records) operated by the National Institute of Advanced Industrial Science and Technology (AIST). It is noted that the estimated data were obtained by taking account of seismic local site effects and the actually observed ones. The tsunami height data at each site of the company were obtained by interpolating the confirmed data compiled by the 2011 Tohoku Earthquake Tsunami Joint Survey Group (2013). A frequency-damage level distribution for each seismic intensity is well correlated with a binominal distribution where the only parameter characterizing the distribution is an average value of the damage levels in each seismic intensity. The averaged damage levels of all the data for respective seismic intensity scales are 0.016 for SIj 5 lower, 0.042 for SIj 5 upper, 0.067 for SIj 6 lower, 0.092 for SIj 6 upper, and 0.16 for SIj 7, where SIj stands for the Japanese seismic intensity scale. The data were sorted into several classified industries and fragility curve for each classified industry is found to have a different character from each other. The tsunami fragilities are also obtained as a function of the tsunami height in the same way. The averaged damage levels of all

  11. Over half of breakpoints in gene pairs involved in cancer-specific recurrent translocations are mapped to human chromosomal fragile sites

    OpenAIRE

    Pierce Levi CT; Williams Laura E; Burrow Allison A; Wang Yuh-Hwa

    2009-01-01

    Abstract Background Gene rearrangements such as chromosomal translocations have been shown to contribute to cancer development. Human chromosomal fragile sites are regions of the genome especially prone to breakage, and have been implicated in various chromosome abnormalities found in cancer. However, there has been no comprehensive and quantitative examination of the location of fragile sites in relation to all chromosomal aberrations. Results Using up-to-date databases containing all cancer...

  12. Over half of breakpoints in gene pairs involved in cancer-specific recurrent translocations are mapped to human chromosomal fragile sites

    Directory of Open Access Journals (Sweden)

    Pierce Levi CT

    2009-01-01

    Full Text Available Abstract Background Gene rearrangements such as chromosomal translocations have been shown to contribute to cancer development. Human chromosomal fragile sites are regions of the genome especially prone to breakage, and have been implicated in various chromosome abnormalities found in cancer. However, there has been no comprehensive and quantitative examination of the location of fragile sites in relation to all chromosomal aberrations. Results Using up-to-date databases containing all cancer-specific recurrent translocations, we have examined 444 unique pairs of genes involved in these translocations to determine the correlation of translocation breakpoints and fragile sites in the gene pairs. We found that over half (52% of translocation breakpoints in at least one gene of these gene pairs are mapped to fragile sites. Among these, we examined the DNA sequences within and flanking three randomly selected pairs of translocation-prone genes, and found that they exhibit characteristic features of fragile DNA, with frequent AT-rich flexibility islands and the potential of forming highly stable secondary structures. Conclusion Our study is the first to examine gene pairs involved in all recurrent chromosomal translocations observed in tumor cells, and to correlate the location of more than half of breakpoints to positions of known fragile sites. These results provide strong evidence to support a causative role for fragile sites in the generation of cancer-specific chromosomal rearrangements.

  13. High rates of hybridisation reveal fragile reproductive barriers between endangered Australian sea snakes

    DEFF Research Database (Denmark)

    Sanders, Kate L; Redsted Rasmussen, Arne; Guinea, Michael L.

    2014-01-01

    The viviparous sea snakes include 62 ecologically diverse species, many of which are of very recent evolutionary origin and have overlapping distributions. Peak sea snake diversity and endemism is recorded from the isolated emergent reefs of the Timor Sea in Northwest Australia. However, nine...... designations, but revealed high frequencies of hybrids on all four reefs and individuals of pure A. fuscus ancestry only at Scott and (historically) Ashmore. Most unexpectedly, 95% of snakes sampled at Hibernia were hybrids that resembled A. laevis in phenotype, revealing a collapse of reproductive barriers...

  14. Interaction between fragile histamine triad and protein kinase C alpha in human non-small cell lung cancer tissues

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Objective To investigate the interaction between fragile histamine triad (FHIT) and protein kinase C alpha (PKCα) in human non-small cell lung cancer tissues. Methods FHIT and PKCα double positive samples were screened by immunohistochemical staining from 13 human non-small cell lung cancer tissues. Co-immunoprecipitation was performed by using anti-FHIT and anti-PKCα. The immune precipitate was analyzed by SDS-PAGE and Western blot. Results Immune precipitate staining detection showed that 3 samples out of...

  15. EXPRESSION OF FRAGILE HISTIDINE TRIAD AND P53 IN NON-SMALL CELL LUNG CANCER

    Institute of Scientific and Technical Information of China (English)

    HOU Xing-hua; ZHANG Dao-rong

    2006-01-01

    Objective: To investigate the expression of fragile histidine triad (FHIT) and p53 protein in non-small cell lung cancer (NSCLC) and explore the relationship between their expressions and the clinicopathological features. Methods: FHIT protein and p53 protein were detected by immunohistochemistry in 76 cases of NSCLCs and matched normal lung tissues. Results:Fifty-one cases (67.1%) showed negative expression of FHIT (apparent reduction or loss) and thirty-seven cases (48.7%)showed p53 positive expression (overexpression). The difference was significant (P=0.04). However, there was no significant difference in FHIT expression between the p53-positive group and the p53-negative group (64.9% versus 69.2%, P=0.686).The negative rate of FHIT protein expression was higher in squamous cell carcinoma than in adenocarcinoma, in moderately and poorly differentiated carcinoma than in well-differentiated carcinoma, and in cases with smoking history than in cases without smoking history (P<0.05). There was no relationship between FHIT expression and clinical stage or lymph node metastasis. The negative FHIT expression was not an independent predictor of overall survival (P=0.338). Conclusion: The frequency of negative expression of FHIT protein is higher than that of positive expression of p53 in NSCLCs. The negative expression of FHIT is independent of the expression of p53. The change of expression of FHIT may play a role in the smoking related lung tumorigenesis while it may have no relationship with the progress of NSCLC or prognosis of the patients.

  16. Interaction between fragile histamine triad and protein kinase C alpha in human non-small cell lung cancer tissues

    Institute of Scientific and Technical Information of China (English)

    Peng-hui Zhuang; Zhao-hui Liu; Xiao-gang Jiang; Cheng-en Pan

    2009-01-01

    Objective To investigate the interaction between fragile histamine triad (FHIT) and protein kinase C alpha (PKCα) in human non-small cell lung cancer tissues. Methods FHIT and PKC伪 double positive samples were screened by immunohistochemical staining from 13 human non-small cell lung cancer tissues. Co-immunoprecipitation was performed by using anti-FHIT and anti-PKCα. The immune precipitate was analyzed by SDS-PAGE and Western blot. Results Immune precipitate staining detection showed that 3 samples out of the 13 cases were double positive for FHIT and PKCα. FHIT protein was present in the immune precipitate of anti-PKCα while there was PKCα in the immune precipitate of anti-FHITmAb. Conclusion FHIT and PKCα exist as a complex in human non-small cell lung cancer tissues, which will provide a new route for studying the pathogenesis and immunotherapy of human non-small cell lung cancer.

  17. A novel fragile X syndrome mutation reveals a conserved role for the carboxy-terminus in FMRP localization and function

    NARCIS (Netherlands)

    Z. Okray (Zeynep); C. de Esch (Celine); H. van Esch (Hilde); K. Devriendt (Koenraad); A. Claeys (Annelies); J. Yan (Jiekun); J. Verbeeck (Jelle); G. Froyen (Guy); R. Willemsen; F.M.S. Vrij (Femke); B.A. Hassan (Bassem)

    2015-01-01

    textabstractLoss of function of the FMR1 gene leads to fragile X syndrome (FXS), the most common form of intellectual disability. The loss of FMR1 function is usually caused by epigenetic silencing of the FMR1 promoter leading to expansion and subsequent methylation of a CGG repeat in the 5′ untrans

  18. Fragile States

    DEFF Research Database (Denmark)

    Brock, Lothar; Holm, Hans-Henrik; Sørensen, Georg;

    What does state fragility means and how is it adressed. Case studies of where it went wrong and where it did not......What does state fragility means and how is it adressed. Case studies of where it went wrong and where it did not...

  19. Randomly detected genetically modified (GM maize (Zea mays L. near a transport route revealed a fragile 45S rDNA phenotype.

    Directory of Open Access Journals (Sweden)

    Nomar Espinosa Waminal

    Full Text Available Monitoring of genetically modified (GM crops has been emphasized to prevent their potential effects on the environment and human health. Monitoring of the inadvertent dispersal of transgenic maize in several fields and transport routes in Korea was carried out by qualitative multiplex PCR, and molecular analyses were conducted to identify the events of the collected GM maize. Cytogenetic investigations through fluorescence in situ hybridization (FISH of the GM maize were performed to check for possible changes in the 45S rDNA cluster because this cluster was reported to be sensitive to replication and transcription stress. Three GM maize kernels were collected from a transport route near Incheon port, Korea, and each was found to contain NK603, stacked MON863 x NK603, and stacked NK603 x MON810 inserts, respectively. Cytogenetic analysis of the GM maize containing the stacked NK603 x MON810 insert revealed two normal compact 5S rDNA signals, but the 45S rDNA showed a fragile phenotype, demonstrating a "beads-on-a-string" fragmentation pattern, which seems to be a consequence of genetic modification. Implications of the 45S rDNA cluster fragility in GM maize are also discussed.

  20. Subcellular fractionation and localization studies reveal a direct interaction of the fragile X mental retardation protein (FMRP with nucleolin.

    Directory of Open Access Journals (Sweden)

    Mohamed S Taha

    Full Text Available Fragile X mental Retardation Protein (FMRP is a well-known regulator of local translation of its mRNA targets in neurons. However, despite its ubiquitous expression, the role of FMRP remains ill-defined in other cell types. In this study we investigated the subcellular distribution of FMRP and its protein complexes in HeLa cells using confocal imaging as well as detergent-free fractionation and size exclusion protocols. We found FMRP localized exclusively to solid compartments, including cytosolic heavy and light membranes, mitochondria, nuclear membrane and nucleoli. Interestingly, FMRP was associated with nucleolin in both a high molecular weight ribosomal and translation-associated complex (≥6 MDa in the cytosol, and a low molecular weight complex (∼200 kDa in the nucleoli. Consistently, we identified two functional nucleolar localization signals (NoLSs in FMRP that are responsible for a strong nucleolar colocalization of the C-terminus of FMRP with nucleolin, and a direct interaction of the N-terminus of FMRP with the arginine-glycine-glycine (RGG domain of nucleolin. Taken together, we propose a novel mechanism by which a transient nucleolar localization of FMRP underlies a strong nucleocytoplasmic translocation, most likely in a complex with nucleolin and possibly ribosomes, in order to regulate translation of its target mRNAs.

  1. The Fragile Definition of State Fragility

    OpenAIRE

    Graziella Bertocchi; Andrea Guerzoni

    2010-01-01

    We investigates the link between fragility and economic development in sub-Saharan Africa over a yearly panel including 28 countries for the 1999-2004 period. Beside the conventional definition of fragility adopted by the OECD Development Assistance Committee, we introduce the more severe definition of extreme fragility. We show that only the latter exerts a significantly negative impact on economic development, once standard economic, demographic, and institutional regressors are accounted f...

  2. National Fragile X Foundation

    Science.gov (United States)

    ... Anthology Advocacy National Fragile X Foundation Advocacy Day STAR: Local Advocacy Agenda and Accomplishments Community Events International ... Making Sense of the Alphabet Soup Teaching Your Child to Ask for Something Behavior and Fragile X ...

  3. BANKING SYSTEM FRAGILITY: CASE OF THE REPUBLIC OF MOLDOVA

    OpenAIRE

    Dorina CLICHICI

    2014-01-01

    The paper studied the determinants of Moldovan banking system fragility. It underlines the existing researches into the empirical determinants of banking fragility. The analysis revealed that there are numerous channels through which weaknesses within the macroeconomic conditions and structural characteristics might increase banking system fragility. The main macroeconomic determinants which may have an impact on Moldovan banking system fragility are: excessive domestic liquidity, pro-cyclica...

  4. Fragile X Syndrome Overview

    Science.gov (United States)

    ... NICHD Research Information Clinical Trials Resources and Publications Fragile X Syndrome: Overview Skip sharing on social media links Share ... menu on the left. ​ Common Name Fragile X syndrome or Fragile X Medical or Scientific Names Martin-Bell syndrome Last ...

  5. MUS81 promotes common fragile site expression

    DEFF Research Database (Denmark)

    Ying, Songmin; Minocherhomji, Sheroy; Chan, Kok Lung;

    2013-01-01

    Fragile sites are chromosomal loci with a propensity to form gaps or breaks during early mitosis, and their instability is implicated as being causative in certain neurological disorders and cancers. Recent work has demonstrated that the so-called common fragile sites (CFSs) often impair the...... faithful disjunction of sister chromatids in mitosis. However, the mechanisms by which CFSs express their fragility, and the cellular factors required to suppress CFS instability, remain largely undefined. Here, we report that the DNA structure-specific nuclease MUS81-EME1 localizes to CFS loci in early...

  6. Examination of Replication Dynamics in Fragile Sites Through Molecular Combing

    Directory of Open Access Journals (Sweden)

    Chumki, Shahana Ahmed

    2015-08-01

    Full Text Available Chromosomal fragile sites are specific loci that exhibit instability visible as gaps and breaks on the chromosome following inhibition of DNA synthesis and are generally categorized into two main classes: rare fragile sites (RFSs and common fragile sites (CFSs. Under standard conditions, CFSs are typically stable but are prone to breakage in cells subjected to replication stress. In recent years, their role in the generation of gross chromosome rearrangements has become increasingly evident, and fragile sites have now connected to chromosome instability in cancer cells. The connection between CFSs and cancer thus highlights the importance of the regulation of DNA replication to prevent cancer development. The study of fragile sites in the yeast model organism has provided insight into the mechanisms that lead to breakage and genome instability. Through the process of molecular combing, replication dynamics can be observed at fragile sites to further understand the consequence of replication stress on DNA damage.

  7. Features of Fragile X Syndrome

    Science.gov (United States)

    ... Figuring Out CGG Repeats! Donate | Print Fragile X Syndrome Fragile X syndrome (FXS) is a genetic condition that causes ... health concerns associated with the condition. Features of Fragile X Syndrome in Males Read our Story The majority of ...

  8. Fragile X Syndrome: Other FAQs

    Science.gov (United States)

    ... NICHD Research Information Clinical Trials Resources and Publications Fragile X Syndrome: Other FAQs Skip sharing on social media links ... Are there specific disorders or conditions associated with Fragile X syndrome? Among the other conditions associated with Fragile X ...

  9. Fragile X syndrome.

    OpenAIRE

    Wiebe, E.; A. Wiebe

    1994-01-01

    Fragile X syndrome is the most common form of inherited mental retardation. Only recently has it been possible to detect all carriers and transmitters. We review the syndrome and discuss the pedigree of a large fragile X family. Family doctors should identify cases in their practices so genetic counseling can be offered to the families.

  10. Equipment fragility testing

    International Nuclear Information System (INIS)

    Current probabilistic risk assessment (PRA) methods for nuclear power plants utilize component fragilities which are for the most part based on a limited data base and engineering judgement. The seismic design of components is based on code limits and NRC requirements that do not reflect the actual capacity of a component to resist failure. In order to improve the present component fragility data base and establish component seismic design margins, the NRC has commissioned a projected three-year program to compile existing fragilities data and at the same time independently perform fragilities tests on selected mechanical and electrical components. This paper presents the planning and technical approach being taken by LLNL in the NRC Component Fragility Program

  11. Chromosomal fragility syndrome and family history of radiosensitivity as indicators for radiotherapy dose modification

    International Nuclear Information System (INIS)

    Beside a few known radiosensitive syndromes, a patient's reaction to radiotherapy is difficult to predict. In this report we describe the management of a pediatric cancer patient presented with a family history of radiosensitivity and cancer proneness. Laboratory investigations revealed a chromosomal fragility syndrome and an increased cellular radiosensitivity in vitro. AT gene sequencing revealed no mutations. The patient was treated with reduced radiation doses to avoid the presumed increased risks of toxicity to normal tissues. The patient tolerated well the treatment with no significant acute or late radiation sequelae. Five years later, the patient remains both disease and complications free. While an accurate laboratory test for radiosensitivity is still lacking, assessments of chromosomal fragility, cell survival and clinical medicine will continue to be useful for a small number of patients

  12. Preserved entropy and fragile magnetism

    Science.gov (United States)

    Canfield, Paul C.; Bud’ko, Sergey L.

    2016-08-01

    A large swath of quantum critical and strongly correlated electron systems can be associated with the phenomena of preserved entropy and fragile magnetism. In this overview we present our thoughts and plans for the discovery and development of lanthanide and transition metal based, strongly correlated systems that are revealed by suppressed, fragile magnetism, quantum criticality, or grow out of preserved entropy. We will present and discuss current examples such as YbBiPt, YbAgGe, YbFe2Zn20, PrAg2In, BaFe2As2, CaFe2As2, LaCrSb3 and LaCrGe3 as part of our motivation and to provide illustrative examples.

  13. Visual gene-network analysis reveals the cancer gene co-expression in human endometrial cancer

    OpenAIRE

    Chou, Wei-Chun; Cheng, An-Lin; Brotto, Marco; Chuang, Chun-Yu

    2014-01-01

    Background Endometrial cancers (ECs) are the most common form of gynecologic malignancy. Recent studies have reported that ECs reveal distinct markers for molecular pathogenesis, which in turn is linked to the various histological types of ECs. To understand further the molecular events contributing to ECs and endometrial tumorigenesis in general, a more precise identification of cancer-associated molecules and signaling networks would be useful for the detection and monitoring of malignancy,...

  14. Trio Fragile / Olga Kaljundi

    Index Scriptorium Estoniae

    Kaljundi, Olga, 1941-2001

    1998-01-01

    Tallinna Vene Draamateatri galeriis esinenud trupi "Trio Fragile" vernissaazhist. Trio loomingust ja osalejatest : kahe muusiku seltskonnas esineb ka 1984.a. Kunstiülikooli lõpetanud kunstnik Tõnu Talve.

  15. Fragile States : Securing Development

    OpenAIRE

    Zoellick, R.

    2008-01-01

    Fragile states are the toughest development challenge of our era. But we ignore them at our peril: about one billion people live in fragile states, including a disproportionate number of the world's extreme poor, and they account for most of today's wars. These situations require a different framework of building security, legitimacy, governance, and the economy. Only by securing development - bringing security and development together to smooth the transition from conflict to peace and then ...

  16. Fragility and MDG Progress: How useful is the Fragility Concept?

    OpenAIRE

    Harttgen, Kenneth; Klasen, Stephan

    2010-01-01

    While progress in developing countries as a whole, in terms of growth, poverty reduction, and several MDGs, has been quite good in recent years, fragile states lag behind in levels of MDG achievement. To understand the link between fragility and MDG progress, and also to identify the most effective policy interventions to achieve the MDGs, it is essential that fragile states are appropriately defined and classified. While the amount of literature on how to engage with fragile stat...

  17. Biodiversity and its fragility in Yunnan, China

    Institute of Scientific and Technical Information of China (English)

    PU Ying-shan; ZHANG Zhi-yi; PU Li-na; HUI Chao-mao

    2007-01-01

    In Yunnan, 8 major aspects of biodiversity and fragility in landforms, ecosystems, distribution populations, alien invasion, segregation, pollution and maladministration with various menace factors causing biodiversity loss have been described. It is revealed that the facts that the biodiversity and fragility coexists in this paper. Accordingly, 6 major countermeasures for effective conservation and rational utilization of the provincial biodiversity were suggested on the basis of thescientific development concepts, principles of nature protection,conservation biology, resource management and ethnobotany and present status in Yunnan with rich intangible resources such as climatic,ethnical and cultural diversity, etc.

  18. Component fragilities. Data collection, analysis and interpretation

    International Nuclear Information System (INIS)

    As part of the component fragility research program sponsored by the US NRC, BNL is involved in establishing seismic fragility levels for various nuclear power plant equipment with emphasis on electrical equipment. To date, BNL has reviewed approximately seventy test reports to collect fragility or high level test data for switchgears, motor control centers and similar electrical cabinets, valve actuators and numerous electrical and control devices, e.g., switches, transmitters, potentiometers, indicators, relays, etc., of various manufacturers and models. BNL has also obtained test data from EPRI/ANCO. Analysis of the collected data reveals that fragility levels can best be described by a group of curves corresponding to various failure modes. The lower bound curve indicates the initiation of malfunctioning or structural damage, whereas the upper bound curve corresponds to overall failure of the equipment based on known failure modes occurring separately or interactively. For some components, the upper and lower bound fragility levels are observed to vary appreciably depending upon the manufacturers and models. For some devices, testing even at the shake table vibration limit does not exhibit any failure. Failure of a relay is observed to be a frequent cause of failure of an electrical panel or a system. An extensive amount of additional fregility or high level test data exists

  19. Practical Approach to Fragility Analysis of Bridges

    Directory of Open Access Journals (Sweden)

    Yasamin Rafie Nazari

    2012-12-01

    Full Text Available Damages during past earthquakes reveal seismic vulnerability of bridge structures and the necessity of probabilistic approach toward seismic performance evaluation of bridges and its interpretation in terms of decision variables such as repair cost, downtime and life loss. This Procedure involves hazard analysis, structural analysis, damage analysis and loss analysis. The purpose of present study is reviewing different methods developed to derive fragility curves for damage analysis of bridges and demonstrating a simple procedure for fragility analysis using Microsoft Office Excel worksheet to reach probability of occurring predefined level of damage due to different levels of seismic demand parameters. The input of this procedure is the intensity of ground motion and the output is an appropriate estimate of the expected damage. Different observed damages of the bridges are discussed and compared the practical definition of damage states. Different methods of fragility analyses are discussed and a practical step by step example is illustrated.

  20. State fragility: Concept and measurement

    OpenAIRE

    Baliamoune-Lutz, Mina; McGillivray, Mark

    2008-01-01

    The international donor community has grave concerns about the prospects for poverty reduction in what it terms fragile states. A state is classified as fragile if its country policy and institutional assessment (CPIA) score falls below a particular threshold. Recognizing that all states are fragile to varying degrees, this paper questions the method used by the international community to deem a country fragile. This paper develops a framework that uses fuzzy-set theory to deem a country as f...

  1. Component fragility research program

    International Nuclear Information System (INIS)

    To demonstrate how ''high-level'' qualification test data can be used to estimate the ultimate seismic capacity of nuclear power plant equipment, we assessed in detail various electrical components tested by the Pacific Gas ampersand Electric Company for its Diablo Canyon plant. As part of our Phase I Component Fragility Research Program, we evaluated seismic fragility for five Diablo Canyon components: medium-voltage (4kV) switchgear; safeguard relay board; emergency light battery pack; potential transformer; and station battery and racks. This report discusses our Phase II fragility evaluation of a single Westinghouse Type W motor control center column, a fan cooler motor controller, and three local starters at the Diablo Canyon nuclear power plant. These components were seismically qualified by means of biaxial random motion tests on a shaker table, and the test response spectra formed the basis for the estimate of the seismic capacity of the components. The seismic capacity of each component is referenced to the zero period acceleration (ZPA) and, in our Phase II study only, to the average spectral acceleration (ASA) of the motion at its base. For the motor control center, the seismic capacity was compared to the capacity of a Westinghouse Five-Star MCC subjected to actual fragility tests by LLNL during the Phase I Component Fragility Research Program, and to generic capacities developed by the Brookhaven National Laboratory for motor control center. Except for the medium-voltage switchgear, all of the components considered in both our Phase I and Phase II evaluations were qualified in their standard commercial configurations or with only relatively minor modifications such as top bracing of cabinets. 8 refs., 67 figs., 7 tabs

  2. Hierarchical clustering of breast cancer methylomes revealed differentially methylated and expressed breast cancer genes.

    Directory of Open Access Journals (Sweden)

    I-Hsuan Lin

    Full Text Available Oncogenic transformation of normal cells often involves epigenetic alterations, including histone modification and DNA methylation. We conducted whole-genome bisulfite sequencing to determine the DNA methylomes of normal breast, fibroadenoma, invasive ductal carcinomas and MCF7. The emergence, disappearance, expansion and contraction of kilobase-sized hypomethylated regions (HMRs and the hypomethylation of the megabase-sized partially methylated domains (PMDs are the major forms of methylation changes observed in breast tumor samples. Hierarchical clustering of HMR revealed tumor-specific hypermethylated clusters and differential methylated enhancers specific to normal or breast cancer cell lines. Joint analysis of gene expression and DNA methylation data of normal breast and breast cancer cells identified differentially methylated and expressed genes associated with breast and/or ovarian cancers in cancer-specific HMR clusters. Furthermore, aberrant patterns of X-chromosome inactivation (XCI was found in breast cancer cell lines as well as breast tumor samples in the TCGA BRCA (breast invasive carcinoma dataset. They were characterized with differentially hypermethylated XIST promoter, reduced expression of XIST, and over-expression of hypomethylated X-linked genes. High expressions of these genes were significantly associated with lower survival rates in breast cancer patients. Comprehensive analysis of the normal and breast tumor methylomes suggests selective targeting of DNA methylation changes during breast cancer progression. The weak causal relationship between DNA methylation and gene expression observed in this study is evident of more complex role of DNA methylation in the regulation of gene expression in human epigenetics that deserves further investigation.

  3. A genome-wide systematic analysis reveals different and predictive proliferation expression signatures of cancerous vs. non-cancerous cells.

    Directory of Open Access Journals (Sweden)

    Yedael Y Waldman

    Full Text Available Understanding cell proliferation mechanisms has been a long-lasting goal of the scientific community and specifically of cancer researchers. Previous genome-scale studies of cancer proliferation determinants have mainly relied on knockdown screens aimed to gauge their effects on cancer growth. This powerful approach has several limitations such as off-target effects, partial knockdown, and masking effects due to functional backups. Here we employ a complementary approach and assign each gene a cancer Proliferation Index (cPI that quantifies the association between its expression levels and growth rate measurements across 60 cancer cell lines. Reassuringly, genes found essential in cancer gene knockdown screens exhibit significant positive cPI values, while tumor suppressors exhibit significant negative cPI values. Cell cycle, DNA replication, splicing and protein production related processes are positively associated with cancer proliferation, while cellular migration is negatively associated with it - in accordance with the well known "go or grow" dichotomy. A parallel analysis of genes' non-cancerous proliferation indices (nPI across 224 lymphoblastoid cell lines reveals surprisingly marked differences between cancerous and non-cancerous proliferation. These differences highlight genes in the translation and spliceosome machineries as selective cancer proliferation-associated proteins. A cross species comparison reveals that cancer proliferation resembles that of microorganisms while non-cancerous proliferation does not. Furthermore, combining cancerous and non-cancerous proliferation signatures leads to enhanced prediction of patient outcome and gene essentiality in cancer. Overall, these results point to an inherent difference between cancerous and non-cancerous proliferation determinants, whose understanding may contribute to the future development of novel cancer-specific anti-proliferative drugs.

  4. Fragile X Syndrome

    Directory of Open Access Journals (Sweden)

    Wilmar Saldarriaga

    2015-01-01

    Full Text Available Fragile X Syndrome (FXS is a genetic disease due to a CGG trinucleotide expansion, named full mutation (greater than 200 CGG repeats, in the fragile X mental retardation 1 gene locus Xq27.3; which leads to an hypermethylated region in the gene promoter therefore silencing it and lowering the expression levels of the fragile X mental retardation 1, a protein involved in synaptic plasticity and maturation.  Individuals with FXS present with intellectual disability, autism, hyperactivity, long face, large or prominent ears and macroorchidism at puberty and thereafter. Most of the young children with FXS will present with language delay, sensory hyper arousal and anxiety. Girls are less affected than boys, only 25% have intellectual disability. Given the genomic features of the syndrome, there are patients with a number of triplet repeats between 55 and 200, known as premutation carriers. Most carriers have a normal IQ but some have developmental problems. The diagnosis of FXS has evolved from karyotype with special culture medium, to molecular techniques that are more sensitive and specific including PCR and Southern Blot. During the last decade, the advances in the knowledge of FXS, has led to the development of investigations on pharmaceutical management or targeted treatments for FXS. Minocycline and sertraline have shown efficacy in children.

  5. FRAGILITY AND MDG PROGRESS: HOW USEFUL IS THE FRAGILITY CONCEPT?

    OpenAIRE

    Kenneth Harttgen and Stephan Klasen

    2010-01-01

    While progress in developing countries as a whole, in terms of growth, poverty reduc-tion, and several MDGs, has been quite good in recent years, fragile states lag behind in levels of MDG achievement. To understand the link between fragility and MDG progress, and also to identify the most effective policy interventions to achieve the MDGs, it is es-sential that fragile states are appropriately defined and classified. While the amount of literature on how to engage with fragile states is rapi...

  6. Fragility and cooperativity concepts in hydrogen-bonded organic glasses

    Energy Technology Data Exchange (ETDEWEB)

    Delpouve, N., E-mail: delpouve.nicolas@gmail.com [AMME-LECAP EA 4528 International Laboratory, University of Rouen, Avenue de l' Universite BP 12, 76801 Saint Etienne du Rouvray (France); Vuillequez, A.; Saiter, A.; Youssef, B.; Saiter, J.M. [AMME-LECAP EA 4528 International Laboratory, University of Rouen, Avenue de l' Universite BP 12, 76801 Saint Etienne du Rouvray (France)

    2012-09-01

    Molecular dynamics at the glass transition of three lactose/oil glassy systems have been investigated according to the cooperativity and fragility approaches. From Donth's approach, the cooperativity length is estimated by modulated temperature calorimetric measurements. Results reveal that modification of the disaccharide by oil leads to increase the disorder degree in the lactose, the size of the cooperative domains and the fragility index. These particular hydrogen-bonded organic glasses follow the general tendency observed on organic and inorganic polymers: the higher the cooperativity length, the higher the value of the fragility index at T{sub g}.

  7. Fragility and cooperativity concepts in hydrogen-bonded organic glasses

    International Nuclear Information System (INIS)

    Molecular dynamics at the glass transition of three lactose/oil glassy systems have been investigated according to the cooperativity and fragility approaches. From Donth's approach, the cooperativity length is estimated by modulated temperature calorimetric measurements. Results reveal that modification of the disaccharide by oil leads to increase the disorder degree in the lactose, the size of the cooperative domains and the fragility index. These particular hydrogen-bonded organic glasses follow the general tendency observed on organic and inorganic polymers: the higher the cooperativity length, the higher the value of the fragility index at Tg.

  8. Avoiding the Fragility Trap in Africa

    OpenAIRE

    Andrimihaja, Noro Aina; Cinyabuguma, Matthias; Devarajan, Shantayanan

    2011-01-01

    Not only do Africa's fragile states grow more slowly than non-fragile states, but they seem to be caught in a "fragility trap". For instance, the probability that a fragile state in 2001 was still fragile in 2009 was 0.95. This paper presents an economic model where three features -- political instability and violence, insecure property rights and unenforceable contracts, and corruption --...

  9. Fragile histidine triad gene and gastric cancer%脆性组氨酸三联体基因与胃癌

    Institute of Scientific and Technical Information of China (English)

    王俊; 吴云飞

    2005-01-01

    脆性组氨酸三联体(fragile histidine triad,FHIT)基因定位于人3号染色体短臂(3p14.2)上,许多研究表明其表达改变与人类多种肿瘤疾病关系密切.本文重点描述有关FHIT基因的分子生物学研究新进展,以及在胃癌诊治方面的意义.

  10. Phosphoproteome Integration Reveals Patient-Specific Networks in Prostate Cancer.

    OpenAIRE

    Drake, JM; Paull, EO; Graham, NA; Lee, JK; Smith, BA; Titz, B; Stoyanova, T; Faltermeier, CM; Uzunangelov, V; Carlin,, R.; Fleming, DT; Wong, CK; Newton, Y; Sudha, S; Vashisht, AA

    2016-01-01

    We used clinical tissue from lethal metastatic castration-resistant prostate cancer (CRPC) patients obtained at rapid autopsy to evaluate diverse genomic, transcriptomic, and phosphoproteomic datasets for pathway analysis. Using Tied Diffusion through Interacting Events (TieDIE), we integrated differentially expressed master transcriptional regulators, functionally mutated genes, and differentially activated kinases in CRPC tissues to synthesize a robust signaling network consisting of drugga...

  11. BANKING SYSTEM FRAGILITY: CASE OF THE REPUBLIC OF MOLDOVA

    Directory of Open Access Journals (Sweden)

    Dorina CLICHICI

    2014-04-01

    Full Text Available The paper studied the determinants of Moldovan banking system fragility. It underlines the existing researches into the empirical determinants of banking fragility. The analysis revealed that there are numerous channels through which weaknesses within the macroeconomic conditions and structural characteristics might increase banking system fragility. The main macroeconomic determinants which may have an impact on Moldovan banking system fragility are: excessive domestic liquidity, pro-cyclical character of the banking system, dependence on remittances, financial dollarization. There are also several banking characteristics which play a role for Moldovan banking system fragility: the undermined intermediation function, high level of bad loans, uncertainties in the ownership structure, low presence of foreign strategic investors. The paper employed a quantitative, a qualitative and a comparative analysis using the financial soundness and structural indicators of the Moldovan banking system in order to assess the impact of various determinants on Moldovan banking system fragility. The results reveal a high degree of capitalization and liquidity of Moldovan banking system, factors which contribute and maintain the general stability of the entire financial system.

  12. Diabetes mellitus and colorectal cancer – a revealed connection

    Directory of Open Access Journals (Sweden)

    Mihăiță Pătrășescu

    2015-08-01

    Full Text Available The burden of colorectal cancer (CRC is increasing all over the world. The prevalence of diabetes mellitus is increasing. It is estimated that diabetes affects 387 million people worldwide. It is predicted that 552 million people worldwide will develop diabetes by 2030. A large pool of data indicate that DM increases by 2 fold the risk of CRC. This is the reason to firmly suggest the inclusion of DM in the criteria for CRC screening as an important measure to decrease the mortality of this ailment.

  13. Diabetes mellitus and colorectal cancer – a revealed connection

    OpenAIRE

    Mihăiță Pătrășescu; Petruț Nuță; Raluca S. Costache; Săndica Bucurică; Bogdan Macadon; Andrada Popescu; Vasile Balaban; Florentina Ioniță Radu; Mariana Jinga

    2015-01-01

    The burden of colorectal cancer (CRC) is increasing all over the world. The prevalence of diabetes mellitus is increasing. It is estimated that diabetes affects 387 million people worldwide. It is predicted that 552 million people worldwide will develop diabetes by 2030. A large pool of data indicate that DM increases by 2 fold the risk of CRC. This is the reason to firmly suggest the inclusion of DM in the criteria for CRC screening as an important measure to decrease the mortality of thi...

  14. MDM2 inhibition rescues neurogenic and cognitive deficits in a mouse model of fragile X syndrome.

    Science.gov (United States)

    Li, Yue; Stockton, Michael E; Bhuiyan, Ismat; Eisinger, Brian E; Gao, Yu; Miller, Jessica L; Bhattacharyya, Anita; Zhao, Xinyu

    2016-04-27

    Fragile X syndrome, the most common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein (FMRP). However, the mechanism remains unclear, and effective treatment is lacking. We show that loss of FMRP leads to activation of adult mouse neural stem cells (NSCs) and a subsequent reduction in the production of neurons. We identified the ubiquitin ligase mouse double minute 2 homolog (MDM2) as a target of FMRP. FMRP regulates Mdm2 mRNA stability, and loss of FMRP resulted in elevated MDM2 mRNA and protein. Further, we found that increased MDM2 expression led to reduced P53 expression in adult mouse NSCs, leading to alterations in NSC proliferation and differentiation. Treatment with Nutlin-3, a small molecule undergoing clinical trials for treating cancer, specifically inhibited the interaction of MDM2 with P53, and rescued neurogenic and cognitive deficits in FMRP-deficient mice. Our data reveal a potential regulatory role for FMRP in the balance between adult NSC activation and quiescence, and identify a potential new treatment for fragile X syndrome. PMID:27122614

  15. Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer.

    Science.gov (United States)

    Ahmad, Imran; Mui, Ernest; Galbraith, Laura; Patel, Rachana; Tan, Ee Hong; Salji, Mark; Rust, Alistair G; Repiscak, Peter; Hedley, Ann; Markert, Elke; Loveridge, Carolyn; van der Weyden, Louise; Edwards, Joanne; Sansom, Owen J; Adams, David J; Leung, Hing Y

    2016-07-19

    Prostate cancer (CaP) is the most common adult male cancer in the developed world. The paucity of biomarkers to predict prostate tumor biology makes it important to identify key pathways that confer poor prognosis and guide potential targeted therapy. Using a murine forward mutagenesis screen in a Pten-null background, we identified peroxisome proliferator-activated receptor gamma (Pparg), encoding a ligand-activated transcription factor, as a promoter of metastatic CaP through activation of lipid signaling pathways, including up-regulation of lipid synthesis enzymes [fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), ATP citrate lyase (ACLY)]. Importantly, inhibition of PPARG suppressed tumor growth in vivo, with down-regulation of the lipid synthesis program. We show that elevated levels of PPARG strongly correlate with elevation of FASN in human CaP and that high levels of PPARG/FASN and PI3K/pAKT pathway activation confer a poor prognosis. These data suggest that CaP patients could be stratified in terms of PPARG/FASN and PTEN levels to identify patients with aggressive CaP who may respond favorably to PPARG/FASN inhibition. PMID:27357679

  16. Fragile X Mental Retardation Syndrome: Structure of the KH1-KH2 Domains of Fragile X Mental Retardation Protein

    Energy Technology Data Exchange (ETDEWEB)

    Valverde,R.; Poznyakova, I.; Kajander, T.; Venkatraman, J.; Regan, L.

    2007-01-01

    Fragile X syndrome is the most common form of inherited mental retardation in humans, with an estimated prevalence of about 1 in 4000 males. Although several observations indicate that the absence of functional Fragile X Mental Retardation Protein (FMRP) is the underlying basis of Fragile X syndrome, the structure and function of FMRP are currently unknown. Here, we present an X-ray crystal structure of the tandem KH domains of human FMRP, which reveals the relative orientation of the KH1 and KH2 domains and the location of residue Ile304, whose mutation to Asn is associated with a particularly severe incidence of Fragile X syndrome. We show that the Ile304Asn mutation both perturbs the structure and destabilizes the protein.

  17. Novel personalized pathway-based metabolomics models reveal key metabolic pathways for breast cancer diagnosis

    DEFF Research Database (Denmark)

    Huang, Sijia; Chong, Nicole; Lewis, Nathan;

    2016-01-01

    Background: More accurate diagnostic methods are pressingly needed to diagnose breast cancer, the most common malignant cancer in women worldwide. Blood-based metabolomics is a promising diagnostic method for breast cancer. However, many metabolic biomarkers are difficult to replicate among studies.......993. Moreover, important metabolic pathways, such as taurine and hypotaurine metabolism and the alanine, aspartate, and glutamate pathway, are revealed as critical biological pathways for early diagnosis of breast cancer. Conclusions: We have successfully developed a new type of pathway-based model to study...... metabolomics data for disease diagnosis. Applying this method to blood-based breast cancer metabolomics data, we have discovered crucial metabolic pathway signatures for breast cancer diagnosis, especially early diagnosis. Further, this modeling approach may be generalized to other omics data types for disease...

  18. What can digital transcript profiling reveal about human cancers?

    Directory of Open Access Journals (Sweden)

    J.M. Cerutti

    2003-08-01

    Full Text Available Important biological and clinical features of malignancy are reflected in its transcript pattern. Recent advances in gene expression technology and informatics have provided a powerful new means to obtain and interpret these expression patterns. A comprehensive approach to expression profiling is serial analysis of gene expression (SAGE, which provides digital information on transcript levels. SAGE works by counting transcripts and storing these digital values electronically, providing absolute gene expression levels that make historical comparisons possible. SAGE produces a comprehensive profile of gene expression and can be used to search for candidate tumor markers or antigens in a limited number of samples. The Cancer Genome Anatomy Project has created a SAGE database of human gene expression levels for many different tumors and normal reference tissues and provides online tools for viewing, comparing, and downloading expression profiles. Digital expression profiling using SAGE and informatics have been useful for identifying genes that have a role in tumor invasion and other aspects of tumor progression.

  19. Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility.

    Science.gov (United States)

    Piccolo, Stephen R; Hoffman, Laura M; Conner, Thomas; Shrestha, Gajendra; Cohen, Adam L; Marks, Jeffrey R; Neumayer, Leigh A; Agarwal, Cori A; Beckerle, Mary C; Andrulis, Irene L; Spira, Avrum E; Moos, Philip J; Buys, Saundra S; Johnson, William Evan; Bild, Andrea H

    2016-03-01

    The signaling events that drive familial breast cancer (FBC) risk remain poorly understood. While the majority of genomic studies have focused on genetic risk variants, known risk variants account for at most 30% of FBC cases. Considering that multiple genes may influence FBC risk, we hypothesized that a pathway-based strategy examining different data types from multiple tissues could elucidate the biological basis for FBC. In this study, we performed integrated analyses of gene expression and exome-sequencing data from peripheral blood mononuclear cells and showed that cell adhesion pathways are significantly and consistently dysregulated in women who develop FBC. The dysregulation of cell adhesion pathways in high-risk women was also identified by pathway-based profiling applied to normal breast tissue data from two independent cohorts. The results of our genomic analyses were validated in normal primary mammary epithelial cells from high-risk and control women, using cell-based functional assays, drug-response assays, fluorescence microscopy, and Western blotting assays. Both genomic and cell-based experiments indicate that cell-cell and cell-extracellular matrix adhesion processes seem to be disrupted in non-malignant cells of women at high risk for FBC and suggest a potential role for these processes in FBC development. PMID:26969729

  20. Seismic fragility of nuclear power plant components. Phase I

    International Nuclear Information System (INIS)

    As part of the Component Fragility Research Program, sponsored by the US Nuclear Regulatory Commission, BNL is involved in establishing seismic fragility levels for various nuclear power plant equipment by identifying, collecting and analyzing existing test data from various sources. In Phase I of this program, BNL has reviewed approximately seventy test reports to collect fragility or high level test data for switchgears, motor control centers and similar electrical cabinets, valve actuators and numerous electrical devices of various manufacturers and models. This report provides an assessment and evaluation of the data collected in Phase I. The fragility data for medium voltage and low voltage switchgears and motor control centers are analyzed using the test response spectra (TRS) as a measure of the fragility level. The analysis reveals that fragility levels can best be described by a group of TRS curves corresponding to various failure modes. The lower-bound curve indicates the initiation of malfunctioning or structural damage; whereas, the upper-bound curve corresponds to overall failure of the equipment based on known failure modes. High level test data for some components are included in the report. These data indicate that some components are inherently strong and do not exhibit any failure mode even when tested at the vibration limit of a shake table. The common failure modes are identified in the report. The fragility levels determined in this report have been compared with those used in the PRA and Seismic Margin Studies. It appears that the BNL data better correlate with the HCLPF (High Confidence of a Low Probability of Failure) level used in Seismic Margin Studies and can improve this level as high as 60% for certain applications. Specific recommendations are provided for proper application of BNL fragility data to other studies

  1. A comparison of cancer burden and research spending reveals discrepancies in the distribution of research funding

    Directory of Open Access Journals (Sweden)

    Carter Ashley JR

    2012-07-01

    Full Text Available Abstract Background Ideally, the distribution of research funding for different types of cancer should be equitable with respect to the societal burden each type of cancer imposes. These burdens can be estimated in a variety of ways; “Years of Life Lost” (YLL measures the severity of death in regard to the age it occurs, "Disability-Adjusted Life-Years" (DALY estimates the effects of non-lethal disabilities incurred by disease and economic metrics focus on the losses to tax revenue, productivity or direct medical expenses. We compared research funding from the National Cancer Institute (NCI to a variety of burden metrics for the most common types of cancer to identify mismatches between spending and societal burden. Methods Research funding levels were obtained from the NCI website and information for societal health and economic burdens were collected from government databases and published reports. We calculated the funding levels per unit burden for a wide range of different cancers and burden metrics and compared these values to identify discrepancies. Results Our analysis reveals a considerable mismatch between funding levels and burden. Some cancers are funded at levels far higher than their relative burden suggests (breast cancer, prostate cancer, and leukemia while other cancers appear underfunded (bladder, esophageal, liver, oral, pancreatic, stomach, and uterine cancers. Conclusions These discrepancies indicate that an improved method of health care research funding allocation should be investigated to better match funding levels to societal burden.

  2. Analysis of oral cancer epidemiology in the US reveals state-specific trends: implications for oral cancer prevention

    Directory of Open Access Journals (Sweden)

    Ditmyer Marcia

    2008-03-01

    Full Text Available Abstract Background Downward trends have been observed in oral cancer incidence and mortality in the US over the past 30 years; however, these declines are not uniform within this population. Several studies have now demonstrated an increase in the incidence and mortality from oral cancers among certain demographic groups, which may have resulted from increased risks or risk behaviors. This study examines the underlying data that comprise these trends, to identify specific populations that may be at greater risk for morbidity and mortality from oral cancers. Methods Oral cancer incidence and mortality data analyzed for this study were generated using the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER program. Results While oral cancer incidence and mortality rates have been declining over the past thirty years, these declines have reversed in the past five years among some demographic groups, including black females and white males. Sorting of these data by state revealed that eight states exhibited increasing rates of oral cancer deaths, Nevada, North Carolina, Iowa, Ohio, Maine, Idaho, North Dakota, and Wyoming, in stark contrast to the national downward trend. Furthermore, a detailed analysis of data from these states revealed increasing rates of oral cancer among older white males, also contrary to the overall trends observed at the national level. Conclusion These results signify that, despite the declining long-term trends in oral cancer incidence and mortality nationally, localized geographic areas exist where the incidence and mortality from oral cancers have been increasing. These areas represent sites where public health education and prevention efforts may be focused to target these specific populations in an effort to improve health outcomes and reduce disparities within these populations.

  3. Fragile States and Development Policy

    OpenAIRE

    Besley, Timothy J.; Persson, Torsten

    2011-01-01

    It is widely recognized that fragile states are key symptoms of under-development in many parts of the world. Such states are incapable of delivering basic services to their citizens and political violence is commonplace. As of yet, mainstream development economics has not dealt in any systematic way with such concerns and the implications for development assistance. This paper puts forward a frame-work for analyzing fragile states and applies it to a variety of development policies in differ...

  4. Aid allocation and fragile states

    OpenAIRE

    McGillivray, Mark

    2006-01-01

    This paper summarises research on aid allocation and effectiveness, highlighting the current findings of recent research on aid allocation to fragile states. Fragile states are defined by the donor community as those with either critically poor policies or poorly performing institutions, or both. The paper examines the research findings in the broader context of research and analysis on how aid should and is being allocated across all developing countries. Various aid allocation models and th...

  5. Potential microRNA-mediated oncogenic intercellular communication revealed by pan-cancer analysis

    Science.gov (United States)

    Li, Yue; Zhang, Zhaolei

    2014-11-01

    Carcinogenesis consists of oncogenesis and metastasis, and intriguingly microRNAs (miRNAs) are involved in both processes. Although aberrant miRNA activities are prevalent in diverse tumor types, the exact mechanisms for how they regulate cancerous processes are not always clear. To this end, we performed a large-scale pan-cancer analysis via a novel probabilistic approach to infer recurrent miRNA-target interactions implicated in 12 cancer types using data from The Cancer Genome Atlas. We discovered ~20,000 recurrent miRNA regulations, which are enriched for cancer-related miRNAs/genes. Notably, miRNA 200 family (miR-200/141/429) is among the most prominent miRNA regulators, which is known to be involved in metastasis. Importantly, the recurrent miRNA regulatory network is not only enriched for cancer pathways but also for extracellular matrix (ECM) organization and ECM-receptor interactions. The results suggest an intriguing cancer mechanism involving miRNA-mediated cell-to-cell communication, which possibly involves delivery of tumorigenic miRNA messengers to adjacent cells via exosomes. Finally, survival analysis revealed 414 recurrent-prognostic associations, where both gene and miRNA involved in each interaction conferred significant prognostic power in one or more cancer types. Together, our comprehensive pan-cancer analysis provided not only biological insights into metastasis but also brought to bear the clinical relevance of the proposed recurrent miRNA-gene associations.

  6. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin

    DEFF Research Database (Denmark)

    Hoadley, Katherine A; Yau, Christina; Wolf, Denise M;

    2014-01-01

    on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset......Recent genomic analyses of pathologically defined tumor types identify "within-a-tissue" disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform...... of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides...

  7. Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer.

    Science.gov (United States)

    Liang, Han; Cheung, Lydia W T; Li, Jie; Ju, Zhenlin; Yu, Shuangxing; Stemke-Hale, Katherine; Dogruluk, Turgut; Lu, Yiling; Liu, Xiuping; Gu, Chao; Guo, Wei; Scherer, Steven E; Carter, Hannah; Westin, Shannon N; Dyer, Mary D; Verhaak, Roeland G W; Zhang, Fan; Karchin, Rachel; Liu, Chang-Gong; Lu, Karen H; Broaddus, Russell R; Scott, Kenneth L; Hennessy, Bryan T; Mills, Gordon B

    2012-11-01

    Endometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Although previous studies have identified important common somatic mutations in endometrial cancer, they have primarily focused on a small set of known cancer genes and have thus provided a limited view of the molecular basis underlying this disease. Here we have developed an integrated systems-biology approach to identifying novel cancer genes contributing to endometrial tumorigenesis. We first performed whole-exome sequencing on 13 endometrial cancers and matched normal samples, systematically identifying somatic alterations with high precision and sensitivity. We then combined bioinformatics prioritization with high-throughput screening (including both shRNA-mediated knockdown and expression of wild-type and mutant constructs) in a highly sensitive cell viability assay. Our results revealed 12 potential driver cancer genes including 10 tumor-suppressor candidates (ARID1A, INHBA, KMO, TTLL5, GRM8, IGFBP3, AKTIP, PHKA2, TRPS1, and WNT11) and two oncogene candidates (ERBB3 and RPS6KC1). The results in the "sensor" cell line were recapitulated by siRNA-mediated knockdown in endometrial cancer cell lines. Focusing on ARID1A, we integrated mutation profiles with functional proteomics in 222 endometrial cancer samples, demonstrating that ARID1A mutations frequently co-occur with mutations in the phosphatidylinositol 3-kinase (PI3K) pathway and are associated with PI3K pathway activation. siRNA knockdown in endometrial cancer cell lines increased AKT phosphorylation supporting ARID1A as a novel regulator of PI3K pathway activity. Our study presents the first unbiased view of somatic coding mutations in endometrial cancer and provides functional evidence for diverse driver genes and mutations in this disease. PMID:23028188

  8. Analyzing proteasomal subunit expression reveals Rpt4 as a prognostic marker in stage II colorectal cancer.

    LENUS (Irish Health Repository)

    2012-02-01

    Colorectal cancer is a leading cause of cancer-related deaths worldwide. Early diagnosis and treatment of colorectal cancer is the key to improving survival rates and as such a need exists to identify patients who may benefit from adjuvant chemotherapy. The dysregulation of the ubiquitin-proteasome system (UPS) has been implicated in oncogenesis and cancer cell survival, and proteasome inhibitors are in clinical use for a number of malignancies including multiple myeloma. In our study, we examined the protein expression of several key components of the UPS in colorectal cancer using immunohistochemistry to determine expression levels of ubiquitinylated proteins and the proteasomal subunits, 20S core and Rpt4 in a cohort of 228 patients with colon cancer. Multivariate Cox analysis revealed that neither the intensity of either ubiquitinylated proteins or the 20S core was predictive in either Stage II or III colon cancer for disease free survival or overall survival. In contrast, in Stage II patients increased Rpt4 staining was significantly associated with disease free survival (Cox proportional hazard ratio 0.605; p = 0.0217). Our data suggest that Rpt4 is an independent prognostic variable for Stage II colorectal cancer and may aid in the decision of which patients undergo adjuvant chemotherapy.

  9. Expression and identification of folate-sensitive fragile sites in British Suffolk sheep (Ovis aries)

    Indian Academy of Sciences (India)

    Ahmad Ali; Muhammad Abdullah; Masroor Ellahi Babar; Khalid Javed; Asif Nadeem

    2008-12-01

    An investigation to understand the dynamics and biological significance of fragile site expression, and identification of 5-fluorodeoxyuridine (FUdR) induced chromosomal gaps/breaks, were carried out in an experimental flock of 45 Suffolk sheep. The statistical comparison revealed, highly significant variation in the frequency of chromosomal fragile site expression between control and FUdR cultures. Mean (± S.D.) values for cells with gaps and breaks, or aberrant cell count (AC), and the number of aberrations (NoA) per animal were 2.02 ± 0.34, 2.42 ± 0.48, 13.26 ± 0.85 and 21.87 ± 1.88 ($P \\lt 0.01$) in control and FUdR cultures, respectively. The comparison of age revealed nonsignificant variation between control and FUdR cultures. The G-band analysis of fragile site data revealed gaps in 29 autosomal and two X-chromosomal bands in the control cultures, whereas FUdR treated cultures scored 78 unstable bands in autosomes of which 56 were significantly fragile. X-chromosomes expressed breaks and gaps in six G-negative bands and five of them (Xq13, Xq15, Xq17, Xq24 and Xq26) were significantly fragile. The distribution comparison of autosomal fragile sites between sex groups did not reveal any significant variation. Female X-chromosomes were significantly more fragile than the male X-chromosomes. The distribution comparison for age groups (lambs versus adults) revealed significantly higher number of fragile bands in adults. Comparison of published data on reciprocal translocations in sheep with the fragile-site data obtained in this study indicated that the break sites of both phenomena were correlated. Similarities were also found between fragile sites and breakpoints of evolutionary significance in family Bovidae.

  10. Resilience and the Fragile City

    Directory of Open Access Journals (Sweden)

    John de Boer

    2015-04-01

    Full Text Available Humanitarian, security, and development actors are witnessing two distinct but intertwined trends that will have a dramatic impact on their operations. The first relates to the fact that the locus of global poverty and vulnerability to disaster are increasingly concentrated in fragile and conflict affected states. The second trend is associated with the notion that the world has entered a period of unprecedented urbanization. For the first time in history, more people live inside urban centres than outside of them. As the world continues to urbanize, global emergencies will increasingly be concentrated in cities, particularly in lower income and fragile countries where the pace of urbanization is fastest. Yet, despite the growing risks facing urban populations living in fragile and conflict affected countries, there is very little understanding of what can be done to reduce the risks posed to these cities and their populations.

  11. Molecular Subtyping of Serous Ovarian Tumors Reveals Multiple Connections to Intrinsic Breast Cancer Subtypes

    DEFF Research Database (Denmark)

    Jönsson, Jenny-Maria; Johansson, Ida; Dominguez-Valentin, Mev;

    2014-01-01

    OBJECTIVE: Transcriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities with the...... well-established intrinsic molecular subtypes of breast cancer. METHODS: Global gene expression profiling using Illumina's HT12 Bead Arrays was applied to 59 fresh-frozen serous ovarian malignant, benign and borderline tumors. Nearest centroid classification was performed applying previously published...... gene profiles for the ovarian and breast cancer subtypes. Correlations to gene expression modules representing key biological breast cancer features were also sought. Validation was performed using an independent, publicly available dataset. RESULTS: 5,944 genes were significantly differentially...

  12. Infantile Autism Associated with the Fragile-X Syndrome.

    Science.gov (United States)

    Meryash, David L.; And Others

    1982-01-01

    A six-year-old mentally retarded child is presented with a clinical picture consistent with the diagnosis of childhood autism. Chromosomal studies revealed a male karyotype with approximately 11 percent of the cells counted containing a fragile site on the X chromosome. (Author)

  13. Quantitative proteomics reveals middle infrared radiation-interfered networks in breast cancer cells.

    Science.gov (United States)

    Chang, Hsin-Yi; Li, Ming-Hua; Huang, Tsui-Chin; Hsu, Chia-Lang; Tsai, Shang-Ru; Lee, Si-Chen; Huang, Hsuan-Cheng; Juan, Hsueh-Fen

    2015-02-01

    Breast cancer is one of the leading cancer-related causes of death worldwide. Treatment of triple-negative breast cancer (TNBC) is complex and challenging, especially when metastasis has developed. In this study, we applied infrared radiation as an alternative approach for the treatment of TNBC. We used middle infrared (MIR) with a wavelength range of 3-5 μm to irradiate breast cancer cells. MIR significantly inhibited cell proliferation in several breast cancer cells but did not affect the growth of normal breast epithelial cells. We performed iTRAQ-coupled LC-MS/MS analysis to investigate the MIR-triggered molecular mechanisms in breast cancer cells. A total of 1749 proteins were identified, quantified, and subjected to functional enrichment analysis. From the constructed functionally enriched network, we confirmed that MIR caused G2/M cell cycle arrest, remodeled the microtubule network to an astral pole arrangement, altered the actin filament formation and focal adhesion molecule localization, and reduced cell migration activity and invasion ability. Our results reveal the coordinative effects of MIR-regulated physiological responses in concentrated networks, demonstrating the potential implementation of infrared radiation in breast cancer therapy. PMID:25556991

  14. Human pluripotent stem cell models of Fragile X syndrome.

    Science.gov (United States)

    Bhattacharyya, Anita; Zhao, Xinyu

    2016-06-01

    Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism. The causal mutation in FXS is a trinucleotide CGG repeat expansion in the FMR1 gene that leads to human specific epigenetic silencing and loss of Fragile X Mental Retardation Protein (FMRP) expression. Human pluripotent stem cells (PSCs), including human embryonic stem cells (ESCs) and particularly induced PSCs (iPSCs), offer a model system to reveal cellular and molecular events underlying human neuronal development and function in FXS. Human FXS PSCs have been established and have provided insight into the epigenetic silencing of the FMR1 gene as well as aspects of neuronal development. PMID:26640241

  15. Learning to deliver education in fragile states

    Directory of Open Access Journals (Sweden)

    Martin Greeley

    2006-07-01

    Full Text Available The Fragile States Group within the Development AssistanceCommittee (DAC of the Organisation for EconomicCooperation and Development is working to advise donors onprovision of education (and other services in ‘fragile states’.

  16. Learning to deliver education in fragile states

    OpenAIRE

    Martin Greeley; Pauline Rose

    2006-01-01

    The Fragile States Group within the Development AssistanceCommittee (DAC) of the Organisation for EconomicCooperation and Development is working to advise donors onprovision of education (and other) services in ‘fragile states’.

  17. Genetics Home Reference: fragile X syndrome

    Science.gov (United States)

    ... College of Medical Genetics Practice Guideline Boston Children's Hospital Centre for Genetics Education (Australia) Disease InfoSearch: Fragile X Syndrome Emory University School of Medicine: Fragile X Premutation--a Cause ...

  18. International Companies in Fragile States

    DEFF Research Database (Denmark)

    Patey, Luke; Kragelund, Peter

    Denmark must not fail to promote corporate social responsibility in fragile states. International companies remain active in these environments, and often worsen rather than alleviate poor governance. Financial transparency and human rights initiatives offer the first step in ensuring that this...

  19. Suicide Gene-Engineered Stromal Cells Reveal a Dynamic Regulation of Cancer Metastasis

    Science.gov (United States)

    Shen, Keyue; Luk, Samantha; Elman, Jessica; Murray, Ryan; Mukundan, Shilpaa; Parekkadan, Biju

    2016-02-01

    Cancer-associated fibroblasts (CAFs) are a major cancer-promoting component in the tumor microenvironment (TME). The dynamic role of human CAFs in cancer progression has been ill-defined because human CAFs lack a unique marker needed for a cell-specific, promoter-driven knockout model. Here, we developed an engineered human CAF cell line with an inducible suicide gene to enable selective in vivo elimination of human CAFs at different stages of xenograft tumor development, effectively circumventing the challenge of targeting a cell-specific marker. Suicide-engineered CAFs were highly sensitive to apoptosis induction in vitro and in vivo by the addition of a simple small molecule inducer. Selection of timepoints for targeted CAF apoptosis in vivo during the progression of a human breast cancer xenograft model was guided by a bi-phasic host cytokine response that peaked at early timepoints after tumor implantation. Remarkably, we observed that the selective apoptosis of CAFs at these early timepoints did not affect primary tumor growth, but instead increased the presence of tumor-associated macrophages and the metastatic spread of breast cancer cells to the lung and bone. The study revealed a dynamic relationship between CAFs and cancer metastasis that has counter-intuitive ramifications for CAF-targeted therapy.

  20. Genome-wide mRNA and miRNA expression profiling reveal multiple regulatory networks in colorectal cancer

    DEFF Research Database (Denmark)

    Vishnubalaji, R; Hamam, R; Abdulla, M-H;

    2015-01-01

    Despite recent advances in cancer management, colorectal cancer (CRC) remains the third most common cancer and a major health-care problem worldwide. MicroRNAs have recently emerged as key regulators of cancer development and progression by targeting multiple cancer-related genes; however...... upregulated and 1902 downregulated genes in CRC. Pathway analysis revealed significant enrichment in cell cycle, integrated cancer, Wnt (wingless-type MMTV integration site family member), matrix metalloproteinase, and TGF-β pathways in CRC. Pharmacological inhibition of Wnt (using XAV939 or IWP-2) or TGF...

  1. High-Resolution Genomic and Expression Profiling Reveals 105 Putative Amplification Target Genes in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Eija H. Mahlamaki

    2004-09-01

    Full Text Available Comparative genomic hybridization (CGH studies have provided a wealth of information on common copy number aberrations in pancreatic cancer, but the genes affected by these aberrations are largely unknown. To identify putative amplification target genes in pancreatic cancer, we performed a parallel copy number and expression survey in 13 pancreatic cancer cell lines using a 12,232-clone cDNA microarray, providing an average resolution of 300 kb throughout the human genome. CGH on cDNA microarray allowed highly accurate mapping of copy number increases and resulted in identification of 24 independent amplicons, ranging in size from 130 kb to 11 Mb. Statistical evaluation of gene copy number and expression data across all 13 cell lines revealed a set of 105 genes whose elevated expression levels were directly attributable to increased copy number. These included genes previously reported to be amplified in cancer as well as several novel targets for copy number alterations, such as p21-activated kinase 4 (PAK4, which was previously shown to be involved in cell migration, cell adhesion, and anchorage-independent growth. In conclusion, our results implicate a set of 105 genes that is likely to be actively involved in the development and progression of pancreatic cancer.

  2. Solutions to Peto's paradox revealed by mathematical modelling and cross-species cancer gene analysis.

    Science.gov (United States)

    Caulin, Aleah F; Graham, Trevor A; Wang, Li-San; Maley, Carlo C

    2015-07-19

    Whales have 1000-fold more cells than humans and mice have 1000-fold fewer; however, cancer risk across species does not increase with the number of somatic cells and the lifespan of the organism. This observation is known as Peto's paradox. How much would evolution have to change the parameters of somatic evolution in order to equalize the cancer risk between species that differ by orders of magnitude in size? Analysis of previously published models of colorectal cancer suggests that a two- to three-fold decrease in the mutation rate or stem cell division rate is enough to reduce a whale's cancer risk to that of a human. Similarly, the addition of one to two required tumour-suppressor gene mutations would also be sufficient. We surveyed mammalian genomes and did not find a positive correlation of tumour-suppressor genes with increasing body mass and longevity. However, we found evidence of the amplification of TP53 in elephants, MAL in horses and FBXO31 in microbats, which might explain Peto's paradox in those species. Exploring parameters that evolution may have fine-tuned in large, long-lived organisms will help guide future experiments to reveal the underlying biology responsible for Peto's paradox and guide cancer prevention in humans. PMID:26056366

  3. Ectodermal Dysplasia Skin Fragility Syndrome

    Directory of Open Access Journals (Sweden)

    Ayça Alan Atalay

    2014-06-01

    Full Text Available Ectodermal dysplasia-skin fragility syndrome (EDSFS is a rare autosomal recessive genodermatosis first described in 1997 by Mc Grath. EDSFS results from loss of function mutations in plakophilin-1 (PKP1. PKP1 is a structural component of desmosomes, cellcell adhesion complexes. It is also found as a nuclear protein in several cell types that are lack of desmosomes. In skin, however, PKP1 expression is confined mainly to suprabasal keratinocytes and the outer root sheath of hair follicules. Loss of function mutation in PKP1 leads to extensive skin fragility, bullae and erosions following minor trauma, focal keratoderma with painful fissures, alopecia, and nail dystrophy. In some patients hypohidrosis may also be seen. EDSFS is now considered as a specific suprabasal form of epidermolysis bullosa simplex. In this report we describe a 20 year old EDSFS case.

  4. Functional proteomic analysis reveals the involvement of KIAA1199 in breast cancer growth, motility and invasiveness

    International Nuclear Information System (INIS)

    KIAA1199 is a recently identified novel gene that is up-regulated in human cancer with poor survival. Our proteomic study on signaling polarity in chemotactic cells revealed KIAA1199 as a novel protein target that may be involved in cellular chemotaxis and motility. In the present study, we examined the functional significance of KIAA1199 expression in breast cancer growth, motility and invasiveness. We validated the previous microarray observation by tissue microarray immunohistochemistry using a TMA slide containing 12 breast tumor tissue cores and 12 corresponding normal tissues. We performed the shRNA-mediated knockdown of KIAA1199 in MDA-MB-231 and HS578T cells to study the role of this protein in cell proliferation, migration and apoptosis in vitro. We studied the effects of KIAA1199 knockdown in vivo in two groups of mice (n = 5). We carried out the SILAC LC-MS/MS based proteomic studies on the involvement of KIAA1199 in breast cancer. KIAA1199 mRNA and protein was significantly overexpressed in breast tumor specimens and cell lines as compared with non-neoplastic breast tissues from large-scale microarray and studies of breast cancer cell lines and tumors. To gain deeper insights into the novel role of KIAA1199 in breast cancer, we modulated KIAA1199 expression using shRNA-mediated knockdown in two breast cancer cell lines (MDA-MB-231 and HS578T), expressing higher levels of KIAA1199. The KIAA1199 knockdown cells showed reduced motility and cell proliferation in vitro. Moreover, when the knockdown cells were injected into the mammary fat pads of female athymic nude mice, there was a significant decrease in tumor incidence and growth. In addition, quantitative proteomic analysis revealed that knockdown of KIAA1199 in breast cancer (MDA-MB-231) cells affected a broad range of cellular functions including apoptosis, metabolism and cell motility. Our findings indicate that KIAA1199 may play an important role in breast tumor growth and invasiveness, and that it

  5. Financial Liberalization and Financial Fragility

    OpenAIRE

    Demirguc-Kent, Asli; Detragiache, Enrica

    1998-01-01

    The authors study the empirical relationship between banking crises and financial liberalization using a panel of data for 53 countries for 1980-95. They find that banking crises are more likely to occur in liberalized financial systems. But financial liberalization's impact on a fragile banking sector is weaker where the institutional environment is strong--especially where there is respect for the rule of law, a low level of corruption, and good contract enforcement. They examine evidence o...

  6. Parental Relationships in Fragile Families

    OpenAIRE

    McLanahan, Sara; Beck, Audrey N.

    2010-01-01

    As nonmarital childbearing escalated in the United States over the past half century, fragile families—defined as unmarried couples with children—drew increased interest from researchers and policy makers. Sara McLanahan and Audrey Beck discuss four aspects of parental relationships in these families: the quality of parents’ intimate relationship, the stability of that relationship, the quality of the co-parenting relationship among parents who live apart, and nonresident fathers’ involvement...

  7. Intermediation Costs and Financial Fragility

    OpenAIRE

    Kaplan, Cafer; Salman, Ferhan

    2007-01-01

    This paper studies implications of intermediation costs in credit markets. The presence of intermediation costs increases the amount of risky projects therefore results in financial fragility. Moreover, for an open economy that has a perfectly liberal capital account, prudent firms finance their projects from foreign markets therefore shrinking the domestic credit markets. The theoretical predictions of our model gains support by Turkish data for the 1991 – 2004 period. Data suggests that an ...

  8. UNION FORMATION IN FRAGILE FAMILIES*

    OpenAIRE

    Carlson, Marcia; McLanahan, Sara; England, Paula

    2004-01-01

    In this paper, we use data from a new longitudinal survey—the Fragile Families and Child Wellbeing Study—to examine union formation among unmarried parents who have just had a child together. We use multinomial logistic regression to estimate the effects of economic, cultural/interpersonal, and other factors on whether (relative to having no romantic relationship) parents are romantically involved living apart, cohabiting, or married to each other about one year after the child’s birth. Net o...

  9. Resilience and the Fragile City

    OpenAIRE

    John de Boer

    2015-01-01

    Humanitarian, security, and development actors are witnessing two distinct but intertwined trends that will have a dramatic impact on their operations. The first relates to the fact that the locus of global poverty and vulnerability to disaster are increasingly concentrated in fragile and conflict affected states. The second trend is associated with the notion that the world has entered a period of unprecedented urbanization. For the first time in history, more people live inside urban centre...

  10. LRpath analysis reveals common pathways dysregulated via DNA methylation across cancer types

    Directory of Open Access Journals (Sweden)

    Kim Jung H

    2012-10-01

    Full Text Available Abstract Background The relative contribution of epigenetic mechanisms to carcinogenesis is not well understood, including the extent to which epigenetic dysregulation and somatic mutations target similar genes and pathways. We hypothesize that during carcinogenesis, certain pathways or biological gene sets are commonly dysregulated via DNA methylation across cancer types. The ability of our logistic regression-based gene set enrichment method to implicate important biological pathways in high-throughput data is well established. Results We developed a web-based gene set enrichment application called LRpath with clustering functionality that allows for identification and comparison of pathway signatures across multiple studies. Here, we employed LRpath analysis to unravel the commonly altered pathways and other gene sets across ten cancer studies employing DNA methylation data profiled with the Illumina HumanMethylation27 BeadChip. We observed a surprising level of concordance in differential methylation across multiple cancer types. For example, among commonly hypomethylated groups, we identified immune-related functions, peptidase activity, and epidermis/keratinocyte development and differentiation. Commonly hypermethylated groups included homeobox and other DNA-binding genes, nervous system and embryonic development, and voltage-gated potassium channels. For many gene sets, we observed significant overlap in the specific subset of differentially methylated genes. Interestingly, fewer DNA repair genes were differentially methylated than expected by chance. Conclusions Clustering analysis performed with LRpath revealed tightly clustered concepts enriched for differential methylation. Several well-known cancer-related pathways were significantly affected, while others were depleted in differential methylation. We conclude that DNA methylation changes in cancer tend to target a subset of the known cancer pathways affected by genetic aberrations.

  11. Study on seismic equipment fragility analysis method

    International Nuclear Information System (INIS)

    Vulnerable points of nuclear power plants can be found through seismic PSA which is an effective method to evaluate the seismic effect on nuclear power plants, and fragility analysis is one important step for seismic PSA. In this paper, the concept of seismic equipment fragility is introduced, the mathematic model of seismic fragility is given, the determination of equipment failure modes is discussed, fragility analysis variables and methods (i. e. method based-on analysis and method based-on dynamic testing) are mainly studied, and finally median fragility, the distribution of randomness and uncertainty and HCLPF capacity can be calculated by formulations. On the other hand, when developing seismic fragility, there are three types of information that can be relied on: data from real earthquake experience, test data and analysis data, and this data used in specific nuclear plant need to be collected and completed. (authors)

  12. Jamming, Force Chains and Fragile Matter

    OpenAIRE

    Cates, M. E.; Wittmer, J.; Bouchaud, J. P.; Claudin, P.

    1998-01-01

    We consider materials whose mechanical integrity is the result of a jamming process. We argue that such media are generically "fragile": unable to support certain types of incremental loading without plastic rearrangement. Fragility is linked to the marginal stability of force chain networks within the material. Such ideas may be relevant to jammed colloids and poured sand. The crossover from fragile (when particles are rigid) to elastoplastic behavior is explored.

  13. Genotype prediction in the fragile X syndrome.

    OpenAIRE

    Hirst, M C; Nakahori, Y; Knight, S J; Schwartz, C.; Thibodeau, S.N.; Roche, A; Flint, T J; Connor, J M; Fryns, J P; Davies, K E

    1991-01-01

    Fragile X positive, mentally retarded males have been shown to have an insertion or amplification of DNA sequences at, or close to, the site of expression of the fragile site. We show here the application of the detection of such changes to the diagnosis of affected males and female carriers and the identification of normal transmitting males. One fragile X negative male with the clinical features of the Martin-Bell syndrome also possesses an inserted/amplified DNA sequence. The implications ...

  14. Development Strategies - The Future of Fragile States?

    OpenAIRE

    Clausen, Bo; Østerholt Jensen, Jeppe; Thurøe, Tess; Møllegaard Nielsen, Stefanie

    2013-01-01

    Taking a point of departure in a reflection on the future of fragile states, this project aims at proposing a theoretical framework for how to most effectively generate development in fragile states. The international development strategy of the Millennium Development Goals and the New Deal for Engagement in Fragile States will be used as empirical data due to representing, respectively, a one-fits-all strategy to development and a ‘new deal’ on how to engage in fragile states before being ab...

  15. Diffuse Muscular Pain, Skin Tightening, and Nodular Regenerative Hyperplasia Revealing Paraneoplastic Amyopathic Dermatomyositis due to Testicular Cancer

    Directory of Open Access Journals (Sweden)

    Sarah Norrenberg

    2012-01-01

    Full Text Available Paraneoplastic dermatomyositis (DM associated with testicular cancer is extremely rare. We report the case of a patient with skin tightening, polymyalgia, hypereosinophilia, and nodular regenerative hyperplasia revealing seminoma and associated paraneoplastic DM.

  16. An Investigation of Narrative Ability in Boys with Autism and Fragile X Syndrome

    OpenAIRE

    Hogan-Brown, Abigail L; Losh, Molly; Martin, Gary E.; Mueffelmann, Deborah J.

    2013-01-01

    Whereas pragmatic language difficulties are characteristic of both autism and Fragile X syndrome, it is unclear whether such deficits are qualitatively similar or whether certain skills are differentially affected. This study compared narrative competence in boys with autism, Fragile X syndrome, Down syndrome, and typical development. Results revealed that an interaction between diagnosis and nonverbal mental age predicted narrative microstructure (e.g., complex syntax) but not macrostructure...

  17. Meta-Analysis of Public Microarray Datasets Reveals Voltage-Gated Calcium Gene Signatures in Clinical Cancer Patients.

    Directory of Open Access Journals (Sweden)

    Chih-Yang Wang

    Full Text Available Voltage-gated calcium channels (VGCCs are well documented to play roles in cell proliferation, migration, and apoptosis; however, whether VGCCs regulate the onset and progression of cancer is still under investigation. The VGCC family consists of five members, which are L-type, N-type, T-type, R-type and P/Q type. To date, no holistic approach has been used to screen VGCC family genes in different types of cancer. We analyzed the transcript expression of VGCCs in clinical cancer tissue samples by accessing ONCOMINE (www.oncomine.org, a web-based microarray database, to perform a systematic analysis. Every member of the VGCCs was examined across 21 different types of cancer by comparing mRNA expression in cancer to that in normal tissue. A previous study showed that altered expression of mRNA in cancer tissue may play an oncogenic role and promote tumor development; therefore, in the present findings, we focus only on the overexpression of VGCCs in different types of cancer. This bioinformatics analysis revealed that different subtypes of VGCCs (CACNA1C, CACNA1D, CACNA1B, CACNA1G, and CACNA1I are implicated in the development and progression of diverse types of cancer and show dramatic up-regulation in breast cancer. CACNA1F only showed high expression in testis cancer, whereas CACNA1A, CACNA1C, and CACNA1D were highly expressed in most types of cancer. The current analysis revealed that specific VGCCs likely play essential roles in specific types of cancer. Collectively, we identified several VGCC targets and classified them according to different cancer subtypes for prospective studies on the underlying carcinogenic mechanisms. The present findings suggest that VGCCs are possible targets for prospective investigation in cancer treatment.

  18. Extreme genetic fragility of the HIV-1 capsid.

    Science.gov (United States)

    Rihn, Suzannah J; Wilson, Sam J; Loman, Nick J; Alim, Mudathir; Bakker, Saskia E; Bhella, David; Gifford, Robert J; Rixon, Frazer J; Bieniasz, Paul D

    2013-01-01

    Genetic robustness, or fragility, is defined as the ability, or lack thereof, of a biological entity to maintain function in the face of mutations. Viruses that replicate via RNA intermediates exhibit high mutation rates, and robustness should be particularly advantageous to them. The capsid (CA) domain of the HIV-1 Gag protein is under strong pressure to conserve functional roles in viral assembly, maturation, uncoating, and nuclear import. However, CA is also under strong immunological pressure to diversify. Therefore, it would be particularly advantageous for CA to evolve genetic robustness. To measure the genetic robustness of HIV-1 CA, we generated a library of single amino acid substitution mutants, encompassing almost half the residues in CA. Strikingly, we found HIV-1 CA to be the most genetically fragile protein that has been analyzed using such an approach, with 70% of mutations yielding replication-defective viruses. Although CA participates in several steps in HIV-1 replication, analysis of conditionally (temperature sensitive) and constitutively non-viable mutants revealed that the biological basis for its genetic fragility was primarily the need to coordinate the accurate and efficient assembly of mature virions. All mutations that exist in naturally occurring HIV-1 subtype B populations at a frequency >3%, and were also present in the mutant library, had fitness levels that were >40% of WT. However, a substantial fraction of mutations with high fitness did not occur in natural populations, suggesting another form of selection pressure limiting variation in vivo. Additionally, known protective CTL epitopes occurred preferentially in domains of the HIV-1 CA that were even more genetically fragile than HIV-1 CA as a whole. The extreme genetic fragility of HIV-1 CA may be one reason why cell-mediated immune responses to Gag correlate with better prognosis in HIV-1 infection, and suggests that CA is a good target for therapy and vaccination strategies

  19. What Should You Know about Fragile X Syndrome (FXS)?

    Science.gov (United States)

    ... is working to learn more about fragile X syndrome and fragile X-associated disorders to improve the health and well- ... Overview of other conditions that often occur with fragile X syndrome. Share with Your Friends How can my child ...

  20. Seismic fragility of nuclear power plant components (Phase 2): A fragility handbook on eighteen components

    International Nuclear Information System (INIS)

    Fragility estimates of seven equipment classes were published in earlier reports. This report presents fragility analysis results from eleven additional equipment categories. The fragility levels are expressed in probabilistic terms. For users' convenience, this concluding report includes a summary of fragility results of all eighteen equipment classes. A set of conversion factors based on judgment is recommended for use of the information for early vintage equipment. The knowledge gained in conducting the Component Fragility Program and similar other programs is expected to provide a new direction for seismic verification and qualification of equipment. 15 refs., 12 tabs

  1. Reversing the Effects of Fragile X Syndrome

    Science.gov (United States)

    Ogren, Marilee P.; Lombroso, Paul J.

    2008-01-01

    A research on how synaptic plasticity is abnormally regulated in fragile X syndrome and how this abnormality can be reversed by therapeutic interventions is presented. Fragile X syndrome is a disorder of synaptic plasticity that contributes to abnormal development and interferes with normal learning and memory.

  2. Speech Fluency in Fragile X Syndrome

    Science.gov (United States)

    Van Borsel, John; Dor, Orianne; Rondal, Jean

    2008-01-01

    The present study investigated the dysfluencies in the speech of nine French speaking individuals with fragile X syndrome. Type, number, and loci of dysfluencies were analysed. The study confirms that dysfluencies are a common feature of the speech of individuals with fragile X syndrome but also indicates that the dysfluency pattern displayed is…

  3. The Role of Chain Length in Nonergodicity Factor and Fragility of Polymers

    DEFF Research Database (Denmark)

    Dalle-Ferrie, Cecile; Niss, Kristine; Sokolov, Alexei;

    2010-01-01

    The mechanism that leads to different fragility values upon approaching the glass transition remains a topic of active discussion. Many researchers are trying to find an answer in the properties of the frozen glassy state. Following this approach, we focus here on a previously proposed relationship...... between the fragility of glass-formers and their nonergodicity factor, determined by inelastic X-ray scattering (IXS) in the glass. We extend this molecular liquid study to two model polymers— polystyrene (PS) and polyisobutylene (PIB)—for which we change the molecular weight. Polymers offer the...... opportunity to change the fragility without altering the chemical structure, just by changing the chain length. Thus, we specifically chose PS and PIB because they exhibit opposite dependences of fragility with molecular weight. Our analysis for these two polymers reveals no unique correlation between the...

  4. Chromosome fragility in Freemartin cattle

    Directory of Open Access Journals (Sweden)

    V. Barbieri

    2010-04-01

    Full Text Available The aim of the present study was to verify chromosome fragility in freemartin cattle using chromosome aberration (CA and sister chromatid exchange (SCE tests. A total of eighteen co-twins were investigated. Fourteen animals were identified as cytogenetically chimeric (2n=60, XX/XY while 4 were classified as normal. Freemartin cattle showed a higher percentage of aneuploid cells (18.64% and highly significant statistical differences (P < 0.001 in mean values of gaps (4.53 ± 2.05, chromatid breaks (0.26 ± 0.51, and significant statistical differences (P < 0.005 in mean values of chromosome breaks (0.12 ± 0.43 when compared to 10 control animals from single births (aneuploid cells, 11.20%; gaps, 2.01 ± 1.42; chromatid breaks, 0.05 ± 0.22; chromosome breaks, 0.02 ± 0.14.

  5. Phenotype-based cell-specific metabolic modeling reveals metabolic liabilities of cancer

    OpenAIRE

    Yizhak, Keren; Gaude, Edoardo; Le Dévédec, Sylvia; Waldman, Yedael Y.; Stein, Gideon Y.; van de Water, Bob; Frezza, Christian; Ruppin, Eytan

    2014-01-01

    eLife digest Cancer is not just one disease, but a collection of disorders; as such there is no single general treatment that is effective against all cancers. Different tissues and organs—including the lungs, skin, and kidneys—can get cancer, and each need different treatments. Even two patients with the same type of cancer might respond differently to the same treatment. Being able to distinguish between different cancer types would help doctors personalize a patient's cancer therapy—which ...

  6. Genomic Profiling of Thyroid Cancer Reveals a Role for Thyroglobulin in Metastasis.

    Science.gov (United States)

    Siraj, Abdul K; Masoodi, Tariq; Bu, Rong; Beg, Shaham; Al-Sobhi, Saif S; Al-Dayel, Fouad; Al-Dawish, Mohammed; Alkuraya, Fowzan S; Al-Kuraya, Khawla S

    2016-06-01

    Papillary thyroid carcinoma (PTC) has a wide geographic variation in incidence; it is most common in Saudi Arabia, where it is only second to breast cancer as the most common cancer among females. Genomic profiling of PTC from Saudi Arabia has not been attempted previously. We performed whole-exome sequencing of 101 PTC samples and the corresponding genomic DNA to identify genes with recurrent somatic mutations, then sequenced these genes by using a next-generation gene-panel approach in an additional 785 samples. In addition to BRAF, N-RAS, and H-RAS, which have previously been shown to be recurrently mutated in PTC, our analysis highlights additional genes, including thyroglobulin (TG), which harbored somatic mutations in 3% of the entire cohort. Surprisingly, although TG mutations were not exclusive to mutations in the RAS-MAP kinase pathway, their presence was associated with a significantly worse clinical outcome, which suggests a pathogenic role beyond driving initial oncogenesis. Analysis of metastatic PTC tissue revealed significant enrichment for TG mutations (p evolution. PMID:27236916

  7. Exome sequencing of a colorectal cancer family reveals shared mutation pattern and predisposition circuitry along tumor pathways.

    Science.gov (United States)

    Suleiman, Suleiman H; Koko, Mahmoud E; Nasir, Wafaa H; Elfateh, Ommnyiah; Elgizouli, Ubai K; Abdallah, Mohammed O E; Alfarouk, Khalid O; Hussain, Ayman; Faisal, Shima; Ibrahim, Fathelrahamn M A; Romano, Maurizio; Sultan, Ali; Banks, Lawrence; Newport, Melanie; Baralle, Francesco; Elhassan, Ahmed M; Mohamed, Hiba S; Ibrahim, Muntaser E

    2015-01-01

    The molecular basis of cancer and cancer multiple phenotypes are not yet fully understood. Next Generation Sequencing promises new insight into the role of genetic interactions in shaping the complexity of cancer. Aiming to outline the differences in mutation patterns between familial colorectal cancer cases and controls we analyzed whole exomes of cancer tissues and control samples from an extended colorectal cancer pedigree, providing one of the first data sets of exome sequencing of cancer in an African population against a background of large effective size typically with excess of variants. Tumors showed hMSH2 loss of function SNV consistent with Lynch syndrome. Sets of genes harboring insertions-deletions in tumor tissues revealed, however, significant GO enrichment, a feature that was not seen in control samples, suggesting that ordered insertions-deletions are central to tumorigenesis in this type of cancer. Network analysis identified multiple hub genes of centrality. ELAVL1/HuR showed remarkable centrality, interacting specially with genes harboring non-synonymous SNVs thus reinforcing the proposition of targeted mutagenesis in cancer pathways. A likely explanation to such mutation pattern is DNA/RNA editing, suggested here by nucleotide transition-to-transversion ratio that significantly departed from expected values (p-value 5e-6). NFKB1 also showed significant centrality along with ELAVL1, raising the suspicion of viral etiology given the known interaction between oncogenic viruses and these proteins. PMID:26442106

  8. Behavioral Phenotype of Fragile X Syndrome in Adolescence and Adulthood

    Science.gov (United States)

    Smith, Leann E.; Barker, Erin T.; Seltzer, Marsha Mailick; Abbeduto, Leonard; Greenberg, Jan S.

    2012-01-01

    The present study explored the behavioral profile of individuals with fragile X syndrome during adolescence and adulthood. Individuals with both fragile X syndrome and autism (n = 30) were compared with (a) individuals diagnosed with fragile X syndrome (but not autism; n = 106) and (b) individuals diagnosed with autism (but not fragile X syndrome;…

  9. Guidelines for the diagnosis of fragile X syndrome. National Fragile X Foundation.

    OpenAIRE

    Oostra, B A; Jacky, P B; Brown, W T; Rousseau, F.

    1993-01-01

    Direct DNA analysis of the fragile X mutation has become available with the isolation of DNA probes that detect the unstable DNA sequence containing the CGG repeat. We present the various alternatives of combinations of probes and enzymes that can be used for the diagnosis of fragile X syndrome. An overview is given of all the different available probes. A different protocol is presented for postnatal and prenatal diagnosis of fragile X syndrome. This includes Southern blot analysis as well a...

  10. Molecular portrait of breast cancer in China reveals comprehensive transcriptomic likeness to Caucasian breast cancer and low prevalence of luminal A subtype

    International Nuclear Information System (INIS)

    The recent dramatic increase in breast cancer incidence across China with progressive urbanization and economic development has signaled the urgent need for molecular and clinical detailing of breast cancer in the Chinese population. Our analyses of a unique transethnic collection of breast cancer frozen specimens from Shanghai Fudan Cancer Center (Chinese Han) profiled simultaneously with an analogous Caucasian Italian series revealed consistent transcriptomic data lacking in batch effects. The prevalence of Luminal A subtype was significantly lower in Chinese series, impacting the overall prevalence of estrogen receptor (ER)-positive disease in a large cohort of Chinese/Caucasian patients. Unsupervised and supervised comparison of gene and microRNA (miRNA) profiles of Chinese and Caucasian samples revealed extensive similarity in the comprehensive taxonomy of transcriptional elements regulating breast cancer biology. Partition of gene expression data using gene lists relevant to breast cancer as “intrinsic” and “extracellular matrix” genes identified Chinese and Caucasian subgroups with equivalent global gene and miRNA profiles. These findings indicate that in the Chinese and Caucasian groups, breast neoplasia and the surrounding stromal characteristics undergo the same differentiation and molecular processes. Transcriptional similarity across transethnic cohorts may simplify translational medicine approaches and clinical management of breast cancer patients worldwide

  11. Comprehensive profiling of DNA methylation in colorectal cancer reveals subgroups with distinct clinicopathological and molecular features

    International Nuclear Information System (INIS)

    Most previous studies of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) have been conducted on a relatively small numbers of CpG sites. In the present study we performed comprehensive DNA methylation profiling of CRC with the aim of characterizing CIMP subgroups. DNA methylation at 1,505 CpG sites in 807 cancer-related genes was evaluated using the Illumina GoldenGate® methylation array in 28 normal colonic mucosa and 91 consecutive CRC samples. Methylation data was analyzed using unsupervised hierarchical clustering. CIMP subgroups were compared for various clinicopathological and molecular features including patient age, tumor site, microsatellite instability (MSI), methylation at a consensus panel of CpG islands and mutations in BRAF and KRAS. A total of 202 CpG sites were differentially methylated between tumor and normal tissue. Unsupervised hierarchical clustering of methylation data from these sites revealed the existence of three CRC subgroups referred to as CIMP-low (CIMP-L, 21% of cases), CIMP-mid (CIMP-M, 14%) and CIMP-high (CIMP-H, 65%). In comparison to CIMP-L tumors, CIMP-H tumors were more often located in the proximal colon and showed more frequent mutation of KRAS and BRAF (P < 0.001). Comprehensive DNA methylation profiling identified three CRC subgroups with distinctive clinicopathological and molecular features. This study suggests that both KRAS and BRAF mutations are involved with the CIMP-H pathway of CRC rather than with distinct CIMP subgroups

  12. Mexico's crisis: financial modernisation and financial fragility

    OpenAIRE

    G. J. LÓPEZ

    1997-01-01

    The work seeks to analyse Mexico's recent exchange-rate crisis in relation to the debate on financial modernisation and external financial fragility. The author reviews some key features of Mexico's 1988-1994 economic recovery before analysing some aspects of the country's evolution in the light of the financial modernisation debate. An explanation of the crisis in which Mexico's external financial fragility is emphasised is provided. Finally, the relationship between financial modernisation ...

  13. Cardiac abnormalities in the fragile X syndrome.

    OpenAIRE

    Sreeram, N.; WREN, C.; Bhate, M; Robertson, P.; Hunter, S

    1989-01-01

    Twenty three patients with fragile X syndrome underwent cardiovascular assessment. Echocardiography showed dilatation of the aortic root in 12 (52%) and mitral valve prolapse in five (22%), four of whom had an apical mid-systolic click on auscultation. Patients with fragile X syndrome have cardiac defects similar to those seen in other disorders of connective tissue such as Marfan's syndrome and Ehlers-Danlos syndrome. These, and other somatic features, suggest an underlying connective tissue...

  14. Origins of Epilepsy in Fragile X Syndrome

    OpenAIRE

    Hagerman, Paul J.; STAFSTROM, CARL E

    2009-01-01

    Fragile X syndrome is the leading heritable form of cognitive impairment and the leading known monogenic disorder associated with autism. Roughly one-quarter of children with this disorder have seizures, most of which are relatively benign and are resolved beyond childhood. Because of the prevalence of fragile X syndrome, numerous animal models have been developed and electrophysiological studies have taken place to investigate its pathogenesis. The investigations have yielded a wealth of inf...

  15. Fragile African States: What Should Donors Do?

    OpenAIRE

    Collier, Paul

    2014-01-01

    1. IntroductionNecessarily, all donors will focus increasingly on fragile states. The more successful countries in Africa have achieved growing tax bases and are consequently now gaining access to global capital markets. For such countries, aid is becoming marginal. In contrast, fragile states, by the nature of their condition, have small tax bases and face risks which deter private capital: for them aid remains potentially important. Not only do donors provide a substantial proportion of gov...

  16. 'Fragile States' : introducing a political concept

    OpenAIRE

    Grimm, Sonja; Lemay-Hébert, Nicolas; Nay, Olivier

    2014-01-01

    The special issue 'Fragile States: A Political Concept’ investigates the emergence, dissemination and reception of the notion of ‘state fragility’. It analyses the process of conceptualisation, examining how the ‘fragile states’ concept was framed by policy makers to describe reality in accordance with their priorities in the fields of development and security. The contributors to the issue investigate the instrumental use of the ‘state fragility’ label in the legitimisation of Western polic...

  17. A common promoter hypomethylation signature in invasive breast, liver and prostate cancer cell lines reveals novel targets involved in cancer invasiveness

    Science.gov (United States)

    Yi, Cao; Li, Chen Chen; Yu, Patricia; Arakelian, Ani; Tanvir, Imrana; Khan, Haseeb Ahmed; Rabbani, Shafaat

    2015-01-01

    Cancer invasion and metastasis is the most morbid aspect of cancer and is governed by different cellular mechanisms than those driving the deregulated growth of tumors. We addressed here the question of whether a common DNA methylation signature of invasion exists in cancer cells from different origins that differentiates invasive from non-invasive cells. We identified a common DNA methylation signature consisting of hyper- and hypomethylation and determined the overlap of differences in DNA methylation with differences in mRNA expression using expression array analyses. A pathway analysis reveals that the hypomethylation signature includes some of the major pathways that were previously implicated in cancer migration and invasion such as TGF beta and ERBB2 triggered pathways. The relevance of these hypomethylation events in human tumors was validated by identification of the signature in several publicly available databases of human tumor transcriptomes. We shortlisted novel invasion promoting candidates and tested the role of four genes in cellular invasiveness from the list C11orf68, G0S2, SHISA2 and TMEM156 in invasiveness using siRNA depletion. Importantly these genes are upregulated in human cancer specimens as determined by immunostaining of human normal and cancer breast, liver and prostate tissue arrays. Since these genes are activated in cancer they constitute a group of targets for specific pharmacological inhibitors of cancer invasiveness. SUMMARY Our study provides evidence that common DNA hypomethylation signature exists between cancer cells derived from different tissues, pointing to a common mechanism of cancer invasiveness in cancer cells from different origins that could serve as drug targets. PMID:26427334

  18. A Genome-Wide Systematic Analysis Reveals Different and Predictive Proliferation Expression Signatures of Cancerous vs. Non-Cancerous Cells

    OpenAIRE

    Waldman, Yedael Y.; Geiger, Tamar; Ruppin, Eytan

    2013-01-01

    Understanding cell proliferation mechanisms has been a long-lasting goal of the scientific community and specifically of cancer researchers. Previous genome-scale studies of cancer proliferation determinants have mainly relied on knockdown screens aimed to gauge their effects on cancer growth. This powerful approach has several limitations such as off-target effects, partial knockdown, and masking effects due to functional backups. Here we employ a complementary approach and assign each gene ...

  19. Loss of fragile histidine triad protein in human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Po Zhao; Xin Song; Yuan-Yuan Nin; Ya-Li Lu; Xiang-Hong Li

    2003-01-01

    AIM: To investigate the expression of fragile histidine triad (FHIT) gene protein, Fhit, which is recently thought to be a candidate tumor suppressor. Abnormal expression of fragile histidine triad has been found in a variety of human cancers,but little is known about its expression in human hepatocellular carcinogenesis and evolution.METHODS: Sections of 83 primary human hepatocellular carcionoma with corresponding para-neoplastic liver tissue and 10 normal liver tissue were evaluated immunohistochemically for Fhit protein expression.RESULTS: All normal liver tissue and para-neoplastic liver tissue showed a strong expression of Fhit, whereas 50 of 83(65.0 %) carcinomas showed a marked loss or absence of Fhit expression. The differences of Fhit expression between carcinoma and normal or para-neoplastic liver tissue werehighly significant (P=0.000). The proportion of carcinomas with reduced Fhit expression showed an increasing trend (a) with decreasing differentiation or higher histological grade (P=0.219); (b) in tumors with higher clinical stage Ⅲ and ⅣV (91.3 %, P=0.000), compared with tumors with lower stage Ⅰ and Ⅱ (27.6 %); and (c) in cancers with bigger tumor size (>50 mm) (75.0 %, P=0.017), compared withsmaller tumor size (≤ 50 mm). CONCLUSION: FHIT inactivation seems to be both an earlyand a later event, associated with carcinogenesis andprogression to more aggressive hepatocellular carcinomas.Thus, evaluation of Fhit expression by immunohistochemistryin hepatocellular carcinoma may provide important diagnosticand prognostic information in clinical application.

  20. High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities.

    Science.gov (United States)

    Hart, Traver; Chandrashekhar, Megha; Aregger, Michael; Steinhart, Zachary; Brown, Kevin R; MacLeod, Graham; Mis, Monika; Zimmermann, Michal; Fradet-Turcotte, Amelie; Sun, Song; Mero, Patricia; Dirks, Peter; Sidhu, Sachdev; Roth, Frederick P; Rissland, Olivia S; Durocher, Daniel; Angers, Stephane; Moffat, Jason

    2015-12-01

    The ability to perturb genes in human cells is crucial for elucidating gene function and holds great potential for finding therapeutic targets for diseases such as cancer. To extend the catalog of human core and context-dependent fitness genes, we have developed a high-complexity second-generation genome-scale CRISPR-Cas9 gRNA library and applied it to fitness screens in five human cell lines. Using an improved Bayesian analytical approach, we consistently discover 5-fold more fitness genes than were previously observed. We present a list of 1,580 human core fitness genes and describe their general properties. Moreover, we demonstrate that context-dependent fitness genes accurately recapitulate pathway-specific genetic vulnerabilities induced by known oncogenes and reveal cell-type-specific dependencies for specific receptor tyrosine kinases, even in oncogenic KRAS backgrounds. Thus, rigorous identification of human cell line fitness genes using a high-complexity CRISPR-Cas9 library affords a high-resolution view of the genetic vulnerabilities of a cell. PMID:26627737

  1. Exon-level transcriptome profiling in murine breast cancer reveals splicing changes specific to tumors with different metastatic abilities.

    Directory of Open Access Journals (Sweden)

    Amandine Bemmo

    Full Text Available BACKGROUND: Breast cancer is the second most frequent type of cancer affecting women. We are increasingly aware that changes in mRNA splicing are associated with various characteristics of cancer. The most deadly aspect of cancer is metastasis, the process by which cancer spreads from the primary tumor to distant organs. However, little is known specifically about the involvement of alternative splicing in the formation of macroscopic metastases. Our study investigates transcript isoform changes that characterize tumors of different abilities to form growing metastases. METHODS AND FINDINGS: To identify alternative splicing events (ASEs that are associated with the fully metastatic phenotype in breast cancer, we used Affymetrix Exon Microarrays to profile mRNA isoform variations genome-wide in weakly metastatic (168FARN and 4T07 and highly metastatic (4T1 mammary carcinomas. Statistical analysis identified significant expression changes in 7606 out of 155,994 (4% exons and in 1725 out of 189,460 (1% intronic regions, which affect 2623 out of 16,654 (16% genes. These changes correspond to putative alternative isoforms-several of which are novel-that are differentially expressed between tumors of varying metastatic phenotypes. Gene pathway analysis showed that 1224 of genes expressing alternative isoforms were involved in cell growth, cell interactions, cell proliferation, cell migration and cell death and have been previously linked to cancers and genetic disorders. We chose ten predicted splice variants for RT-PCR validation, eight of which were successfully confirmed (MED24, MFI2, SRRT, CD44, CLK1 and HNRNPH1. These include three novel intron retentions in CD44, a gene in which isoform variations have been previously associated with the metastasis of several cancers. CONCLUSION: Our findings reveal that various genes are differently spliced and/or expressed in association with the metastatic phenotype of tumor cells. Identification of

  2. Fragile X syndrome associated with tic disorders.

    Science.gov (United States)

    Schneider, Susanne A; Robertson, Mary M; Rizzo, Renata; Turk, Jeremy; Bhatia, Kailash P; Orth, Michael

    2008-06-15

    Movement disorders other than late onset tremor-ataxia in association with fragile X syndrome, the most common identifiable cause of inherited mental retardation, seem to be rare. Here we describe five male patients from three unrelated families with fragile X syndrome that presented with motor and phonic tics. Clinically, 4 patients fulfilled diagnostic criteria for Gilles de la Tourette syndrome (GTS) while 1 patient would have been diagnosed with an adult onset tic disorder. However, in all patients onset of tics was considerably later than in typical GTS. Three patients had atypical tics and two patients reported waxing and waning of tic intensity over time. Four of the 5 patients showed clinical signs typical of fragile X syndrome, in particular dysmorphic features, learning difficulties and speech and language problems that required special treatment. All patients had co-morbidities common to both GTS and fragile X syndrome. We suggest considering fragile X syndrome in GTS complicated by co-morbidity with late onset of atypical tics, in particular when learning disability and dysmorphic features are present. PMID:18383111

  3. Cytogenomic profiling of breast cancer brain metastases reveals potential for repurposing targeted therapeutics

    OpenAIRE

    Bollig-Fischer, Aliccia; Michelhaugh, Sharon K.; Wijesinghe, Priyanga; Dyson, Greg; Kruger, Adele; Palanisamy, Nallasivam; Choi, Lydia; Alosh, Baraa; Ali-Fehmi, Rouba; Mittal, Sandeep

    2015-01-01

    Breast cancer brain metastases remain a significant clinical problem. Chemotherapy is ineffective and a lack of treatment options result in poor patient outcomes. Targeted therapeutics have proven to be highly effective in primary breast cancer, but lack of molecular genomic characterization of metastatic brain tumors is hindering the development of new treatment regimens. Here we contribute to fill this void by reporting on gene copy number variation (CNV) in 10 breast cancer metastatic brai...

  4. Gene expression profiling revealed novel mechanism of action of Taxotere and Furtulon in prostate cancer cells

    International Nuclear Information System (INIS)

    Both Taxotere and Capecitabine have shown anti-cancer activity against various cancers including prostate cancer. In combination, Taxotere plus Capecitabine has demonstrated higher anti-cancer activity in advanced breast cancers. However, the molecular mechanisms of action of Taxotere and Capecitabine have not been fully elucidated in prostate cancer. The total RNA from PC3 and LNCaP prostate cells untreated and treated with 2 nM Taxotere, 110 μM Furtulon (active metabolite of Capecitabine), or 1 nM Taxotere plus 50 μM Furtulon for 6, 36, and 72 hours, was subjected to Affymetrix Human Genome U133A Array analysis. Real-time PCR and Western Blot analysis were conducted to confirm microarray data. Taxotere and Furtulon down-regulated some genes critical for cell proliferation, cell cycle progression, transcription factor, cell signaling, and oncogenesis, and up-regulated some genes related to the induction of apoptosis, cell cycle arrest, and differentiation in both cell lines. Taxotere and Furtulon also up-regulated some genes responsible for chemotherapeutic resistance, suggesting the induction of cancer cell resistance to these agents. Taxotere and Furtulon caused the alternation of a large number of genes, many of which may contribute to the molecular mechanisms by which Taxotere and Furtulon inhibit the growth of prostate cancer cells. This information could be utilized for further mechanistic research and for devising optimized therapeutic strategies against prostate cancer

  5. Comments on seismic fragility of nuclear power plant components

    International Nuclear Information System (INIS)

    Recent advances in the prediction of seismic hazard have resulted in concern that some nuclear power plant sites could experience seismic events in excess of their design bases. This concern, along with the considerable interest that has arisen from interpretations of probabilistic risk assessments, has resulted in significant professional activity in the prediction of fragilities of structures and equipment. Several programs sponsored by utilities, regulators and EPRI are addressing many of the aspects of seismic fragility. This paper discusses the current state-of-the-art in fragility prediction, fragility data sources, relative seismic ruggedness of power plant components, problem areas in fragility prediction, and suggested future work in fragility testing

  6. Integrated analysis of whole genome and transcriptome sequencing reveals diverse transcriptomic aberrations driven by somatic genomic changes in liver cancers.

    Directory of Open Access Journals (Sweden)

    Yuichi Shiraishi

    Full Text Available Recent studies applying high-throughput sequencing technologies have identified several recurrently mutated genes and pathways in multiple cancer genomes. However, transcriptional consequences from these genomic alterations in cancer genome remain unclear. In this study, we performed integrated and comparative analyses of whole genomes and transcriptomes of 22 hepatitis B virus (HBV-related hepatocellular carcinomas (HCCs and their matched controls. Comparison of whole genome sequence (WGS and RNA-Seq revealed much evidence that various types of genomic mutations triggered diverse transcriptional changes. Not only splice-site mutations, but also silent mutations in coding regions, deep intronic mutations and structural changes caused splicing aberrations. HBV integrations generated diverse patterns of virus-human fusion transcripts depending on affected gene, such as TERT, CDK15, FN1 and MLL4. Structural variations could drive over-expression of genes such as WNT ligands, with/without creating gene fusions. Furthermore, by taking account of genomic mutations causing transcriptional aberrations, we could improve the sensitivity of deleterious mutation detection in known cancer driver genes (TP53, AXIN1, ARID2, RPS6KA3, and identified recurrent disruptions in putative cancer driver genes such as HNF4A, CPS1, TSC1 and THRAP3 in HCCs. These findings indicate genomic alterations in cancer genome have diverse transcriptomic effects, and integrated analysis of WGS and RNA-Seq can facilitate the interpretation of a large number of genomic alterations detected in cancer genome.

  7. Kerr black holes are not fragile

    Energy Technology Data Exchange (ETDEWEB)

    McInnes, Brett, E-mail: matmcinn@nus.edu.sg [Centro de Estudios Cientificos (CECs), Valdivia (Chile); National University of Singapore (Singapore)

    2012-04-21

    Certain AdS black holes are 'fragile', in the sense that, if they are deformed excessively, they become unstable to a fundamental non-perturbative stringy effect analogous to Schwinger pair-production [of branes]. Near-extremal topologically spherical AdS-Kerr black holes, which are natural candidates for string-theoretic models of the very rapidly rotating black holes that have actually been observed to exist, do represent a very drastic deformation of the AdS-Schwarzschild geometry. One therefore has strong reason to fear that these objects might be 'fragile', which in turn could mean that asymptotically flat rapidly rotating black holes might be fragile in string theory. Here we show that this does not happen: despite the severe deformation implied by near-extremal angular momenta, brane pair-production around topologically spherical AdS-Kerr-Newman black holes is always suppressed.

  8. FRAGILE X-SYNDROME AND MENTAL RETARDATION

    Directory of Open Access Journals (Sweden)

    Ana MOMIROVSKA

    2000-06-01

    Full Text Available Fragile X-Syndrome is the most common inherited form of mental retardation. The disease is caused by defect of the fragile X mental retardation gene (FMR 1, located on X chromosome, due to expansion of the repetitive CGG sequence in the promoter region. The modern approach for diagnosis of the disease is based on the use of direct DNA analysis of the FMR 1 gene. Recombinant DNA technology techniques overcome the deficiencies of the cyto-genetic test, such as large number of false positive results.In the molecular diagnostics of Fragile X-Syndrome, two basic DNA methods are used: a Southern blot analysis of Eco RI or Eco R I/Eag I digested DNA samples and b PCR for amplification of CG rich regions. Southern blot is used for detection of full mutations and premutations, and PCR for normal and premutation alleles sizing.

  9. Transcriptome network analysis reveals potential candidate genes for squamous lung cancer.

    Science.gov (United States)

    Bai, Jing; Hu, Sheng

    2012-01-01

    Squamous lung cancer is a common type of lung cancer; however, its mechanism of oncogenesis is still unknown. The aim of this study was to screen candidate genes of squamous lung cancer using a bioinformatics strategy and elucidate the mechanism of squamous lung cancer. Published microarray data of the GSE3268 series was obtained from Gene Expression Omnibus (GEO). Significance analysis of microarrays was performed using the software R, and differentially expressed genes by R analysis were harvested. The relationship between transcription factors and target genes in cancer were collected from the Transcriptional regulatory element database. A transcriptome network analysis method was used to construct gene regulation networks and select the candidate genes for squamous lung cancer. SPI1, FLI1, FOS, ETS2, EGR1 and PPARG were defined as candidate genes for squamous lung cancer by the transcriptome network analysis method. Among them, 5 genes had been reported to be involved in lung cancer, except SPI1 and FLI1. Effective recall on previous knowledge conferred strong confidence in these methods. It is demonstrated that transcriptome network analysis is useful in the identification of candidate genes in disease. PMID:21922129

  10. Insular Volume Reduction in Fragile X Syndrome

    OpenAIRE

    Cohen, Jeremy D.; Nichols, Taylor; Brignone, Laura; Hall, Scott S.; Reiss, Allan L.

    2011-01-01

    Fragile X Syndrome (FraX) is the most common form of inherited mental deficit and is caused by mutations of the Fragile X Mental Retardation 1 (FMR1) gene on the X chromosome. While males and females with the full FMR1 mutation are affected differently because the disorder is X-linked, both suffer from varying degrees of cognitive impairment, attention deficits and social anxiety. The insula is a sensory integrative region that has been increasingly suggested as a critical area involved in an...

  11. Aid and growth in fragile states

    OpenAIRE

    McGillivray, Mark; Feeny, Simon

    2008-01-01

    The literature on aid has come a long way in recent years, and as a result we now know much more about aid effectiveness than possibly ever before. But significant gaps in knowledge remain. One such gap is the effectiveness of aid in the so-called ‘fragile states’, countries with critically low policy and institutional performance ratings. The current paper addresses this void by examining possible links between aid and economic growth in fragile states. It finds that: (i) growth would have b...

  12. Mass Spectrometry-Based Quantitative Metabolomics Revealed a Distinct Lipid Profile in Breast Cancer Patients

    Directory of Open Access Journals (Sweden)

    Yun Yen

    2013-04-01

    Full Text Available Breast cancer accounts for the largest number of newly diagnosed cases in female cancer patients. Although mammography is a powerful screening tool, about 20% of breast cancer cases cannot be detected by this method. New diagnostic biomarkers for breast cancer are necessary. Here, we used a mass spectrometry-based quantitative metabolomics method to analyze plasma samples from 55 breast cancer patients and 25 healthy controls. A number of 30 patients and 20 age-matched healthy controls were used as a training dataset to establish a diagnostic model and to identify potential biomarkers. The remaining samples were used as a validation dataset to evaluate the predictive accuracy for the established model. Distinct separation was obtained from an orthogonal partial least squares-discriminant analysis (OPLS-DA model with good prediction accuracy. Based on this analysis, 39 differentiating metabolites were identified, including significantly lower levels of lysophosphatidylcholines and higher levels of sphingomyelins in the plasma samples obtained from breast cancer patients compared with healthy controls. Using logical regression, a diagnostic equation based on three metabolites (lysoPC a C16:0, PC ae C42:5 and PC aa C34:2 successfully differentiated breast cancer patients from healthy controls, with a sensitivity of 98.1% and a specificity of 96.0%.

  13. Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS)

    Science.gov (United States)

    ... Resources and Publications Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS): Overview Skip sharing on social media ... this: Page Content Fragile X-associated tremor and ataxia syndrome (FXTAS) is a late-onset condition (occurs ...

  14. What Are the Treatments for Fragile X Syndrome?

    Science.gov (United States)

    ... Resources and Publications What are the treatments for Fragile X syndrome? Skip sharing on social media links Share this: Page Content There is no single treatment for Fragile X syndrome, but there are treatments that help minimize the ...

  15. How Do Health Care Providers Diagnose Fragile X Syndrome?

    Science.gov (United States)

    ... and Publications How do health care providers diagnose Fragile X syndrome? Skip sharing on social media links Share this: ... information helps families and providers to prepare for Fragile X syndrome and to intervene as early as possible. Possible ...

  16. A Way to Effective Service Delivery in Fragile States

    OpenAIRE

    Swaminath, Anoop

    2009-01-01

    Success and effectiveness in service delivery can establish the legitimacy of a fragile state’s government, and thereby reduce its fragility. Public-private partnerships offer a viable approach to achieving this goal.

  17. Fragility Assessment of Piping System in Ulchin 5, 6 NPP based on JNES Results

    International Nuclear Information System (INIS)

    A Piping system is one of the most important systems in NPP, because a piping system carries coolant of NPP system. Failure of piping system reveals LOCA (loss of coolant accident) which can cause core damage. LOCA divide as large, medium and small LOCA according to a size of piping system. Even though LOCA is one of the most important accidents in NPP, LOCA is only considered in the case of internal event in Korea. But JNES (Japan Nuclear Energy Safety Organization) already performed a fragility analysis about piping systems in PWR and BWR system in Japan. And also Japan considered a failure of piping system in the case of seismic event. In this study, fragility results of Japanese NPP were investigated and fragility of piping system in Korea was evaluated by applying to Japanese method

  18. Biomarker screening of oral cancer cell lines revealed sub-populations of CD133-, CD44-, CD24- and ALDH1- positive cancer stem cells

    Directory of Open Access Journals (Sweden)

    Kendall K

    2013-05-01

    Full Text Available Head and neck squamous cell carcinoma (HNSCC ranks sixth worldwide for cancer-related mortality. For the past several decades the mainstay of treatment for HNSCC has been surgery and external beam radiation, although more recent trials combining chemotherapy and radiation have demonstrated improvements. However, cancer recurrence and treatment failures continue to occur in a significant percentage of patients. Recent advances in tumor biology have led to the discovery that many cancers, including HNSCC, may contain subpopulations of cells with stem cell-like properties that may explain relapse and recurrence. The objective of this study was to screen existing oral cancer cell lines for biomarkers specific for cells with stem cell-like properties. RNA was isolated for RT-PCR screening using primers for specific mRNA of the biomarkers: CD44, CD24, CD133, NANOG, Nestin, ALDH1, and ABCG2 in CAL27, SCC25 and SCC15 cells. This analysis revealed that some oral cancer cell lines (CAL27 and SCC25 may contain small subpopulations of adhesion- and contact-independent cells (AiDC that also express tumor stem cell markers, including CD44, CD133, and CD24. In addition, CAL27 cells also expressed the intracellular tumor stem cell markers, ALDH1 and ABCG2. Isolation and culture of the adhesion- and contact-independent cells from CAL27 and SCC25 populations revealed differential proliferation rates and more robust inhibition by the MEK inhibitor PD98059, as well as the chemotherapeutic agents Cisplatin and Paclitaxel, within the AiDC CAL27 cells. At least one oral cancer cell line (CAL27 contained subpopulations of cells that express specific biomarkers associated with tumor stem cells which were morphologically and phenotypically distinct from other cells within this cell line.

  19. Behavioral Phenotype of Fragile X Syndrome in Adolescence and Adulthood

    OpenAIRE

    Smith, Leann E.; Barker, Erin T.; Seltzer, Marsha Mailick; Abbeduto, Leonard; Greenberg, Jan S.

    2012-01-01

    The present study explored the behavioral profile of individuals with fragile X syndrome during adolescence and adulthood. Individuals with both fragile X syndrome and autism (n = 30) were compared with (a) individuals diagnosed with fragile X syndrome (but not autism; n = 106) and (b) individuals diagnosed with autism (but not fragile X syndrome; n = 135) on measures of autism symptoms, adaptive functioning, behavior problems, and psychological symptoms. Results indicated that individuals du...

  20. Sovereignty in fragile states in the age of international intervention

    OpenAIRE

    Jensen, Maria Mørch

    2012-01-01

    This thesis examines what influence United Nations peacebuilding missions have on the sovereignty of fragile states in Africa. The starting point for the analysis is the nature of the fragile state and an examination of how the condition of fragility influences the presence of sovereignty in these states. The thesis distinguishes itself by recognising the relationship between the two entities and establishes an understanding of fragile state’s sovereignty as a tool for negotiation when it com...

  1. Aging in Fragile X Premutation Carriers.

    Science.gov (United States)

    Lozano, Reymundo; Saito, Naomi; Reed, Dallas; Eldeeb, Marwa; Schneider, Andrea; Hessl, David; Tassone, Flora; Beckett, Laurel; Hagerman, Randi

    2016-10-01

    It is now recognized that FMR1 premutation carriers (PC) are at risk to develop a range of neurological, psychiatric, and immune-mediated disorders during adulthood. There are conflicting findings regarding the incidence of hypertension, hypothyroidism, diabetes, and cancer in these patients that warrant further study. A retrospective controlled study was performed in a convenience sample of 248 controls (130 men, 118 women) and 397 FMR1 PC with and without fragile X-associated tremor ataxia syndrome (FXTAS) (176 men, 221 women); all participants were at least 45 years old (men: mean 62.4, SD 9.5; women: mean 62.8, SD 9.9; p = 0.63). Memory and cognitive assessments (Wechsler Adult Intelligence Scale (WAIS-III), Wechsler Memory Scale (WMS-III)) and molecular testing (CGG repeats and FMR1-mRNA levels) were performed. Additional data included body mass index (BMI), cholesterol levels, blood pressure, hemoglobin A1c (HbA1c) levels, and medical history. A higher percentage of PC subjects self-reported having a diagnosis of hypertension (50.0 vs. 35.0 %, p = 0.006) and thyroid problems (20.4 vs. 10.0 %, p = 0.012) than control subjects. When comparing controls versus PC with FXTAS, the association was higher for diabetes (p = 0.043); however, the effect was not significant after adjusting for demographic predictors. Blood pressure, blood glucose levels, HbA1c, and BMI values were not significantly different between the two groups. The PC with FXTAS group performed consistently lower in neuropsychological testing compared with the PC without FXTAS group, but the differences were very small for all but the WAIS full-scale IQ. Based on these findings, it appears that the risk for hypertension, thyroid problems, and diabetes may be more frequent in PC with FXTAS, which will require verification in future studies. PMID:27334385

  2. Deep Proteomics of Breast Cancer Cells Reveals that Metformin Rewires Signaling Networks Away from a Pro-growth State.

    Science.gov (United States)

    Sacco, Francesca; Silvestri, Alessandra; Posca, Daniela; Pirrò, Stefano; Gherardini, Pier Federico; Castagnoli, Luisa; Mann, Matthias; Cesareni, Gianni

    2016-03-23

    Metformin is the most frequently prescribed drug for type 2 diabetes. In addition to its hypoglycemic effects, metformin also lowers cancer incidence. This anti-cancer activity is incompletely understood. Here, we profiled the metformin-dependent changes in the proteome and phosphoproteome of breast cancer cells using high-resolution mass spectrometry. In total, we quantified changes of 7,875 proteins and 15,813 phosphosites after metformin changes. To interpret these datasets, we developed a generally applicable strategy that overlays metformin-dependent changes in the proteome and phosphoproteome onto a literature-derived network. This approach suggested that metformin treatment makes cancer cells more sensitive to apoptotic stimuli and less sensitive to pro-growth stimuli. These hypotheses were tested in vivo; as a proof-of-principle, we demonstrated that metformin inhibits the p70S6K-rpS6 axis in a PP2A-phosphatase dependent manner. In conclusion, analysis of deep proteomics reveals both detailed and global mechanisms that contribute to the anti-cancer activity of metformin. PMID:27135362

  3. Comprehensive long-span paired-end-tag mapping reveals characteristic patterns of structural variations in epithelial cancer genomes

    Science.gov (United States)

    Hillmer, Axel M.; Yao, Fei; Inaki, Koichiro; Lee, Wah Heng; Ariyaratne, Pramila N.; Teo, Audrey S.M.; Woo, Xing Yi; Zhang, Zhenshui; Zhao, Hao; Ukil, Leena; Chen, Jieqi P.; Zhu, Feng; So, Jimmy B.Y.; Salto-Tellez, Manuel; Poh, Wan Ting; Zawack, Kelson F.B.; Nagarajan, Niranjan; Gao, Song; Li, Guoliang; Kumar, Vikrant; Lim, Hui Ping J.; Sia, Yee Yen; Chan, Chee Seng; Leong, See Ting; Neo, Say Chuan; Choi, Poh Sum D.; Thoreau, Hervé; Tan, Patrick B.O.; Shahab, Atif; Ruan, Xiaoan; Bergh, Jonas; Hall, Per; Cacheux-Rataboul, Valère; Wei, Chia-Lin; Yeoh, Khay Guan; Sung, Wing-Kin; Bourque, Guillaume; Liu, Edison T.; Ruan, Yijun

    2011-01-01

    Somatic genome rearrangements are thought to play important roles in cancer development. We optimized a long-span paired-end-tag (PET) sequencing approach using 10-Kb genomic DNA inserts to study human genome structural variations (SVs). The use of a 10-Kb insert size allows the identification of breakpoints within repetitive or homology-containing regions of a few kilobases in size and results in a higher physical coverage compared with small insert libraries with the same sequencing effort. We have applied this approach to comprehensively characterize the SVs of 15 cancer and two noncancer genomes and used a filtering approach to strongly enrich for somatic SVs in the cancer genomes. Our analyses revealed that most inversions, deletions, and insertions are germ-line SVs, whereas tandem duplications, unpaired inversions, interchromosomal translocations, and complex rearrangements are over-represented among somatic rearrangements in cancer genomes. We demonstrate that the quantitative and connective nature of DNA–PET data is precise in delineating the genealogy of complex rearrangement events, we observe signatures that are compatible with breakage-fusion-bridge cycles, and we discover that large duplications are among the initial rearrangements that trigger genome instability for extensive amplification in epithelial cancers. PMID:21467267

  4. An association of vertebral breast cancer metastasis and multiple myeloma, revealed by a spinal cord compression

    OpenAIRE

    Kherfani, Abdelhakim; Amri, Khalil; Hachem, Mahjoub; Abid, Leila; Bouaziz, Mouna; Mestiri, Mondher

    2014-01-01

    Authors describe the case of a patient with breast cancer and multiple myeloma as the second metachronous disease responsible for spinal cord compression. Synchronous occurrence of bone marrow breast cancer disease and multiple myeloma has not been described in the literature, as in this case. By presenting this case, we point to possible association between both diseases and the possible factors involved in the development of second malignant disease.

  5. Network analysis of ChIP-Seq data reveals key genes in prostate cancer

    OpenAIRE

    Zhang, Yu; Huang, Zhen; Zhu, Zhiqiang; Liu, Jianwei; Zheng, Xin; Zhang, Yuhai

    2014-01-01

    Background Prostate cancer (PC) is the second most common cancer among men in the United States, and it imposes a considerable threat to human health. A deep understanding of its underlying molecular mechanisms is the premise for developing effective targeted therapies. Recently, deep transcriptional sequencing has been used as an effective genomic assay to obtain insights into diseases and may be helpful in the study of PC. Methods In present study, ChIP-Seq data for PC and normal samples we...

  6. Integrated analysis of breast cancer cell lines reveals unique signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Heiser, Laura M.; Wang, Nicholas J.; Talcott, Carolyn L.; Laderoute, Keith R.; Knapp, Merrill; Guan, Yinghui; Hu, Zhi; Ziyad, Safiyyah; Weber, Barbara L.; Laquerre, Sylvie; Jackson, Jeffrey R.; Wooster, Richard F.; Kuo, Wen-Lin; Gray, Joe W.; Spellman, Paul T.

    2009-03-31

    Cancer is a heterogeneous disease resulting from the accumulation of genetic defects that negatively impact control of cell division, motility, adhesion and apoptosis. Deregulation in signaling along the EGFR-MAPK pathway is common in breast cancer, though the manner in which deregulation occurs varies between both individuals and cancer subtypes. We were interested in identifying subnetworks within the EGFR-MAPK pathway that are similarly deregulated across subsets of breast cancers. To that end, we mapped genomic, transcriptional and proteomic profiles for 30 breast cancer cell lines onto a curated Pathway Logic symbolic systems model of EGFR-MEK signaling. This model was comprised of 539 molecular states and 396 rules governing signaling between active states. We analyzed these models and identified several subtype specific subnetworks, including one that suggested PAK1 is particularly important in regulating the MAPK cascade when it is over-expressed. We hypothesized that PAK1 overexpressing cell lines would have increased sensitivity to MEK inhibitors. We tested this experimentally by measuring quantitative responses of 20 breast cancer cell lines to three MEK inhibitors. We found that PAK1 over-expressing luminal breast cancer cell lines are significantly more sensitive to MEK inhibition as compared to those that express PAK1 at low levels. This indicates that PAK1 over-expression may be a useful clinical marker to identify patient populations that may be sensitive to MEK inhibitors. All together, our results support the utility of symbolic system biology models for identification of therapeutic approaches that will be effective against breast cancer subsets.

  7. Gene expression and epigenetic discovery screen reveal methylation of SFRP2 in prostate cancer.

    LENUS (Irish Health Repository)

    Perry, Antoinette S

    2013-04-15

    Aberrant activation of Wnts is common in human cancers, including prostate. Hypermethylation associated transcriptional silencing of Wnt antagonist genes SFRPs (Secreted Frizzled-Related Proteins) is a frequent oncogenic event. The significance of this is not known in prostate cancer. The objectives of our study were to (i) profile Wnt signaling related gene expression and (ii) investigate methylation of Wnt antagonist genes in prostate cancer. Using TaqMan Low Density Arrays, we identified 15 Wnt signaling related genes with significantly altered expression in prostate cancer; the majority of which were upregulated in tumors. Notably, histologically benign tissue from men with prostate cancer appeared more similar to tumor (r = 0.76) than to benign prostatic hyperplasia (BPH; r = 0.57, p < 0.001). Overall, the expression profile was highly similar between tumors of high (≥ 7) and low (≤ 6) Gleason scores. Pharmacological demethylation of PC-3 cells with 5-Aza-CdR reactivated 39 genes (≥ 2-fold); 40% of which inhibit Wnt signaling. Methylation frequencies in prostate cancer were 10% (2\\/20) (SFRP1), 64.86% (48\\/74) (SFRP2), 0% (0\\/20) (SFRP4) and 60% (12\\/20) (SFRP5). SFRP2 methylation was detected at significantly lower frequencies in high-grade prostatic intraepithelial neoplasia (HGPIN; 30%, (6\\/20), p = 0.0096), tumor adjacent benign areas (8.82%, (7\\/69), p < 0.0001) and BPH (11.43% (4\\/35), p < 0.0001). The quantitative level of SFRP2 methylation (normalized index of methylation) was also significantly higher in tumors (116) than in the other samples (HGPIN = 7.45, HB = 0.47, and BPH = 0.12). We show that SFRP2 hypermethylation is a common event in prostate cancer. SFRP2 methylation in combination with other epigenetic markers may be a useful biomarker of prostate cancer.

  8. The Tasmanian Devil Transcriptome Reveals Schwann Cell Origins of a Clonally Transmissible Cancer

    OpenAIRE

    Murchison, Elizabeth P.; Tovar, Cesar; Hsu, Arthur; Bender, Hannah S.; Kheradpour, Pouya; Rebbeck, Clare A.; Obendorf, David; Conlan, Carly; Bahlo, Melanie; Blizzard, Catherine A.; Pyecroft, Stephen; Kreiss, Alexandre; Kellis, Manolis; Stark, Alexander; Harkins, Timothy T

    2010-01-01

    The Tasmanian devil, a marsupial carnivore, is endangered because of the emergence of a transmissible cancer known as devil facial tumor disease (DFTD). This fatal cancer is clonally derived and is an allograft transmitted between devils by biting. We performed a large-scale genetic analysis of DFTD with microsatellite genotyping, a mitochondrial genome analysis, and deep sequencing of the DFTD transcriptome and microRNAs. These studies confirm that DFTD is a monophyletic clonally transmissib...

  9. Psychiatric treatment with people displaced in or from fragile states

    Directory of Open Access Journals (Sweden)

    Verity Buckley

    2013-05-01

    Full Text Available A fragile state is not an ideal environment for any professional to work within` – psychiatric, medical or otherwise. Psychiatrists working to assess psychological distress and mental health in fragile states, or with refugees from fragile states, need to adopt flexible approaches.

  10. Psychiatric treatment with people displaced in or from fragile states

    OpenAIRE

    Verity Buckley

    2013-01-01

    A fragile state is not an ideal environment for any professional to work within` – psychiatric, medical or otherwise. Psychiatrists working to assess psychological distress and mental health in fragile states, or with refugees from fragile states, need to adopt flexible approaches.

  11. Multipartnered Fertility and Depression among Fragile Families

    Science.gov (United States)

    Turney, Kristin; Carlson, Marcia J.

    2011-01-01

    We used data from the Fragile Families and Child Wellbeing Study to examine the association between multipartnered fertility (MPF)--when parents have children with more than one partner--and depression. Random-effects models suggested that MPF is associated with a greater likelihood of depression, net of family structure and other covariates.…

  12. Essays on financial fragility and regulation

    NARCIS (Netherlands)

    Ma, K.

    2013-01-01

    This thesis investigates various issues in regulation, with three chapters on financial fragility and banking regulation, and one chapter on competition policy. Chapter 2 studies banks’ herding driven by their need for market liquidity, highlighting a trade-off between systemic risk and liquidity cr

  13. Modeling Family Adaptation to Fragile X Syndrome

    Science.gov (United States)

    Raspa, Melissa; Bailey, Donald, Jr.; Bann, Carla; Bishop, Ellen

    2014-01-01

    Using data from a survey of 1,099 families who have a child with Fragile X syndrome, we examined adaptation across 7 dimensions of family life: parenting knowledge, social support, social life, financial impact, well-being, quality of life, and overall impact. Results illustrate that although families report a high quality of life, they struggle…

  14. Emotion Potentiated Startle in Fragile X Syndrome

    Science.gov (United States)

    Ballinger, Elizabeth C.; Cordeiro, Lisa; Chavez, Alyssa D.; Hagerman, Randi J.; Hessl, David

    2014-01-01

    Social avoidance and anxiety are prevalent in fragile X syndrome (FXS) and are potentially mediated by the amygdala, a brain region critical for social behavior. Unfortunately, functional brain resonance imaging investigation of the amygdala in FXS is limited by the difficulties experienced by intellectually impaired and anxious participants. We…

  15. Fragile X Syndrome: An Aging Perspective

    Science.gov (United States)

    Schneider, Andrea; Ligsay, Andrew; Hagerman, Randi J.

    2013-01-01

    Cognitive and behavioral correlates of molecular variations related to the FMR1 gene have been studied rather extensively, but research about the long-term outcome in individuals with fragile X spectrum disorders remains sparse. In this review, we present an overview of aging research and recent findings in regard to cellular and clinical…

  16. Fragile states, collective identities and forced migration

    OpenAIRE

    Kelly Staples

    2013-01-01

    There has been a worrying tendency for the international communityto ignore questions of state capacity when enacting repatriations.Governance and the rule of law should be vital considerations inattempts to deal with forced migration in fragile states such as DRC.

  17. How to engage constructively with fragile states

    OpenAIRE

    Jon Bennett

    2013-01-01

    Donors have allocated increasing resources in fragile states tothe reform and/or rebuilding of the architecture of the state – suchas justice systems, the police and army, and the management ofministries – in efforts to support stability. This has been important for all sectors of society, including displaced people.

  18. Making human rights 'work' in fragile states

    OpenAIRE

    Dyrhagen, Gitte

    2008-01-01

    The thesis analyzes how Denmark as a donor government can best contribute to promote and protect human rights in "fragile states" which are characterized by their lack of capacity and willingness to undertake such duties. This is done by comparing central debates and analytical frameworks with two case studies, Afghanistan and Nepal.

  19. Quantitative cell signalling analysis reveals down-regulation of MAPK pathway activation in colorectal cancer.

    LENUS (Irish Health Repository)

    Gulmann, Christian

    2009-08-01

    Mitogen-activated protein kinases (MAPK) are considered to play significant roles in colonic carcinogenesis and kinase inhibitor therapy has been proposed as a potential tool in the treatment of this disease. Reverse-phase microarray assays using phospho-specific antibodies can directly measure levels of phosphorylated protein isoforms. In the current study, samples from 35 cases of untreated colorectal cancer colectomies were laser capture-microdissected to isolate epithelium and stroma from cancer as well as normal (i.e. uninvolved) mucosa. Lysates generated from these four tissue types were spotted onto reverse-phase protein microarrays and probed with a panel of antibodies to ERK, p-ERK, p38, p-p38, p-JNK, MEK and p-MEK. Whereas total protein levels were unchanged, or slightly elevated (p38, p = 0.0025) in cancers, activated isoforms, including p-ERK, p-p38 and p-JNK, were decreased two- to four-fold in cancers compared with uninvolved mucosa (p < 0.0023 in all cases except for p-JNK in epithelium, where decrement was non-significant). This was backed up by western blotting. Dukes\\' stage B and C cancers displayed lower p-ERK and p-p38 expression than Dukes\\' stage A cancers, although this was not statistically significant. It is concluded that MAPK activity may be down-regulated in colorectal cancer and that further exploration of inhibitory therapy in this system should be carefully evaluated if this finding is confirmed in larger series.

  20. Bone mineral density testing after fragility fracture

    Science.gov (United States)

    Posen, Joshua; Beaton, Dorcas E.; Sale, Joanna; Bogoch, Earl R.

    2013-01-01

    Abstract Objective To determine the proportion of patients with fragility fractures who can be expected to have low bone mineral density (BMD) at the time of fracture and to assist FPs in deciding whether to refer patients for BMD testing. Data sources MEDLINE, EMBASE, and CINAHL were searched from the earliest available dates through September 2009. Study selection English-language articles reporting BMD test results of patients with fragility fractures who were managed in an orthopedic environment (eg, fracture clinic, emergency management by orthopedic surgeons, inpatients) were eligible for review. While the orthopedic environment has been identified as an ideal point for case finding, FPs are often responsible for investigation and treatment. Factors that potentially influenced BMD test results (eg, selection of fracture types, exclusion criteria) were identified. Studies with 2 or more selection factors of potential influence were flagged, and rates of low BMD were calculated including and excluding these studies. Synthesis The distribution of the proportion of persons with low BMD was summarized across studies using descriptive statistics. We calculated lower boundaries on this distribution, using standard statistical thresholds, to determine a lower threshold of the expected rate of low BMD. Conclusion Family physicians evaluating patients with fragility fractures can expect that at least two-thirds of patients with fragility fractures who are older than 50 years of age will have low BMD (T score ≤ −1.0). With this a priori expectation, FPs might more readily conduct a fracture risk assessment and pursue warranted fracture risk reduction strategies following fragility fracture. PMID:24336562

  1. Secretome analysis of multiple pancreatic cancer cell lines reveals perturbations of key functional networks.

    Science.gov (United States)

    Schiarea, Silvia; Solinas, Graziella; Allavena, Paola; Scigliuolo, Graziana Maria; Bagnati, Renzo; Fanelli, Roberto; Chiabrando, Chiara

    2010-09-01

    The cancer secretome is a rich repository in which to mine useful information for both cancer biology and clinical oncology. To help understand the mechanisms underlying the progression of pancreatic cancer, we characterized the secretomes of four human pancreatic ductal adenocarcinoma (PDAC) cell lines versus a normal counterpart. To this end, we used a proteomic workflow based on high-confidence protein identification by mass spectrometry, semiquantitation by a label-free approach, and network enrichment analysis by a system biology tool. Functional networks significantly enriched with PDAC-dysregulated proteins included not only expected alterations within key mechanisms known to be relevant for tumor progression (e.g., cell-cell/cell-matrix adhesion, extracellular matrix remodeling, and cytoskeleton rearrangement), but also other extensive, coordinated perturbations never observed in pancreatic cancer. In particular, we highlighted perturbations possibly favoring tumor progression through immune escape (i.e., inhibition of the complement system, deficiency of selected proteasome components within the antigen-presentation machinery, and inhibition of T cell cytoxicity), and a defective protein folding machinery. Among the proteins found concordantly oversecreted in all of our PDAC cell lines, many are reportedly overexpressed in pancreatic cancer (e.g., CD9 and Vimentin), while others (PLOD3, SH3L3, PCBP1, and SFRS1) represent novel PDAC-secreted proteins that may be worth investigating. PMID:20687567

  2. Protein markers of cancer-associated fibroblasts and tumor-initiating cells reveal subpopulations in freshly isolated ovarian cancer ascites

    Directory of Open Access Journals (Sweden)

    Wintzell My

    2012-08-01

    Full Text Available Abstract Background In ovarian cancer, massive intraperitoneal dissemination is due to exfoliated tumor cells in ascites. Tumor-initiating cells (TICs or cancer stem cells and cells showing epithelial-mesenchymal-transition (EMT are particularly implicated. Spontaneous spherical cell aggregates are sometimes observed, but although similar to those formed by TICs in vitro, their significance is unclear. Methods Cells freshly isolated from malignant ascites were separated into sphere samples (S-type samples, n=9 and monolayer-forming single-cell suspensions (M-type, n=18. Using western blot, these were then compared for expression of protein markers of EMT, TIC, and of cancer-associated fibroblasts (CAFs. Results S-type cells differed significantly from M-type by expressing high levels of E-cadherin and no or little vimentin, integrin-β3 or stem cell transcription factor Oct-4A. By contrast, M-type samples were enriched for CD44, Oct-4A and for CAF markers. Independently of M- and S-type, there was a strong correlation between TIC markers Nanog and EpCAM. The CAF marker α-SMA correlated with clinical stage IV. This is the first report on CAF markers in malignant ascites and on SUMOylation of Oct-4A in ovarian cancer. Conclusions In addition to demonstrating potentially high levels of TICs in ascites, the results suggest that the S-type population is the less tumorigenic one. Nanoghigh/EpCAMhigh samples represent a TIC subset which may be either M- or S-type, and which is separate from the CD44high/Oct-4Ahigh subset observed only in M-type samples. This demonstrates a heterogeneity in TIC populations in vivo which has practical implications for TIC isolation based on cell sorting. The biological heterogeneity will need to be addressed in future therapeutical strategies.

  3. Protein markers of cancer-associated fibroblasts and tumor-initiating cells reveal subpopulations in freshly isolated ovarian cancer ascites

    International Nuclear Information System (INIS)

    In ovarian cancer, massive intraperitoneal dissemination is due to exfoliated tumor cells in ascites. Tumor-initiating cells (TICs or cancer stem cells) and cells showing epithelial-mesenchymal-transition (EMT) are particularly implicated. Spontaneous spherical cell aggregates are sometimes observed, but although similar to those formed by TICs in vitro, their significance is unclear. Cells freshly isolated from malignant ascites were separated into sphere samples (S-type samples, n=9) and monolayer-forming single-cell suspensions (M-type, n=18). Using western blot, these were then compared for expression of protein markers of EMT, TIC, and of cancer-associated fibroblasts (CAFs). S-type cells differed significantly from M-type by expressing high levels of E-cadherin and no or little vimentin, integrin-β3 or stem cell transcription factor Oct-4A. By contrast, M-type samples were enriched for CD44, Oct-4A and for CAF markers. Independently of M- and S-type, there was a strong correlation between TIC markers Nanog and EpCAM. The CAF marker α-SMA correlated with clinical stage IV. This is the first report on CAF markers in malignant ascites and on SUMOylation of Oct-4A in ovarian cancer. In addition to demonstrating potentially high levels of TICs in ascites, the results suggest that the S-type population is the less tumorigenic one. Nanoghigh/EpCAMhigh samples represent a TIC subset which may be either M- or S-type, and which is separate from the CD44high/Oct-4Ahigh subset observed only in M-type samples. This demonstrates a heterogeneity in TIC populations in vivo which has practical implications for TIC isolation based on cell sorting. The biological heterogeneity will need to be addressed in future therapeutical strategies

  4. Comparative genomic mapping of the bovine Fragile Histidine Triad (FHIT tumour suppressor gene: characterization of a 2 Mb BAC contig covering the locus, complete annotation of the gene, analysis of cDNA and of physiological expression profiles

    Directory of Open Access Journals (Sweden)

    Boussaha Mekki

    2006-05-01

    Full Text Available Abstract Background The Fragile Histidine Triad gene (FHIT is an oncosuppressor implicated in many human cancers, including vesical tumors. FHIT is frequently hit by deletions caused by fragility at FRA3B, the most active of human common fragile sites, where FHIT lays. Vesical tumors affect also cattle, including animals grazing in the wild on bracken fern; compounds released by the fern are known to induce chromosome fragility and may trigger cancer with the interplay of latent Papilloma virus. Results The bovine FHIT was characterized by assembling a contig of 78 BACs. Sequence tags were designed on human exons and introns and used directly to select bovine BACs, or compared with sequence data in the bovine genome database or in the trace archive of the bovine genome sequencing project, and adapted before use. FHIT is split in ten exons like in man, with exons 5 to 9 coding for a 149 amino acids protein. VISTA global alignments between bovine genomic contigs retrieved from the bovine genome database and the human FHIT region were performed. Conservation was extremely high over a 2 Mb region spanning the whole FHIT locus, including the size of introns. Thus, the bovine FHIT covers about 1.6 Mb compared to 1.5 Mb in man. Expression was analyzed by RT-PCR and Northern blot, and was found to be ubiquitous. Four cDNA isoforms were isolated and sequenced, that originate from an alternative usage of three variants of exon 4, revealing a size very close to the major human FHIT cDNAs. Conclusion A comparative genomic approach allowed to assemble a contig of 78 BACs and to completely annotate a 1.6 Mb region spanning the bovine FHIT gene. The findings confirmed the very high level of conservation between human and bovine genomes and the importance of comparative mapping to speed the annotation process of the recently sequenced bovine genome. The detailed knowledge of the genomic FHIT region will allow to study the role of FHIT in bovine cancerogenesis

  5. Multi-study integration of brain cancer transcriptomes reveals organ-level molecular signatures.

    Directory of Open Access Journals (Sweden)

    Jaeyun Sung

    Full Text Available We utilized abundant transcriptomic data for the primary classes of brain cancers to study the feasibility of separating all of these diseases simultaneously based on molecular data alone. These signatures were based on a new method reported herein--Identification of Structured Signatures and Classifiers (ISSAC--that resulted in a brain cancer marker panel of 44 unique genes. Many of these genes have established relevance to the brain cancers examined herein, with others having known roles in cancer biology. Analyses on large-scale data from multiple sources must deal with significant challenges associated with heterogeneity between different published studies, for it was observed that the variation among individual studies often had a larger effect on the transcriptome than did phenotype differences, as is typical. For this reason, we restricted ourselves to studying only cases where we had at least two independent studies performed for each phenotype, and also reprocessed all the raw data from the studies using a unified pre-processing pipeline. We found that learning signatures across multiple datasets greatly enhanced reproducibility and accuracy in predictive performance on truly independent validation sets, even when keeping the size of the training set the same. This was most likely due to the meta-signature encompassing more of the heterogeneity across different sources and conditions, while amplifying signal from the repeated global characteristics of the phenotype. When molecular signatures of brain cancers were constructed from all currently available microarray data, 90% phenotype prediction accuracy, or the accuracy of identifying a particular brain cancer from the background of all phenotypes, was found. Looking forward, we discuss our approach in the context of the eventual development of organ-specific molecular signatures from peripheral fluids such as the blood.

  6. Kinome sequencing reveals RET G691S polymorphism in human neuroendocrine lung cancer cell lines

    OpenAIRE

    Sosonkina, Nadiya; HONG, SEUNG-KEUN; Starenki, Dmytro; Park, Jong-In

    2014-01-01

    Neuroendocrine (NE) lung tumors comprise 20–25% of all invasive lung malignancies. Currently, no effective treatments are available to cure these tumors, and it is necessary to identify a molecular alteration(s) that characterizes NE lung tumor cells. We aimed to identify a kinase mutation(s) associated with NE lung tumor by screening 517 kinase-encoding genes in human lung cancer cell lines. Our next-generation sequencing analysis of six NE lung tumor cell lines (four small cell lung cancer ...

  7. Somatic Cell Fusions Reveal Extensive Heterogeneity in Basal-like Breast Cancer

    DEFF Research Database (Denmark)

    Su, Ying; Subedee, Ashim; Bloushtain-Qimron, Noga;

    2015-01-01

    heterogeneity in basal-like breast cancers that correlates with clinical outcome. We also found that protein extracts of basal-like cells are sufficient to induce a luminal-to-basal phenotypic switch, implying a trigger of basal-like autoregulatory circuits. We determined that KDM6A might be required for...

  8. Mucus-secreting 'signet-ring' cells in CSF revealing the site of primary cancer.

    OpenAIRE

    Agnelli, G.; Gresele, P.

    1980-01-01

    A case is reported of leptomeningeal carcinomatosis in which identification of mucus-secreting 'signet-ring' carcinoma cells in the CSF allowed diagnosis of an otherwise asymptomatic gastric cancer. When lumbar puncture is performed, careful cytological examination of the CSF should be carried out in any undiagnosed patient with neurological symptoms and signs.

  9. Open pipelines for integrated tumor genome profiles reveal differences between pancreatic cancer tumors and cell lines

    International Nuclear Information System (INIS)

    We describe open, reproducible pipelines that create an integrated genomic profile of a cancer and use the profile to find mutations associated with disease and potentially useful drugs. These pipelines analyze high-throughput cancer exome and transcriptome sequence data together with public databases to find relevant mutations and drugs. The three pipelines that we have developed are: (1) an exome analysis pipeline, which uses whole or targeted tumor exome sequence data to produce a list of putative variants (no matched normal data are needed); (2) a transcriptome analysis pipeline that processes whole tumor transcriptome sequence (RNA-seq) data to compute gene expression and find potential gene fusions; and (3) an integrated variant analysis pipeline that uses the tumor variants from the exome pipeline and tumor gene expression from the transcriptome pipeline to identify deleterious and druggable mutations in all genes and in highly expressed genes. These pipelines are integrated into the popular Web platform Galaxy at #http://usegalaxy.org/cancer# to make them accessible and reproducible, thereby providing an approach for doing standardized, distributed analyses in clinical studies. We have used our pipeline to identify similarities and differences between pancreatic adenocarcinoma cancer cell lines and primary tumors

  10. A Nanoprinted Model of Interstitial Cancer Migration Reveals a Link between Cell Deformability and Proliferation.

    Science.gov (United States)

    Panagiotakopoulou, Magdalini; Bergert, Martin; Taubenberger, Anna; Guck, Jochen; Poulikakos, Dimos; Ferrari, Aldo

    2016-07-26

    Metastatic progression of tumors requires the coordinated dissemination of cancerous cells through interstitial tissues and their replication in distant body locations. Despite their importance in cancer treatment decisions, key factors, such as cell shape adaptation and the role it plays in dense tissue invasion by cancerous cells, are not well understood. Here, we employ a 3D electrohydrodynamic nanoprinting technology to generate vertical arrays of topographical pores that mimic interstitial tissue resistance to the mesenchymal migration of cancerous cells, in order to determine the effect of nuclear size, cell deformability, and cell-to-substrate adhesion on tissue invasion efficiency. The high spatial and temporal resolution of our analysis demonstrates that the ability of cells to deform depends on the cell cycle phase, peaks immediately after mitosis, and is key to the invasion process. Increased pore penetration efficiency by cells in early G1 phase also coincided with their lower nuclear volume and higher cell deformability, compared with the later cell cycle stages. Furthermore, artificial decondensation of chromatin induced an increase in cell and nuclear deformability and improved pore penetration efficiency of cells in G1. Together, these results underline that along the cell cycle cells have different abilities to dynamically remodel their actin cytoskeleton and induce nuclear shape changes, which determines their pore penetration efficiency. Thus, our results support a mechanism in which cell proliferation and pore penetration are functionally linked to favor the interstitial dissemination of metastatic cells. PMID:27268411

  11. Phenotype-based cell-specific metabolic modeling reveals metabolic liabilities of cancer.

    Science.gov (United States)

    Yizhak, Keren; Gaude, Edoardo; Le Dévédec, Sylvia; Waldman, Yedael Y; Stein, Gideon Y; van de Water, Bob; Frezza, Christian; Ruppin, Eytan

    2014-01-01

    Utilizing molecular data to derive functional physiological models tailored for specific cancer cells can facilitate the use of individually tailored therapies. To this end we present an approach termed PRIME for generating cell-specific genome-scale metabolic models (GSMMs) based on molecular and phenotypic data. We build >280 models of normal and cancer cell-lines that successfully predict metabolic phenotypes in an individual manner. We utilize this set of cell-specific models to predict drug targets that selectively inhibit cancerous but not normal cell proliferation. The top predicted target, MLYCD, is experimentally validated and the metabolic effects of MLYCD depletion investigated. Furthermore, we tested cell-specific predicted responses to the inhibition of metabolic enzymes, and successfully inferred the prognosis of cancer patients based on their PRIME-derived individual GSMMs. These results lay a computational basis and a counterpart experimental proof of concept for future personalized metabolic modeling applications, enhancing the search for novel selective anticancer therapies. PMID:25415239

  12. Papillomavirus genomes associate with BRD4 to replicate at fragile sites in the host genome.

    Directory of Open Access Journals (Sweden)

    Moon Kyoo Jang

    2014-05-01

    Full Text Available It has long been recognized that oncogenic viruses often integrate close to common fragile sites. The papillomavirus E2 protein, in complex with BRD4, tethers the viral genome to host chromatin to ensure persistent replication. Here, we map these targets to a number of large regions of the human genome and name them Persistent E2 and BRD4-Broad Localized Enrichments of Chromatin or PEB-BLOCs. PEB-BLOCs frequently contain deletions, have increased rates of asynchronous DNA replication, and are associated with many known common fragile sites. Cell specific fragile sites were mapped in human C-33 cervical cells by FANCD2 ChIP-chip, confirming the association with PEB-BLOCs. HPV-infected cells amplify viral DNA in nuclear replication foci and we show that these form adjacent to PEB-BLOCs. We propose that HPV replication, which hijacks host DNA damage responses, occurs adjacent to highly susceptible fragile sites, greatly increasing the chances of integration here, as is found in HPV-associated cancers.

  13. Papillomavirus genomes associate with BRD4 to replicate at fragile sites in the host genome.

    Science.gov (United States)

    Jang, Moon Kyoo; Shen, Kui; McBride, Alison A

    2014-05-01

    It has long been recognized that oncogenic viruses often integrate close to common fragile sites. The papillomavirus E2 protein, in complex with BRD4, tethers the viral genome to host chromatin to ensure persistent replication. Here, we map these targets to a number of large regions of the human genome and name them Persistent E2 and BRD4-Broad Localized Enrichments of Chromatin or PEB-BLOCs. PEB-BLOCs frequently contain deletions, have increased rates of asynchronous DNA replication, and are associated with many known common fragile sites. Cell specific fragile sites were mapped in human C-33 cervical cells by FANCD2 ChIP-chip, confirming the association with PEB-BLOCs. HPV-infected cells amplify viral DNA in nuclear replication foci and we show that these form adjacent to PEB-BLOCs. We propose that HPV replication, which hijacks host DNA damage responses, occurs adjacent to highly susceptible fragile sites, greatly increasing the chances of integration here, as is found in HPV-associated cancers. PMID:24832099

  14. Ferritin, heavy polypeptide 1 interacts with fragile X-related protein

    Institute of Scientific and Technical Information of China (English)

    Yun Ma; Shuya He; Yang Yang; Qiong Chen; Weichun Xiao; Binyuan Li; Jiao Su; Xianghui Fu

    2011-01-01

    Fragile X-related protein 1 (FXR1P) is a member of the FXR gene family, which also includes fragile X mental retardation protein and fragile X-related protein 2 (FXR2P). To understand the functions of FXR1P, we screened FXR1P-interacting proteins using a yeast two-hybrid system. FXR1P was fused to pGBKT7 and used as the bait to screen a human fetal brain cDNA library. This screening revealed 10 FXR1P-interacting proteins including FTH1. FTH1 encodes Homo sapiens ferritin,heavy polypeptide 1. The interaction between FXR1P and FTH1 was confirmed by retesting in yeast using both a β-galactosidase assay and growth studies on selective media. A co-immunoprecipitation assay in mammalian cells further confirmed the FXR1P/FTH1 interaction.Moreover, the results revealed that FTH1 colocalized with FXR1P in the cytoplasm around the nucleus in mammalian cells. The present findings suggest that FXR1P plays an important role in iron metabolism in the brain by interacting with FTH1. This provides clues for elucidating the relationship between FXR1P function and fragile X syndrome.

  15. Transcriptomic and Protein Expression Analysis Reveals Clinicopathological Significance of Bloom Syndrome Helicase (BLM) in Breast Cancer.

    Science.gov (United States)

    Arora, Arvind; Abdel-Fatah, Tarek M A; Agarwal, Devika; Doherty, Rachel; Moseley, Paul M; Aleskandarany, Mohammed A; Green, Andrew R; Ball, Graham; Alshareeda, Alaa T; Rakha, Emad A; Chan, Stephen Y T; Ellis, Ian O; Madhusudan, Srinivasan

    2015-04-01

    Bloom syndrome helicase (BLM) has key roles in homologous recombination repair, telomere maintenance, and DNA replication. Germ-line mutations in the BLM gene causes Bloom syndrome, a rare disorder characterized by premature aging and predisposition to multiple cancers, including breast cancer. The clinicopathologic significance of BLM in sporadic breast cancers is unknown. We investigated BLM mRNA expression in the Molecular Taxonomy of Breast Cancer International Consortium cohort (n = 1,950) and validated in an external dataset of 2,413 tumors. BLM protein level was evaluated in the Nottingham Tenovus series comprising 1,650 breast tumors. BLM mRNA overexpression was significantly associated with high histologic grade, larger tumor size, estrogen receptor-negative (ER(-)), progesterone receptor-negative (PR(-)), and triple-negative phenotypes (ps < 0.0001). BLM mRNA overexpression was also linked to aggressive molecular phenotypes, including PAM50.Her2 (P < 0.0001), PAM50.Basal (P < 0.0001), and PAM50.LumB (P < 0.0001) and Genufu subtype (ER(+)/Her2(-)/high proliferation; P < 0.0001). PAM50.LumA tumors and Genufu subtype (ER(+)/Her2(-)/low proliferation) were more likely to express low levels of BLM mRNA (ps < 0.0001). Integrative molecular clusters (intClust) intClust.1 (P < 0.0001), intClust.5 (P < 0.0001), intClust.9 (P < 0.0001), and intClust.10 (P < 0.0001) were also more likely in tumors with high BLM mRNA expression. BLM mRNA overexpression was associated with poor breast cancer-specific survival (BCSS; ps < 0.000001). At the protein level, altered subcellular localization with high cytoplasmic BLM and low nuclear BLM was linked to aggressive phenotypes. In multivariate analysis, BLM mRNA and BLM protein levels independently influenced BCSS. This is the first and the largest study to provide evidence that BLM is a promising biomarker in breast cancer. PMID:25673821

  16. Dynamics between Cancer Cell Subpopulations Reveals a Model Coordinating with Both Hierarchical and Stochastic Concepts

    OpenAIRE

    Wang, Weikang; Quan, Yi; Fu, Qibin; Liu, Yu; Liang, Ying; Wu, Jingwen; Yang, Gen; Luo, Chunxiong; Ouyang, Qi; Wang, Yugang

    2014-01-01

    Tumors are often heterogeneous in which tumor cells of different phenotypes have distinct properties. For scientific and clinical interests, it is of fundamental importance to understand their properties and the dynamic variations among different phenotypes, specifically under radio- and/or chemo-therapy. Currently there are two controversial models describing tumor heterogeneity, the cancer stem cell (CSC) model and the stochastic model. To clarify the controversy, we measured probabilities ...

  17. Lipidomic Profiling of Adipose Tissue Reveals an Inflammatory Signature in Cancer-Related and Primary Lymphedema

    OpenAIRE

    Sedger, Lisa M.; Tull, Dedreia L.; Malcolm J McConville; De Souza, David P.; Rupasinghe, Thusitha W. T.; Williams, Spencer J; Saravanan Dayalan; Daniel Lanzer; Helen Mackie; Lam, Thomas C.; John Boyages

    2016-01-01

    Cancer-related and primary lymphedema (LE) are associated with the production of adipose tissue (AT). Nothing is known, however, about the lipid-based molecules that comprise LE AT. We therefore analyzed lipid molecules in lipoaspirates and serum obtained from LE patients, and compared them to lipoaspirates from cosmetic surgery patients and healthy control cohort serum. LE patient serum analysis demonstrated that triglycerides, HDL- and LDL-cholesterol and lipid transport molecules remained ...

  18. Novel serum protein biomarker panel revealed by mass spectrometry and its prognostic value in breast cancer

    OpenAIRE

    Chung, Liping; Moore, Katrina; Phillips, Leo; Boyle, Frances M.; Marsh, Deborah J.; Baxter, Robert C.

    2014-01-01

    Introduction Serum profiling using proteomic techniques has great potential to detect biomarkers that might improve diagnosis and predict outcome for breast cancer patients (BC). This study used surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry (MS) to identify differentially expressed proteins in sera from BC and healthy volunteers (HV), with the goal of developing a new prognostic biomarker panel. Methods Training set serum samples from 99 BC and 51 H...

  19. A novel p53 mutant in human breast cancer revealed by multiple SSCP analysis.

    Science.gov (United States)

    Nigro, V; Napolitano, M; Abbondanza, C; Medici, N; Puca, A A; Schiavulli, M; Armetta, I; Moncharmont, B; Puca, G A; Molinari, A M

    1994-04-29

    DNA from tumor tissue and peripheral blood lymphocytes of primary breast cancer patients was screened for the presence of p53 mutations. In DNA from one tumor we found that the histidine codon 193 (CAT) was somatically converted to arginine (CGT). This amino acid residue is highly conserved in many species, thus suggesting that such mutation plays an important role in the loss of wt-p53 function. PMID:8187056

  20. Microarray analysis of nemorosone-induced cytotoxic effects on pancreatic cancer cells reveals activation of the unfolded protein response (UPR)

    Science.gov (United States)

    Holtrup, Frank; Bauer, Andrea; Fellenberg, Kurt; Hilger, Ralf A; Wink, Michael; Hoheisel, Jörg D

    2011-01-01

    BACKGROUND AND PURPOSE Pancreatic cancer is one of the leading cancer-related causes of death due to high chemo-resistance and fast metastasation. Nemorosone, a polycyclic polyprenylated acylphloroglucinol, has recently been identified as a promising anticancer agent. Here, we examine its growth-inhibitory effects on pancreatic cancer cells. Based on transcription profiling, a molecular mode of action is proposed. EXPERIMENTAL APPROACH Nemorosone cytotoxicity was assessed by the resazurin proliferation assay on pancreatic cancer cells and fibroblasts. Apoptosis was determined by Annexin V/propidium iodide staining as well as cytochrome c and caspase activation assays. Staining with the voltage-dependent dye JC-1 and fluorescence microscopy were used to detect effects on mitochondrial membrane potential. Total RNA was isolated from treated cell lines and subjected to microarray analysis, subsequent pathway identification and modelling. Gene expression data were validated by quantitative polymerase chain reaction and siRNA-mediated gene knock-down. KEY RESULTS Nemorosone significantly inhibited cancer cell growth, induced cytochrome c release and subsequent caspase-dependent apoptosis, rapidly abolished mitochondrial membrane potential and elevated cytosolic calcium levels, while fibroblasts were largely unaffected. Expression profiling revealed 336 genes to be affected by nemorosone. A total of 75 genes were altered in all three cell lines, many of which were within the unfolded protein response (UPR) network. DNA damage inducible transcript 3 was identified as a key regulator in UPR-mediated cell death. CONCLUSIONS AND IMPLICATIONS Nemorosone could be a lead compound for the development of novel anticancer drugs amplifying the already elevated UPR level in solid tumours, thus driving them into apoptosis. This study forms the basis for further investigations identifying nemorosone's direct molecular target(s). PMID:21091652

  1. Fragility Index of block tailed vectors

    CERN Document Server

    Ferreira, Helena

    2011-01-01

    Financial crises are a recurrent phenomenon with important effects on the real economy. The financial system is inherently fragile and it is therefore of great importance to be able to measure and characterize its systemic stability. Multivariate extreme value theory provide us such a framework through the \\emph{fragility index} (Geluk \\cite{gel+}, \\emph{et al.}, 2007; Falk and Tichy, \\cite{falk+tichy1,falk+tichy2} 2010, 2011). Here we generalize this concept and contribute to the modeling of the stability of a stochastic system divided into blocks. We will find several relations with well-known tail dependence measures in literature, which will provide us immediate estimators. We end with an application to financial data.

  2. Systematic Analysis Reveals that Cancer Mutations Converge on Deregulated Metabolism of Arachidonate and Xenobiotics.

    Science.gov (United States)

    Gatto, Francesco; Schulze, Almut; Nielsen, Jens

    2016-07-19

    Mutations are the basis of the clonal evolution of most cancers. Nevertheless, a systematic analysis of whether mutations are selected in cancer because they lead to the deregulation of specific biological processes independent of the type of cancer is still lacking. In this study, we correlated the genome and transcriptome of 1,082 tumors. We found that nine commonly mutated genes correlated with substantial changes in gene expression, which primarily converged on metabolism. Further network analyses circumscribed the convergence to a network of reactions, termed AraX, that involves the glutathione- and oxygen-mediated metabolism of arachidonic acid and xenobiotics. In an independent cohort of 4,462 samples, all nine mutated genes were consistently correlated with the deregulation of AraX. Among all of the metabolic pathways, AraX deregulation represented the strongest predictor of patient survival. These findings suggest that oncogenic mutations drive a selection process that converges on the deregulation of the AraX network. PMID:27396332

  3. Systematic Analysis Reveals that Cancer Mutations Converge on Deregulated Metabolism of Arachidonate and Xenobiotics

    Directory of Open Access Journals (Sweden)

    Francesco Gatto

    2016-07-01

    Full Text Available Mutations are the basis of the clonal evolution of most cancers. Nevertheless, a systematic analysis of whether mutations are selected in cancer because they lead to the deregulation of specific biological processes independent of the type of cancer is still lacking. In this study, we correlated the genome and transcriptome of 1,082 tumors. We found that nine commonly mutated genes correlated with substantial changes in gene expression, which primarily converged on metabolism. Further network analyses circumscribed the convergence to a network of reactions, termed AraX, that involves the glutathione- and oxygen-mediated metabolism of arachidonic acid and xenobiotics. In an independent cohort of 4,462 samples, all nine mutated genes were consistently correlated with the deregulation of AraX. Among all of the metabolic pathways, AraX deregulation represented the strongest predictor of patient survival. These findings suggest that oncogenic mutations drive a selection process that converges on the deregulation of the AraX network.

  4. Digital quantification of gene expression in sequential breast cancer biopsies reveals activation of an immune response.

    Directory of Open Access Journals (Sweden)

    Rinath M Jeselsohn

    Full Text Available Advancements in molecular biology have unveiled multiple breast cancer promoting pathways and potential therapeutic targets. Large randomized clinical trials remain the ultimate means of validating therapeutic efficacy, but they require large cohorts of patients and are lengthy and costly. A useful approach is to conduct a window of opportunity study in which patients are exposed to a drug pre-surgically during the interval between the core needle biopsy and the definitive surgery. These are non-therapeutic studies and the end point is not clinical or pathological response but rather evaluation of molecular changes in the tumor specimens that can predict response. However, since the end points of the non-therapeutic studies are biologic, it is critical to first define the biologic changes that occur in the absence of treatment. In this study, we compared the molecular profiles of breast cancer tumors at the time of the diagnostic biopsy versus the definitive surgery in the absence of any intervention using the Nanostring nCounter platform. We found that while the majority of the transcripts did not vary between the two biopsies, there was evidence of activation of immune related genes in response to the first biopsy and further investigations of the immune changes after a biopsy in early breast cancer seem warranted.

  5. Long-range Transcriptome Sequencing Reveals Cancer Cell Growth Regulatory Chimeric mRNA

    Directory of Open Access Journals (Sweden)

    Roberto Plebani

    2012-11-01

    Full Text Available mRNA chimeras from chromosomal translocations often play a role as transforming oncogenes. However, cancer transcriptomes also contain mRNA chimeras that may play a role in tumor development, which arise as transcriptional or post-transcriptional events. To identify such chimeras, we developed a deterministic screening strategy for long-range sequence analysis. High-throughput, long-read sequencing was then performed on cDNA libraries from major tumor histotypes and corresponding normal tissues. These analyses led to the identification of 378 chimeras, with an unexpectedly high frequency of expression (≈2 x 10-5 of all mRNA. Functional assays in breast and ovarian cancer cell lines showed that a large fraction of mRNA chimeras regulates cell replication. Strikingly, chimeras were shown to include both positive and negative regulators of cell growth, which functioned as such in a cell-type-specific manner. Replication-controlling chimeras were found to be expressed by most cancers from breast, ovary, colon, uterus, kidney, lung, and stomach, suggesting a widespread role in tumor development.

  6. Detection of gene communities in multi-networks reveals cancer drivers

    Science.gov (United States)

    Cantini, Laura; Medico, Enzo; Fortunato, Santo; Caselle, Michele

    2015-12-01

    We propose a new multi-network-based strategy to integrate different layers of genomic information and use them in a coordinate way to identify driving cancer genes. The multi-networks that we consider combine transcription factor co-targeting, microRNA co-targeting, protein-protein interaction and gene co-expression networks. The rationale behind this choice is that gene co-expression and protein-protein interactions require a tight coregulation of the partners and that such a fine tuned regulation can be obtained only combining both the transcriptional and post-transcriptional layers of regulation. To extract the relevant biological information from the multi-network we studied its partition into communities. To this end we applied a consensus clustering algorithm based on state of art community detection methods. Even if our procedure is valid in principle for any pathology in this work we concentrate on gastric, lung, pancreas and colorectal cancer and identified from the enrichment analysis of the multi-network communities a set of candidate driver cancer genes. Some of them were already known oncogenes while a few are new. The combination of the different layers of information allowed us to extract from the multi-network indications on the regulatory pattern and functional role of both the already known and the new candidate driver genes.

  7. Dynamics inside the cancer cell attractor reveal cell heterogeneity, limits of stability, and escape.

    Science.gov (United States)

    Li, Qin; Wennborg, Anders; Aurell, Erik; Dekel, Erez; Zou, Jie-Zhi; Xu, Yuting; Huang, Sui; Ernberg, Ingemar

    2016-03-01

    The observed intercellular heterogeneity within a clonal cell population can be mapped as dynamical states clustered around an attractor point in gene expression space, owing to a balance between homeostatic forces and stochastic fluctuations. These dynamics have led to the cancer cell attractor conceptual model, with implications for both carcinogenesis and new therapeutic concepts. Immortalized and malignant EBV-carrying B-cell lines were used to explore this model and characterize the detailed structure of cell attractors. Any subpopulation selected from a population of cells repopulated the whole original basin of attraction within days to weeks. Cells at the basin edges were unstable and prone to apoptosis. Cells continuously changed states within their own attractor, thus driving the repopulation, as shown by fluorescent dye tracing. Perturbations of key regulatory genes induced a jump to a nearby attractor. Using the Fokker-Planck equation, this cell population behavior could be described as two virtual, opposing influences on the cells: one attracting toward the center and the other promoting diffusion in state space (noise). Transcriptome analysis suggests that these forces result from high-dimensional dynamics of the gene regulatory network. We propose that they can be generalized to all cancer cell populations and represent intrinsic behaviors of tumors, offering a previously unidentified characteristic for studying cancer. PMID:26929366

  8. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1.

    Science.gov (United States)

    Barbie, David A; Tamayo, Pablo; Boehm, Jesse S; Kim, So Young; Moody, Susan E; Dunn, Ian F; Schinzel, Anna C; Sandy, Peter; Meylan, Etienne; Scholl, Claudia; Fröhling, Stefan; Chan, Edmond M; Sos, Martin L; Michel, Kathrin; Mermel, Craig; Silver, Serena J; Weir, Barbara A; Reiling, Jan H; Sheng, Qing; Gupta, Piyush B; Wadlow, Raymond C; Le, Hanh; Hoersch, Sebastian; Wittner, Ben S; Ramaswamy, Sridhar; Livingston, David M; Sabatini, David M; Meyerson, Matthew; Thomas, Roman K; Lander, Eric S; Mesirov, Jill P; Root, David E; Gilliland, D Gary; Jacks, Tyler; Hahn, William C

    2009-11-01

    The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. A complementary strategy for targeting KRAS is to identify gene products that, when inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkappaB kinase TBK1 was selectively essential in cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappaB anti-apoptotic signals involving c-Rel and BCL-XL (also known as BCL2L1) that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations indicate that TBK1 and NF-kappaB signalling are essential in KRAS mutant tumours, and establish a general approach for the rational identification of co-dependent pathways in cancer. PMID:19847166

  9. The structural pathway of interleukin 1 (IL-1) initiated signaling reveals mechanisms of oncogenic mutations and SNPs in inflammation and cancer

    OpenAIRE

    Gürsoy, Attila; Özbabacan, Saliha Ece Acuner; Keskin, Özlem Zehra; Nussinov, Ruth

    2014-01-01

    The Structural Pathway of Interleukin 1 (IL-1) Initiated Signaling Reveals Mechanisms of Oncogenic Mutations and SNPs in Inflammation and Cancer Saliha Ece Acuner Ozbabacan1, Attila Gursoy1*, Ruth Nussinov2,3, Ozlem Keskin1* 1 Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Sariyer Istanbul, Turkey, 2 Cancer and Inflammation Program, Leidos Biomedical Research, Inc., National Cancer Institute, Frederick National Laboratory, Freder...

  10. The structural pathway of interleukin 1 (IL-1) initiated signaling reveals mechanisms of oncogenic mutations and SNPs in inflammation and cancer.

    OpenAIRE

    Saliha Ece Acuner Ozbabacan; Attila Gursoy; Ruth Nussinov; Ozlem Keskin

    2014-01-01

    The Structural Pathway of Interleukin 1 (IL-1) Initiated Signaling Reveals Mechanisms of Oncogenic Mutations and SNPs in Inflammation and Cancer Saliha Ece Acuner Ozbabacan1, Attila Gursoy1*, Ruth Nussinov2,3, Ozlem Keskin1* 1 Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Sariyer Istanbul, Turkey, 2 Cancer and Inflammation Program, Leidos Biomedical Research, Inc., National Cancer Institute, Frederick National Laboratory, Freder...

  11. Lung Metastasis From Prostate Cancer Revealed by 18F-FDG PET/CT Without Osseous Metastasis on Bone Scan.

    Science.gov (United States)

    Su, Hung-Yi; Chen, Meng-Lin; Hsieh, Ping-Ju; Hsieh, Teh-Sheng; Chao, Ing-Ming

    2016-05-01

    A 54-year-old man, a case of prostate cancer, underwent radical prostatectomy and hormone therapy. Elevated prostate-specific antigen level developed 7 years later, but pelvic MRI and bone scan revealed negative results. Radiotherapy was performed under the suspicion of local recurrence but in vain. F-FDG PET/CT performed 1 more year later showed 3 FDG-avid lesions in the right lung and mediastinum. Lung and lymph node metastases were proved with video-assisted thoracoscopic surgery. Bone scan remained negative at that time. PMID:26859201

  12. A Trans-omics Mathematical Analysis Reveals Novel Functions of the Ornithine Metabolic Pathway in Cancer Stem Cells

    Science.gov (United States)

    Koseki, Jun; Matsui, Hidetoshi; Konno, Masamitsu; Nishida, Naohiro; Kawamoto, Koichi; Kano, Yoshihiro; Mori, Masaki; Doki, Yuichiro; Ishii, Hideshi

    2016-02-01

    Bioinformatics and computational modelling are expected to offer innovative approaches in human medical science. In the present study, we performed computational analyses and made predictions using transcriptome and metabolome datasets obtained from fluorescence-based visualisations of chemotherapy-resistant cancer stem cells (CSCs) in the human oesophagus. This approach revealed an uncharacterized role for the ornithine metabolic pathway in the survival of chemotherapy-resistant CSCs. The present study fastens this rationale for further characterisation that may lead to the discovery of innovative drugs against robust CSCs.

  13. Financial Fragility and the Exchange Rate Regime

    OpenAIRE

    Chang, Roberto; Velasco, Andres

    1998-01-01

    We study financial fragility, exchange rate crises and monetary policy in an open economy model in which banks are maturity transformers as in Diamond-Dybvig. The banking system, the exchange rate regime, and central bank credit policy are seen as parts of a mechanism intended to maximize social welfare; if the mechanism fails, banking crises and speculative attacks become possible. We compare currency boards, fixed rate and flexible rates, with and without a lender of last resort. A currency...

  14. Fragility Analysis of Concrete Gravity Dams

    Science.gov (United States)

    Tekie, Paulos B.; Ellingwood, Bruce R.

    2002-09-01

    Concrete gravity dams are an important part ofthe nation's infrastructure. Many dams have been in service for over 50 years, during which time important advances in the methodologies for evaluation of natural phenomena hazards have caused the design-basis events to be revised upwards, in some cases significantly. Many existing dams fail to meet these revised safety criteria and structural rehabilitation to meet newly revised criteria may be costly and difficult. A probabilistic safety analysis (PSA) provides a rational safety assessment and decision-making tool managing the various sources of uncertainty that may impact dam performance. Fragility analysis, which depicts fl%e uncertainty in the safety margin above specified hazard levels, is a fundamental tool in a PSA. This study presents a methodology for developing fragilities of concrete gravity dams to assess their performance against hydrologic and seismic hazards. Models of varying degree of complexity and sophistication were considered and compared. The methodology is illustrated using the Bluestone Dam on the New River in West Virginia, which was designed in the late 1930's. The hydrologic fragilities showed that the Eluestone Dam is unlikely to become unstable at the revised probable maximum flood (PMF), but it is likely that there will be significant cracking at the heel ofthe dam. On the other hand, the seismic fragility analysis indicated that sliding is likely, if the dam were to be subjected to a maximum credible earthquake (MCE). Moreover, there will likely be tensile cracking at the neck of the dam at this level of seismic excitation. Probabilities of relatively severe limit states appear to be only marginally affected by extremely rare events (e.g. the PMF and MCE). Moreover, the risks posed by the extreme floods and earthquakes were not balanced for the Bluestone Dam, with seismic hazard posing a relatively higher risk.

  15. Equilibrium analysis, banking, contagion and financial fragility

    OpenAIRE

    Tsomocos, Dimitrios P.

    2003-01-01

    This paper contains a General Equilibrium model of an economy with Incomplete Markets (GEI) with money and default. The model is a simplified version of the real world consisting of a non-bank private sector, banks, a Central Bank, a government and a regulator. The model is used to analyse actions by policy makers and to identify policy relevant empirical work. Key analytical results are: A financially fragile system need not collapse; efficiency can be improved with policy intervention; and ...

  16. Multipartnered Fertility and Depression among Fragile Families

    OpenAIRE

    Turney, Kristin; Carlson, Marcia J.

    2011-01-01

    We used data from the Fragile Families and Child Wellbeing Study to examine the association between multipartnered fertility (MPF)—when parents have children with more than one partner—and depression. Random effects models suggested that MPF is associated with a greater likelihood of depression, net of family structure and other covariates. However, these associations disappeared in more conservative fixed effects models that estimated changes in MPF as a function of changes in depression. Re...

  17. Seismic fragility evaluation of unreinforced masonry walls

    International Nuclear Information System (INIS)

    A practical analysis scheme to evaluate the seismic fragility of unreinforced masonry walls which are used at various places in older reactor facilities is presented. Among the several failure modes for such walls, the out-of-plane bending failure is considered to be a major risk contributor in seismic PRA studies. In order to evaluate this failure mode, the use of an equivalent linear approximation method is examined based on comparisons with available test data and nonlinear time history analyses. (author)

  18. The highly fragile glass former Decalin

    International Nuclear Information System (INIS)

    Systems exhibiting the glass transition can be classified by fragility. In this work we studied structural and dynamical aspects of highly fragile C10 H18 Decalin. Trans Decalin is locked into a pseudo-flat centrosymmetric conformation, while cis Decalin interchanges dynamically between chiral, pseudo-spherical ground states. On investigation of the phase behaviour trans Decalin was found to crystallise rapidly and cleanly; its crystal structure could be determined. From the crystal structure the dynamics of crystalline trans Decalin could be calculated using ab-initio lattice energy calculations and compared to measurements. Using neutron diffraction and molecular dynamics simulations the amorphous structure of Decalin was investigated. The difference in structure to the common molecular liquid Cumene is significant. The features of the amorphous structure of sphere-like cis Decalin show strong resemblance to the ones of Argon and metallic glasses. The dynamics of Decalin were investigated in the slightly supercooled liquid range. Using neutron scattering and optical spectroscopy, data was collected for a wide spectral range and several temperatures. The data suggests high fragility for the generic Decalin mixture, which is in agreement with the reported results. By contrast to previous estimations, an extrapolation of our data indicates cis Decalin to be only slightly less fragile than the generic mixture. Finally a lower limit to the four point susceptibility function χ4 could be calculated and the number of correlated molecules determined. The evolution of this value as a function of Tg/T and relaxation time are in agreement with literature. (author)

  19. Correlated fragile site expression allows the identification of candidate fragile genes involved in immunity and associated with carcinogenesis

    Directory of Open Access Journals (Sweden)

    Puliti Alda

    2006-09-01

    Full Text Available Abstract Background Common fragile sites (cfs are specific regions in the human genome that are particularly prone to genomic instability under conditions of replicative stress. Several investigations support the view that common fragile sites play a role in carcinogenesis. We discuss a genome-wide approach based on graph theory and Gene Ontology vocabulary for the functional characterization of common fragile sites and for the identification of genes that contribute to tumour cell biology. Results Common fragile sites were assembled in a network based on a simple measure of correlation among common fragile site patterns of expression. By applying robust measurements to capture in quantitative terms the non triviality of the network, we identified several topological features clearly indicating departure from the Erdos-Renyi random graph model. The most important outcome was the presence of an unexpected large connected component far below the percolation threshold. Most of the best characterized common fragile sites belonged to this connected component. By filtering this connected component with Gene Ontology, statistically significant shared functional features were detected. Common fragile sites were found to be enriched for genes associated to the immune response and to mechanisms involved in tumour progression such as extracellular space remodeling and angiogenesis. Moreover we showed how the internal organization of the graph in communities and even in very simple subgraphs can be a starting point for the identification of new factors of instability at common fragile sites. Conclusion We developed a computational method addressing the fundamental issue of studying the functional content of common fragile sites. Our analysis integrated two different approaches. First, data on common fragile site expression were analyzed in a complex networks framework. Second, outcomes of the network statistical description served as sources for the

  20. Profiling of microRNA-mRNA reveals roles of microRNAs in cervical cancer

    Institute of Scientific and Technical Information of China (English)

    MA Ding; ZHANG You-yi; GUO Yan-li; LI Zi-jian; GENG Li

    2012-01-01

    Background Cervical cancer is one of the most common malignant tumors in women.This study was designed to explore the expression profiles of microRNAs (miRNAs) and mRNAs and the gene regulation network in cervical tumorigenesis and to find candidate molecular markers and key tumorigenic genes in cervical cancer.Methods miRNAs and mRNAs expression microarrays were used to detect the expression of miRNAs and mRNAs in normal and cancer cervical tissues.TargetScan 5.0 database (UK) was used to predict the target genes of the miRNAs,analyze their intersection with differentially expressed mRNAs and negatively correlate the intersection with miRNAs.Bioinformatic approaches were used to analyze functions and pathways of the target genes and establish miRNA-gene network.Results Twenty-nine miRNAs and 2036 mRNAs were differentially expressed in normal and cervical tumor tissues.Among them,13 miRNAs and 754 mRNAs were up-regulated in cervical tumor tissues and 16 miRNAs and 1282 RNA were down-regulated.The 327 target genes negatively related to miRNAs in the intersection were involved in functions and signal pathways.Down-regulated miRNAs targeted genes and up-regulated miRNAs targeted genes were involved in 415 and 163 functions,respectively,and in 37 and 17 significant pathways,respectively (P <0.05,false discovery rate (FDR) <0.05).We constructed the miRNAs-gene network and found that hsa-miR-15a,hsa-miR-106b and hsa-miR-20b were key nodes in the network.Conclusions The differentially expressed miRNAs and mRNAs in cervical cancer and related miRNA-gene network have been identified.They play important roles in cervical tumorigenesis and are involved in many important biological functions and signal transduction pathways.These findings lay a foundation for research on the molecular mechanism of miRNAs in the pathogenesis of cervical cancer.

  1. Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1

    NARCIS (Netherlands)

    D.M. Glubb (Dylan); M. Maranian (Melanie); K. Michailidou (Kyriaki); K.A. Pooley (Karen); K.B. Meyer (Kerstin); S. Kar (Siddhartha); A.F.C. Carlebur; M. O'Reilly (Marian); J.A. Betts (Joshua); K.M. Hillman (Kristine); S. Kaufmann (Susanne); J. Beesley (Jonathan); S. Canisius (Sander); J.L. Hopper (John); M.C. Southey (Melissa); H. Tsimiklis (Helen); C. Apicella (Carmel); M.K. Schmidt (Marjanka); A. Broeks (Annegien); F.B.L. Hogervorst (Frans); C.E. van der Schoot (Ellen); K.R. Muir (K.); A. Lophatananon (Artitaya); S. Stewart-Brown (Sarah); P. Siriwanarangsan (Pornthep); P.A. Fasching (Peter); M. Ruebner (Matthias); A.B. Ekici (Arif); M.W. Beckmann (Matthias W.); J. Peto (Julian); I. dos Santos Silva (Isabel); O. Fletcher (Olivia); N. Johnson (Nichola); P.D.P. Pharoah (Paul D.P.); M.K. Bolla (Manjeet); Q. Wang (Qing); J. Dennis (Joe); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); M. Kerin (Michael); N. Miller (Nicola); B. Burwinkel (Barbara); F. Marme (Federick); R. Yang (Rongxi); H. Surowy (Harald); P. Guénel (Pascal); T. Truong (Thérèse); F. Menegaux (Florence); M. Sanchez (Marie); S.E. Bojesen (Stig); B.G. Nordestgaard (Børge); S.F. Nielsen (Sune); H. Flyger (Henrik); A. González-Neira (Anna); J. Benítez (Javier); M.P. Zamora (Pilar); J.I. Arias Pérez (José Ignacio); H. Anton-Culver (Hoda); S.L. Neuhausen (Susan); H. Brenner (Hermann); A.K. Dieffenbach (Aida Karina); V. Arndt (Volker); C. Stegmaier (Christa); A. Meindl (Alfons); R.K. Schmutzler (Rita); H. Brauch (Hiltrud); Y.-D. Ko (Yon-Dschun); T. Brüning (Thomas); H. Nevanlinna (Heli); T.A. Muranen (Taru); K. Aittomäki (Kristiina); C. Blomqvist (Carl); K. Matsuo (Keitaro); H. Ito (Hidemi); H. Iwata (Hisato); H. Tanaka (Hideo); T. Dörk (Thilo); N.V. Bogdanova (Natalia); S. Helbig (Sonja); A. Lindblom (Annika); S. Margolin (Sara); A. Mannermaa (Arto); V. Kataja (Vesa); V-M. Kosma (Veli-Matti); J.M. Hartikainen (J.); A.H. Wu (Anna H.); C.-C. Tseng (Chiu-Chen); D. Van Den Berg (David); D.O. Stram (Daniel O.); D. Lambrechts (Diether); H. Zhao (Hui); C. Weltens (Caroline); E. van Limbergen (Erik); J. Chang-Claude (Jenny); D. Flesch-Janys (Dieter); A. Rudolph (Anja); P. Seibold (Petra); P. Radice (Paolo); P. Peterlongo (Paolo); M. Barile (Monica); F. Capra (Fabio); F.J. Couch (Fergus); J.E. Olson (Janet); B. Hallberg (Boubou); C. Vachon (Celine); G.G. Giles (Graham); R.L. Milne (Roger); C.A. McLean (Catriona Ann); C.A. Haiman (Christopher); B.E. Henderson (Brian); F.R. Schumacher (Fredrick); L. Le Marchand (Loic); J. Simard (Jacques); M.S. Goldberg (Mark); F. Labrèche (France); M. Dumont (Martine); S.-H. Teo; C.H. Yip (Cheng Har); M.-H. See (Mee-Hoong); B.K. Cornes (Belinda); C.-Y. Cheng (Ching-Yu); M.K. Ikram (Kamran); V. Kristensen (Vessela); W. Zheng (Wei); S.L. Halverson (Sandra L.); M. Shrubsole (Martha); J. Long (Jirong); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); S. Kauppila (Saila); I.L. Andrulis (Irene); J.A. Knight (Julia); G. Glendon (Gord); S. Tchatchou (Sandrine); P. Devilee (Peter); R.A.E.M. Tollenaar (Rob); C.M. Seynaeve (Caroline); C.J. van Asperen (Christi); M. García-Closas (Montserrat); J.D. Figueroa (Jonine); S.J. Chanock (Stephen); J. Lissowska (Jolanta); K. Czene (Kamila); D. Klevebring (Daniel); H. Darabi (Hatef); M. Eriksson (Mikael); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); J.W.M. Martens (John W. M.); J.M. Collee (Margriet); P. Hall (Per); J. Li (Jingmei); K. Humphreys (Keith); X.-O. Shu (Xiao-Ou); W. Lu (Wei); Y.-T. Gao (Yu-Tang); H. Cai (Hui); A. Cox (Angela); S.S. Cross (Simon); M.W.R. Reed (Malcolm); W.J. Blot (William); L.B. Signorello (Lisa B.); Q. Cai (Qiuyin); M. Shah (Mitul); M. Ghoussaini (Maya); D. Kang (Daehee); J.-Y. Choi (J.); S.K. Park (Sue); D-Y. Noh (Dong-Young); M. Hartman (Mikael); X. Miao; W.-Y. Lim (Wei-Yen); A. Tang (Anthony); U. Hamann (Ute); D. Torres (Diana); A. Jakubowska (Anna); J. Lubinski (Jan); K. Jaworska (Katarzyna); K. Durda (Katarzyna); S. Sangrajrang (Suleeporn); V. Gaborieau (Valerie); P. Brennan (Paul); J.D. McKay (James); C. Olswold (Curtis); S. Slager (Susan); A.E. Toland (Amanda); D. Yannoukakos (Drakoulis); C-Y. Shen (Chen-Yang); P.-E. Wu (Pei-Ei); J-C. Yu (Jyh-Cherng); M.-F. Hou (Ming-Feng); A.J. Swerdlow (Anthony ); A. Ashworth (Alan); N. Orr (Nick); M. Jones (Michael); G. Pita (G.); M.R. Alonso (M Rosario); N. Álvarez (Nuria); D. Herrero (Daniel); D.C. Tessier (Daniel C.); D. Vincent (Daniel); F. Bacot (Francois); C. Luccarini (Craig); C. Baynes (Caroline); S. Ahmed (Shahana); S. Healey (Sue); M. Brown (Melissa); B.A.J. Ponder (Bruce A.J.); G. Chenevix-Trench (Georgia); D. Thompson (Deborah); S.L. Edwards (Stacey); D.F. Easton (Douglas); A.M. Dunning (Alison); J.D. French (Juliet)

    2015-01-01

    textabstractGenome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer indiv

  2. International Transmission of Shocks and Fragility of a Bank Network

    CERN Document Server

    Feng, Xiaobing; Kim, Beom Jun

    2014-01-01

    The weighted and directed network of countries based on the number of overseas banks is analyzed in terms of its fragility to the banking crisis of one country. We use two different models to describe transmission of shocks, one local and the other global. Depending on the original source of the crisis, the overall size of crisis impacts is found to differ country by country. For the two-step local spreading model, it is revealed that the scale of the first impact is determined by the out-strength, the total number of overseas branches of the country at the origin of the crisis, while the second impact becomes more serious if the in-strength at the origin is increased. For the global spreading model, some countries named "triggers" are found to play important roles in shock transmission, and the importance of the feed-forward-loop mechanism is pointed out. We also discuss practical policy implications of the present work.

  3. Integrated analysis of DNA methylation and gene expression reveals specific signaling pathways associated with platinum resistance in ovarian cancer

    Directory of Open Access Journals (Sweden)

    Chung Jae

    2009-06-01

    Full Text Available Abstract Background Cisplatin and carboplatin are the primary first-line therapies for the treatment of ovarian cancer. However, resistance to these platinum-based drugs occurs in the large majority of initially responsive tumors, resulting in fully chemoresistant, fatal disease. Although the precise mechanism(s underlying the development of platinum resistance in late-stage ovarian cancer patients currently remains unknown, CpG-island (CGI methylation, a phenomenon strongly associated with aberrant gene silencing and ovarian tumorigenesis, may contribute to this devastating condition. Methods To model the onset of drug resistance, and investigate DNA methylation and gene expression alterations associated with platinum resistance, we treated clonally derived, drug-sensitive A2780 epithelial ovarian cancer cells with increasing concentrations of cisplatin. After several cycles of drug selection, the isogenic drug-sensitive and -resistant pairs were subjected to global CGI methylation and mRNA expression microarray analyses. To identify chemoresistance-associated, biological pathways likely impacted by DNA methylation, promoter CGI methylation and mRNA expression profiles were integrated and subjected to pathway enrichment analysis. Results Promoter CGI methylation revealed a positive association (Spearman correlation of 0.99 between the total number of hypermethylated CGIs and GI50 values (i.e., increased drug resistance following successive cisplatin treatment cycles. In accord with that result, chemoresistance was reversible by DNA methylation inhibitors. Pathway enrichment analysis revealed hypermethylation-mediated repression of cell adhesion and tight junction pathways and hypomethylation-mediated activation of the cell growth-promoting pathways PI3K/Akt, TGF-beta, and cell cycle progression, which may contribute to the onset of chemoresistance in ovarian cancer cells. Conclusion Selective epigenetic disruption of distinct biological

  4. Dynamics between cancer cell subpopulations reveals a model coordinating with both hierarchical and stochastic concepts.

    Science.gov (United States)

    Wang, Weikang; Quan, Yi; Fu, Qibin; Liu, Yu; Liang, Ying; Wu, Jingwen; Yang, Gen; Luo, Chunxiong; Ouyang, Qi; Wang, Yugang

    2014-01-01

    Tumors are often heterogeneous in which tumor cells of different phenotypes have distinct properties. For scientific and clinical interests, it is of fundamental importance to understand their properties and the dynamic variations among different phenotypes, specifically under radio- and/or chemo-therapy. Currently there are two controversial models describing tumor heterogeneity, the cancer stem cell (CSC) model and the stochastic model. To clarify the controversy, we measured probabilities of different division types and transitions of cells via in situ immunofluorescence. Based on the experiment data, we constructed a model that combines the CSC with the stochastic concepts, showing the existence of both distinctive CSC subpopulations and the stochastic transitions from NSCCs to CSCs. The results showed that the dynamic variations between CSCs and non-stem cancer cells (NSCCs) can be simulated with the model. Further studies also showed that the model can be used to describe the dynamics of the two subpopulations after radiation treatment. More importantly, analysis demonstrated that the experimental detectable equilibrium CSC proportion can be achieved only when the stochastic transitions from NSCCs to CSCs occur, indicating that tumor heterogeneity may exist in a model coordinating with both the CSC and the stochastic concepts. The mathematic model based on experimental parameters may contribute to a better understanding of the tumor heterogeneity, and provide references on the dynamics of CSC subpopulation during radiotherapy. PMID:24416258

  5. Dynamics between cancer cell subpopulations reveals a model coordinating with both hierarchical and stochastic concepts.

    Directory of Open Access Journals (Sweden)

    Weikang Wang

    Full Text Available Tumors are often heterogeneous in which tumor cells of different phenotypes have distinct properties. For scientific and clinical interests, it is of fundamental importance to understand their properties and the dynamic variations among different phenotypes, specifically under radio- and/or chemo-therapy. Currently there are two controversial models describing tumor heterogeneity, the cancer stem cell (CSC model and the stochastic model. To clarify the controversy, we measured probabilities of different division types and transitions of cells via in situ immunofluorescence. Based on the experiment data, we constructed a model that combines the CSC with the stochastic concepts, showing the existence of both distinctive CSC subpopulations and the stochastic transitions from NSCCs to CSCs. The results showed that the dynamic variations between CSCs and non-stem cancer cells (NSCCs can be simulated with the model. Further studies also showed that the model can be used to describe the dynamics of the two subpopulations after radiation treatment. More importantly, analysis demonstrated that the experimental detectable equilibrium CSC proportion can be achieved only when the stochastic transitions from NSCCs to CSCs occur, indicating that tumor heterogeneity may exist in a model coordinating with both the CSC and the stochastic concepts. The mathematic model based on experimental parameters may contribute to a better understanding of the tumor heterogeneity, and provide references on the dynamics of CSC subpopulation during radiotherapy.

  6. Combining Chromosomal Arm Status and Significantly Aberrant Genomic Locations Reveals New Cancer Subtypes

    Directory of Open Access Journals (Sweden)

    Tal Shay

    2009-01-01

    Full Text Available Many types of tumors exhibit characteristic chromosomal losses or gains, as well as local amplifications and deletions. Within any given tumor type, sample specific amplifications and deletions are also observed. Typically, a region that is aberrant in more tumors, or whose copy number change is stronger, would be considered as a more promising candidate to be biologically relevant to cancer. We sought for an intuitive method to define such aberrations and prioritize them. We define V, the “volume” associated with an aberration, as the product of three factors: (a fraction of patients with the aberration, (b the aberration’s length and (c its amplitude. Our algorithm compares the values of V derived from the real data to a null distribution obtained by permutations, and yields the statistical significance (p-value of the measured value of V. We detected genetic locations that were significantly aberrant, and combine them with chromosomal arm status (gain/loss to create a succinct fingerprint of the tumor genome. This genomic fingerprint is used to visualize the tumors, highlighting events that are co-occurring or mutually exclusive. We apply the method on three different public array CGH datasets of Medulloblastoma and Neuroblastoma, and demonstrate its ability to detect chromosomal regions that were known to be altered in the tested cancer types, as well as to suggest new genomic locations to be tested. We identified a potential new subtype of Medulloblastoma, which is analogous to Neuroblastoma type 1.

  7. Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression

    Science.gov (United States)

    Lasorsa, Vito Alessandro; Formicola, Daniela; Pignataro, Piero; Cimmino, Flora; Calabrese, Francesco Maria; Mora, Jaume; Esposito, Maria Rosaria; Pantile, Marcella; Zanon, Carlo; De Mariano, Marilena; Longo, Luca; Hogarty, Michael D.; de Torres, Carmen; Tonini, Gian Paolo; Iolascon, Achille; Capasso, Mario

    2016-01-01

    The spectrum of somatic mutation of the most aggressive forms of neuroblastoma is not completely determined. We sought to identify potential cancer drivers in clinically aggressive neuroblastoma. Whole exome sequencing was conducted on 17 germline and tumor DNA samples from high-risk patients with adverse events within 36 months from diagnosis (HR-Event3) to identify somatic mutations and deep targeted sequencing of 134 genes selected from the initial screening in additional 48 germline and tumor pairs (62.5% HR-Event3 and high-risk patients), 17 HR-Event3 tumors and 17 human-derived neuroblastoma cell lines. We revealed 22 significantly mutated genes, many of which implicated in cancer progression. Fifteen genes (68.2%) were highly expressed in neuroblastoma supporting their involvement in the disease. CHD9, a cancer driver gene, was the most significantly altered (4.0% of cases) after ALK. Other genes (PTK2, NAV3, NAV1, FZD1 and ATRX), expressed in neuroblastoma and involved in cell invasion and migration were mutated at frequency ranged from 4% to 2%. Focal adhesion and regulation of actin cytoskeleton pathways, were frequently disrupted (14.1% of cases) thus suggesting potential novel therapeutic strategies to prevent disease progression. Notably BARD1, CHEK2 and AXIN2 were enriched in rare, potentially pathogenic, germline variants. In summary, whole exome and deep targeted sequencing identified novel cancer genes of clinically aggressive neuroblastoma. Our analyses show pathway-level implications of infrequently mutated genes in leading neuroblastoma progression. PMID:27009842

  8. Molecular Cloning and Preliminary Analysis of a Fragile Site Associated Gene

    Institute of Scientific and Technical Information of China (English)

    YI-WEN CAO; CHUAN-LU JIANG; TAO JIANG

    2006-01-01

    Objective To analyze the molecular colning of a fragile site-associated gene. Methods Genomic Chinese hamster ovary (CHO) DNA library was constructed using high molecular weight CHO DNA partially digested with MboI restriction enzyme from cultured CHO cells. Screening of genomic DNA library followed the established procedures. Genomic CHO in the positive clones was sequenced. Appropriate primers were designed for the reverse transcriptase-polymerase chain reactions (RT-PCR). The RT-PCR products were cloned into a pCRⅡ TOPO vector and confirmed by DNA sequencing. Antibodies were prepared using synthetic peptides as antigens by immunizing the rabbits. Immunohistochemical analyses were performed to evaluate the expression of the novel gene in different tissues. Results To investigate the molecular mechanism underlying the initial events of mdrla amplification, we cloned 1q31 fragile site DNA. Strikingly, we found that this fragile site contained a novel gene which was designated as a fragile site-associated (FSA) gene. FSA encoded an unusually large mRNA of ~16 kb. Full-length human FSA cDNA was cloned. FSA mRNA was expressed in many cultured cells and tissue types. Immunohistochemical analyses also revealed an expression pattern of the encoded proteins in postmitotic, well-differentiated epithelial compartments of many organs, including colon, mammary glands, ovary, prostate, and bladder. Conclusion FSA plays an important role in regulating mammalian epithelial cell growth and differentiation.

  9. Quantitative profiling of brain lipid raft proteome in a mouse model of fragile X syndrome.

    Directory of Open Access Journals (Sweden)

    Magdalena Kalinowska

    Full Text Available Fragile X Syndrome, a leading cause of inherited intellectual disability and autism, arises from transcriptional silencing of the FMR1 gene encoding an RNA-binding protein, Fragile X Mental Retardation Protein (FMRP. FMRP can regulate the expression of approximately 4% of brain transcripts through its role in regulation of mRNA transport, stability and translation, thus providing a molecular rationale for its potential pleiotropic effects on neuronal and brain circuitry function. Several intracellular signaling pathways are dysregulated in the absence of FMRP suggesting that cellular deficits may be broad and could result in homeostatic changes. Lipid rafts are specialized regions of the plasma membrane, enriched in cholesterol and glycosphingolipids, involved in regulation of intracellular signaling. Among transcripts targeted by FMRP, a subset encodes proteins involved in lipid biosynthesis and homeostasis, dysregulation of which could affect the integrity and function of lipid rafts. Using a quantitative mass spectrometry-based approach we analyzed the lipid raft proteome of Fmr1 knockout mice, an animal model of Fragile X syndrome, and identified candidate proteins that are differentially represented in Fmr1 knockout mice lipid rafts. Furthermore, network analysis of these candidate proteins reveals connectivity between them and predicts functional connectivity with genes encoding components of myelin sheath, axonal processes and growth cones. Our findings provide insight to aid identification of molecular and cellular dysfunctions arising from Fmr1 silencing and for uncovering shared pathologies between Fragile X syndrome and other autism spectrum disorders.

  10. Large-scale computations on histology images reveal grade-differentiating parameters for breast cancer

    International Nuclear Information System (INIS)

    Tumor classification is inexact and largely dependent on the qualitative pathological examination of the images of the tumor tissue slides. In this study, our aim was to develop an automated computational method to classify Hematoxylin and Eosin (H&E) stained tissue sections based on cancer tissue texture features. Image processing of histology slide images was used to detect and identify adipose tissue, extracellular matrix, morphologically distinct cell nuclei types, and the tubular architecture. The texture parameters derived from image analysis were then applied to classify images in a supervised classification scheme using histologic grade of a testing set as guidance. The histologic grade assigned by pathologists to invasive breast carcinoma images strongly correlated with both the presence and extent of cell nuclei with dispersed chromatin and the architecture, specifically the extent of presence of tubular cross sections. The two parameters that differentiated tumor grade found in this study were (1) the number density of cell nuclei with dispersed chromatin and (2) the number density of tubular cross sections identified through image processing as white blobs that were surrounded by a continuous string of cell nuclei. Classification based on subdivisions of a whole slide image containing a high concentration of cancer cell nuclei consistently agreed with the grade classification of the entire slide. The automated image analysis and classification presented in this study demonstrate the feasibility of developing clinically relevant classification of histology images based on micro- texture. This method provides pathologists an invaluable quantitative tool for evaluation of the components of the Nottingham system for breast tumor grading and avoid intra-observer variability thus increasing the consistency of the decision-making process

  11. Large-scale computations on histology images reveal grade-differentiating parameters for breast cancer

    Directory of Open Access Journals (Sweden)

    Katsinis Constantine

    2006-10-01

    Full Text Available Abstract Background Tumor classification is inexact and largely dependent on the qualitative pathological examination of the images of the tumor tissue slides. In this study, our aim was to develop an automated computational method to classify Hematoxylin and Eosin (H&E stained tissue sections based on cancer tissue texture features. Methods Image processing of histology slide images was used to detect and identify adipose tissue, extracellular matrix, morphologically distinct cell nuclei types, and the tubular architecture. The texture parameters derived from image analysis were then applied to classify images in a supervised classification scheme using histologic grade of a testing set as guidance. Results The histologic grade assigned by pathologists to invasive breast carcinoma images strongly correlated with both the presence and extent of cell nuclei with dispersed chromatin and the architecture, specifically the extent of presence of tubular cross sections. The two parameters that differentiated tumor grade found in this study were (1 the number density of cell nuclei with dispersed chromatin and (2 the number density of tubular cross sections identified through image processing as white blobs that were surrounded by a continuous string of cell nuclei. Classification based on subdivisions of a whole slide image containing a high concentration of cancer cell nuclei consistently agreed with the grade classification of the entire slide. Conclusion The automated image analysis and classification presented in this study demonstrate the feasibility of developing clinically relevant classification of histology images based on micro- texture. This method provides pathologists an invaluable quantitative tool for evaluation of the components of the Nottingham system for breast tumor grading and avoid intra-observer variability thus increasing the consistency of the decision-making process.

  12. Integrative transcriptome analysis reveals dysregulation of canonical cancer molecular pathways in placenta leading to preeclampsia

    OpenAIRE

    Moslehi, Roxana; Mills, James L; Signore, Caroline; Kumar, Anil; Ambroggio, Xavier; Dzutsev, Amiran

    2013-01-01

    We previously suggested links between specific XPD mutations in the fetal genome and the risk of placental maldevelopment and preeclampsia, possibly due to impairment of Transcription Factor (TF)IIH-mediated functions in placenta. To identify the underlying mechanisms, we conducted the current integrative analysis of several relevant transcriptome data sources. Our meta-analysis revealed downregulation of TFIIH subunits in preeclamptic placentas. Our overall integrative analysis suggested tha...

  13. Determinants of Banking System Fragility : A Regional Perspective

    OpenAIRE

    Degryse, H.A.; Elahi, M.A.; Penas, M.F.

    2012-01-01

    Abstract: Banking systems are fragile not only within one country but also within and across regions. We study the role of regional banking system characteristics for regional banking system fragility. We find that regional banking system fragility reduces when banks in the region jointly hold more liquid assets, are better capitalized, and when regional banking systems are more competitive. For Asia and Latin-America, a greater presence of foreign banks also reduces regional banking fragilit...

  14. Can entrepreneurship boost sustainable development in fragile countries?

    OpenAIRE

    Pereira, Marta Manuel Amaral Marques

    2012-01-01

    Fragile countries pose an intricate challenge for governments and traditional aid approaches: they continue to struggle overtime with low resilience and vulnerability, and are now accounting for a growing share of the world’s poor. When every other method has failed, can entrepreneurship be the key ingredient for turnaround? For countries trapped in fragility, little has been researched or elaborated upon. We studied what current authors said about entrepreneurship and fragility, and which...

  15. Delay Eyeblink Classical Conditioning is Impaired in Fragile X Syndrome

    OpenAIRE

    Tobia, Michael J.; Woodruff-Pak, Diana S.

    2009-01-01

    We examined 400 ms delay eyeblink classical conditioning in 20 participants with Fragile X syndrome ages 17-77 years, and 20 age-matched, healthy control participants. The Fragile X group demonstrated impaired learning and abnormal conditioned response timing. Adults with Fragile X (n=16) were also tested at two successive 12-month follow-up sessions to examine reacquisition and long-term retention. Participants in groups older and younger than 45 years demonstrated significant learning durin...

  16. General Anesthesia and Fragile X Syndrome: Report of a Case

    OpenAIRE

    Casamassimo, Paul S.; Mcllvaine, William B.; Hagerman, Randi; Shellhart, Craig

    1985-01-01

    A case report of an 11-year-old Caucasian boy with the fragile X syndrome is presented. The fragile X syndrome is a form of X-linked mental retardation with a connective tissue component that involves mitral valve prolapse. Antibiotic prophylaxis, electrocardiographic abnormalities, and special anesthetic management considerations are elements of treating patients with fragile X syndrome. The patient received morphine sulfate and scopolamine as a preoperative premedication. Ketamine was also ...

  17. Autism and Fragile X: Is There a Neurochemical Link?

    OpenAIRE

    Meguid, Nagwa A.; Atta, Hazem M.; Rashed, Laila A; Amr S. Gouda; Khalil, Rehab O.; Hashish, Adel F.

    2014-01-01

    BACKGROUND:Autism and Fragile X syndrome are intertwined. This study aimed at assessing Serotonin, Glutamate, and Gama Amino Butyric Acid (GABA) in autism and Fragile X syndrome patients and to detect possible neurochemical similarities between the 2 disorders that can be used as metabolic biomarkers. DESIGN AND METHODS: Eighty subjects divided into four groups, two diseased groups (20 male patients with Autism and 20 males with Fragile X syndrome) and two control groups (20 neurotypical m...

  18. Institutions, Trade, and Social Cohesion in Fragile States

    OpenAIRE

    Mina Baliamoune-Lutz

    2008-01-01

    This paper examines the contribution of institutions, social cohesion, and trade to development (per-capita income) with an emphasis on fragile states in Africa. Results from Arellano-Bond GMM estimations suggest that political institutions, openness to trade, and social cohesion affect growth in fragile states via direct and indirect mechanisms. The results indicate that, beyond a certain level, openness to trade may actually be harmful to economic performance in fragile states, particularly...

  19. Fragile site X chromosomes in mentally retarded boys.

    OpenAIRE

    Moon, H. R.; Moon, S. Y.

    1993-01-01

    The fragile X syndrome is a common X-linked mental retardation and autism, affecting females as well as males. The fragile site X chromosomes were studied in a series of 153 mentally retarded boys of unknown etiology to determine the frequency of fragile X syndrome, and to assess the feasibility of making a clinical diagnosis of the fragile X syndrome in young boys before cytogenetic results were known. The 10 boys (6.4%) were positive for fra (X) (q27). The phenotype of fra (X) (q27) positiv...

  20. mRNA profiling reveals determinants of trastuzumab efficiency in HER2-positive breast cancer.

    Directory of Open Access Journals (Sweden)

    Silvia von der Heyde

    Full Text Available Intrinsic and acquired resistance to the monoclonal antibody drug trastuzumab is a major problem in the treatment of HER2-positive breast cancer. A deeper understanding of the underlying mechanisms could help to develop new agents. Our intention was to detect genes and single nucleotide polymorphisms (SNPs affecting trastuzumab efficiency in cell culture. Three HER2-positive breast cancer cell lines with different resistance phenotypes were analyzed. We chose BT474 as model of trastuzumab sensitivity, HCC1954 as model of intrinsic resistance, and BTR50, derived from BT474, as model of acquired resistance. Based on RNA-Seq data, we performed differential expression analyses on these cell lines with and without trastuzumab treatment. Differentially expressed genes between the resistant cell lines and BT474 are expected to contribute to resistance. Differentially expressed genes between untreated and trastuzumab treated BT474 are expected to contribute to drug efficacy. To exclude false positives from the candidate gene set, we removed genes that were also differentially expressed between untreated and trastuzumab treated BTR50. We further searched for SNPs in the untreated cell lines which could contribute to trastuzumab resistance. The analysis resulted in 54 differentially expressed candidate genes that might be connected to trastuzumab efficiency. 90% of 40 selected candidates were validated by RT-qPCR. ALPP, CALCOCO1, CAV1, CYP1A2 and IGFBP3 were significantly higher expressed in the trastuzumab treated than in the untreated BT474 cell line. GDF15, IL8, LCN2, PTGS2 and 20 other genes were significantly higher expressed in HCC1954 than in BT474, while NCAM2, COLEC12, AFF3, TFF3, NRCAM, GREB1 and TFF1 were significantly lower expressed. Additionally, we inferred SNPs in HCC1954 for CAV1, PTGS2, IL8 and IGFBP3. The latter also had a variation in BTR50. 20% of the validated subset have already been mentioned in literature. For half of them we

  1. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients

    Science.gov (United States)

    Chabon, Jacob J.; Simmons, Andrew D.; Lovejoy, Alexander F.; Esfahani, Mohammad S.; Newman, Aaron M.; Haringsma, Henry J.; Kurtz, David M.; Stehr, Henning; Scherer, Florian; Karlovich, Chris A.; Harding, Thomas C.; Durkin, Kathleen A.; Otterson, Gregory A.; Purcell, W. Thomas; Camidge, D. Ross; Goldman, Jonathan W.; Sequist, Lecia V.; Piotrowska, Zofia; Wakelee, Heather A.; Neal, Joel W.; Alizadeh, Ash A.; Diehn, Maximilian

    2016-01-01

    Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment. PMID:27283993

  2. Lipidomic Profiling of Adipose Tissue Reveals an Inflammatory Signature in Cancer-Related and Primary Lymphedema

    Science.gov (United States)

    Sedger, Lisa M.; Tull, Dedreia L.; McConville, Malcolm J.; De Souza, David P.; Rupasinghe, Thusitha W. T.; Williams, Spencer J.; Dayalan, Saravanan; Lanzer, Daniel; Mackie, Helen; Lam, Thomas C.; Boyages, John

    2016-01-01

    Cancer-related and primary lymphedema (LE) are associated with the production of adipose tissue (AT). Nothing is known, however, about the lipid-based molecules that comprise LE AT. We therefore analyzed lipid molecules in lipoaspirates and serum obtained from LE patients, and compared them to lipoaspirates from cosmetic surgery patients and healthy control cohort serum. LE patient serum analysis demonstrated that triglycerides, HDL- and LDL-cholesterol and lipid transport molecules remained within the normal range, with no alterations in individual fatty acids. The lipidomic analysis also identified 275 lipid-based molecules, including triacylglycerides, diacylglycerides, fatty acids and phospholipids in AT oil and fat. Although the majority of lipid molecules were present in a similar abundance in LE and non-LE samples, there were several small changes: increased C20:5-containing triacylglycerides, reduced C10:0 caprinic and C24:1 nervonic acids. LE AT oil also contained a signature of increased cyclopropane-type fatty acids and inflammatory mediators arachidonic acid and ceramides. Interestingly C20:5 and C22:6 omega-3-type lipids are increased in LE AT, correlating with LE years. Hence, LE AT has a normal lipid profile containing a signature of inflammation and omega-3-lipids. It remains unclear, however, whether these differences reflect a small-scale global metabolic disturbance or effects within localised inflammatory foci. PMID:27182733

  3. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients.

    Science.gov (United States)

    Chabon, Jacob J; Simmons, Andrew D; Lovejoy, Alexander F; Esfahani, Mohammad S; Newman, Aaron M; Haringsma, Henry J; Kurtz, David M; Stehr, Henning; Scherer, Florian; Karlovich, Chris A; Harding, Thomas C; Durkin, Kathleen A; Otterson, Gregory A; Purcell, W Thomas; Camidge, D Ross; Goldman, Jonathan W; Sequist, Lecia V; Piotrowska, Zofia; Wakelee, Heather A; Neal, Joel W; Alizadeh, Ash A; Diehn, Maximilian

    2016-01-01

    Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment. PMID:27283993

  4. Lipidomic Profiling of Adipose Tissue Reveals an Inflammatory Signature in Cancer-Related and Primary Lymphedema.

    Directory of Open Access Journals (Sweden)

    Lisa M Sedger

    Full Text Available Cancer-related and primary lymphedema (LE are associated with the production of adipose tissue (AT. Nothing is known, however, about the lipid-based molecules that comprise LE AT. We therefore analyzed lipid molecules in lipoaspirates and serum obtained from LE patients, and compared them to lipoaspirates from cosmetic surgery patients and healthy control cohort serum. LE patient serum analysis demonstrated that triglycerides, HDL- and LDL-cholesterol and lipid transport molecules remained within the normal range, with no alterations in individual fatty acids. The lipidomic analysis also identified 275 lipid-based molecules, including triacylglycerides, diacylglycerides, fatty acids and phospholipids in AT oil and fat. Although the majority of lipid molecules were present in a similar abundance in LE and non-LE samples, there were several small changes: increased C20:5-containing triacylglycerides, reduced C10:0 caprinic and C24:1 nervonic acids. LE AT oil also contained a signature of increased cyclopropane-type fatty acids and inflammatory mediators arachidonic acid and ceramides. Interestingly C20:5 and C22:6 omega-3-type lipids are increased in LE AT, correlating with LE years. Hence, LE AT has a normal lipid profile containing a signature of inflammation and omega-3-lipids. It remains unclear, however, whether these differences reflect a small-scale global metabolic disturbance or effects within localised inflammatory foci.

  5. Lipidomic Profiling of Adipose Tissue Reveals an Inflammatory Signature in Cancer-Related and Primary Lymphedema.

    Science.gov (United States)

    Sedger, Lisa M; Tull, Dedreia L; McConville, Malcolm J; De Souza, David P; Rupasinghe, Thusitha W T; Williams, Spencer J; Dayalan, Saravanan; Lanzer, Daniel; Mackie, Helen; Lam, Thomas C; Boyages, John

    2016-01-01

    Cancer-related and primary lymphedema (LE) are associated with the production of adipose tissue (AT). Nothing is known, however, about the lipid-based molecules that comprise LE AT. We therefore analyzed lipid molecules in lipoaspirates and serum obtained from LE patients, and compared them to lipoaspirates from cosmetic surgery patients and healthy control cohort serum. LE patient serum analysis demonstrated that triglycerides, HDL- and LDL-cholesterol and lipid transport molecules remained within the normal range, with no alterations in individual fatty acids. The lipidomic analysis also identified 275 lipid-based molecules, including triacylglycerides, diacylglycerides, fatty acids and phospholipids in AT oil and fat. Although the majority of lipid molecules were present in a similar abundance in LE and non-LE samples, there were several small changes: increased C20:5-containing triacylglycerides, reduced C10:0 caprinic and C24:1 nervonic acids. LE AT oil also contained a signature of increased cyclopropane-type fatty acids and inflammatory mediators arachidonic acid and ceramides. Interestingly C20:5 and C22:6 omega-3-type lipids are increased in LE AT, correlating with LE years. Hence, LE AT has a normal lipid profile containing a signature of inflammation and omega-3-lipids. It remains unclear, however, whether these differences reflect a small-scale global metabolic disturbance or effects within localised inflammatory foci. PMID:27182733

  6. Seismic fragility evaluation of unreinforced masonry walls

    International Nuclear Information System (INIS)

    A practical analysis scheme to evaluate the seismic fragility of unreinforced masonry walls which are used to various places in older reactor facilities is presented. Among the several failure modes for such walls, the out-of-plane bending failure is considered to be a major risk contributor in seismic PRA studies. In order to evaluate this failure mode, the use of an equivalent linear approximation method is examined based on comparisons with available test data and nonlinear time history analyses. 6 refs., 4 figs., 3 tabs

  7. Quality Control Usage in High-Density Microarrays Reveals Differential Gene Expression Profiles in Ovarian Cancer.

    Science.gov (United States)

    Villegas-Ruiz, Vanessa; Moreno, Jose; Jacome-Lopez, Karina; Zentella-Dehesa, Alejandro; Juarez-Mendez, Sergio

    2016-01-01

    There are several existing reports of microarray chip use for assessment of altered gene expression in different diseases. In fact, there have been over 1.5 million assays of this kind performed over the last twenty years, which have influenced clinical and translational research studies. The most commonly used DNA microarray platforms are Affymetrix GeneChip and Quality Control Software along with their GeneChip Probe Arrays. These chips are created using several quality controls to confirm the success of each assay, but their actual impact on gene expression profiles had not been previously analyzed until the appearance of several bioinformatics tools for this purpose. We here performed a data mining analysis, in this case specifically focused on ovarian cancer, as well as healthy ovarian tissue and ovarian cell lines, in order to confirm quality control results and associated variation in gene expression profiles. The microarray data used in our research were downloaded from ArrayExpress and Gene Expression Omnibus (GEO) and analyzed with Expression Console Software using RMA, MAS5 and Plier algorithms. The gene expression profiles were obtained using Partek Genomics Suite v6.6 and data were visualized using principal component analysis, heat map, and Venn diagrams. Microarray quality control analysis showed that roughly 40% of the microarray files were false negative, demonstrating over- and under-estimation of expressed genes. Additionally, we confirmed the results performing second analysis using independent samples. About 70% of the significant expressed genes were correlated in both analyses. These results demonstrate the importance of appropriate microarray processing to obtain a reliable gene expression profile. PMID:27268623

  8. Fragile X syndrome in incestuous families

    Energy Technology Data Exchange (ETDEWEB)

    Seemanova, E. [Charles Univ., Prague (Czech Republic)

    1996-11-11

    Reed suggested the investigation of children 219 from incestuous unions as a method for calculation of the detrimental heterozygosity of man. Some studies of latent genetics load in man have been based on the comparison of health status of incestuous children with their half-sibs born to the same mothers in matings with nonconsanguineous partners. These studies were limited to the detection of autosomal-recessive genes leading to abnormal phenotypes or mental deficiency in homozygotes. The highest coefficient of inbreeding in human beings is 1/4 in offspring of incestuous matings: hence, the high proportion of affected homozygotes and low incidence of affected individuals among their maternal half-sibs. Mental deficiency in incestuous children represents not only cases of simple recessive inheritance. Recently, we observed three incestuous families in which fragile X syndrome was detected. The fra(X) children were born to carriers from incestuous unions as well as to unrelated partners. Therefore, we recommend use of incestuous children and their maternal half-sibs as a control group for studies estimating latent genetic load after investigation for fra(X). The incidence of fra(X) syndrome is high, and mental retardation in heterozygotes is uncommon. Both of these factors can play a role in the occurrence of incest, and in pregnancy at young age, as well as in multiple partnerships. Families of heterozygotes for fragile X should be excluded from the material for the calculation of human latent detrimental (autosomal-recessive) genetic load. 3 refs., 3 figs.

  9. Fragility Fractures in Patients with Psoriatic Arthritis.

    Science.gov (United States)

    Del Puente, Antonio; Esposito, Antonella; Costa, Luisa; Benigno, Carla; Del Puente, Aurora; Foglia, Francesca; Oriente, Alfonso; Bottiglieri, Paolo; Caso, Francesco; Scarpa, Raffaele

    2015-11-01

    Psoriatic arthritis (PsA) can have peculiar effects on bone, including mechanisms of bone loss such as erosions, but also of bone formation, such as ankylosis or periostitis. The aim of the present study was to describe the prevalence of fractures in patients with PsA as compared to healthy controls and to investigate determinants of fractures among cases. For both cases and controls, radiographs were read to identify vertebral fractures (VF), and the presence of femoral neck or other nonvertebral fractures was obtained from patients' medical history. The prevalence of fragility fractures on radiographic readings did not differ between cases and controls. The number of subjects showing a VF was 33 (36%) among PsA patients and 36 (36%) among controls, with a prevalence of severe VF of 8% among cases and 4% among controls. Controlling for covariates in a logistic model, the only variables showing a significant correlation with the presence of nonvertebral fractures (NVF) were disease duration (p=0.02), age (p=0.03), and bone mineral density at femoral neck (inverse correlation, p=0.04). Fractures should be carefully considered when evaluating the global picture of the patient with PsA for their contribution to the "fragility" profile. PMID:26523054

  10. Obtaining reliable quality data from fragility tests

    International Nuclear Information System (INIS)

    The parameters discussed in this paper are the same as those present in normal seismic qualification testing. These parameters behave differently in high level acceleration tests and their contribution in providing unreliable data is of major concern since there is a significant difference. These parameters need to be considered in developing methodology guidelines for future fragility standards. In seismic qualification testing, a predefined series of tests are performed and measured against a set of acceptance criteria. The response spectra generally has a peak acceleration of between 3-10 g's at a 2% damping value for the Design Basis Event (Safe Shutdown Earthquake). Fragility level testing has minimum starting point of 10 g's at 2% damping and is generally 20 g's at 2% damping. The dynamic characteristics of the simulated earthquake and the corresponding simulator hardware interfaces are the parameters discussed. There are two major parameter contributions in obtaining unreliable data. The first parameter is test specimen system hardware nonlinearities. The second major variable is electronic signal saturations

  11. Babies at Double Jeopardy: Medically Fragile Infants and Child Neglect

    Science.gov (United States)

    Fullar, Suzanne A.

    2008-01-01

    Medically fragile infants, those born prematurely or with other complex medical or genetic problems, are at risk of long-term health and developmental problems. When a medically fragile infant comes home to a family with significant social problems such as domestic violence, mental illness, or substance abuse, the infant is at double jeopardy--at…

  12. Finiteness Marking in Boys with Fragile X Syndrome

    Science.gov (United States)

    Sterling, Audra M.; Rice, Mabel L.; Warren, Steven F.

    2012-01-01

    Purpose: The current study investigated finiteness marking (e.g., he walk "s", he walk "ed") in boys with fragile X syndrome (FXS); the boys were grouped based on receptive vocabulary (i.e., borderline, impaired). Method: Twenty-one boys with the full mutation of fragile X, between the ages of 8 and 16 years participated. The boys completed probes…

  13. Attentional Set-Shifting in Fragile X Syndrome

    Science.gov (United States)

    Van der Molen, M. J. W.; Van der Molen, M. W.; Ridderinkhof, K. R.; Hamel, B. C. J.; Curfs, L. M. G.; Ramakers, G. J. A.

    2012-01-01

    The ability to flexibly adapt to the changing demands of the environment is often reported as a core deficit in fragile X syndrome (FXS). However, the cognitive processes that determine this attentional set-shifting deficit remain elusive. The present study investigated attentional set-shifting ability in fragile X syndrome males with the…

  14. Memory Skills of Boys with Fragile X Syndrome

    Science.gov (United States)

    Ornstein, Peter A.; Schaaf, Jennifer M.; Hooper, Stephen R.; Hatton, Deborah D.; Mirrett, Penny; Bailey, Donald B., Jr.

    2008-01-01

    Multiple aspects of memory were examined in 42 boys with fragile X syndrome and a comparison group of 42 typically developing boys matched on MA. Working memory, incidental memory, and deliberate memory were assessed with a battery that included both free-recall and recognition tasks. Findings indicated that boys with fragile X syndrome performed…

  15. Bilirubin Encephalopathy in a Domestic Shorthair Cat With Increased Osmotic Fragility and Cholangiohepatitis.

    Science.gov (United States)

    Contreras, E T; Giger, U; Malmberg, J L; Quimby, J M; Schaffer, P A

    2016-05-01

    A 7-month-old female domestic shorthair cat was diagnosed with chronic regenerative hemolytic anemia characterized by increased osmotic fragility of unknown etiology. At 13 months of age, the cat was evaluated for acute collapse. The cat was icteric with severe hyperbilirubinemia but no hematocrit changes. Severe obtundation and lateral recumbency progressed to tetraparesis and loss of proprioception in all 4 limbs, and a cerebellar or brainstem lesion was suspected. Postmortem examination revealed suppurative cholangiohepatitis and acute neuronal necrosis in the nuclei of the brainstem and cerebellum, consistent with bilirubin encephalopathy. This is the first known occurrence of cholangiohepatitis and bilirubin encephalopathy in an adult cat with chronic hemolytic anemia. Although rare, bilirubin encephalopathy should be considered a possible sequela to hyperbilirubinemia in adult patients. It remains unknown whether increased osmotic fragility was related to the cholangiohepatopathy. PMID:26354310

  16. Ectodermal dysplasia-skin fragility syndrome

    Directory of Open Access Journals (Sweden)

    Vijay S Adhe

    2011-01-01

    Full Text Available Ectodermal dysplasia-skin fragility (EDSF syndrome is a rare and first described inherited disorder of desmosomes. It occurs due to loss-of-function mutations in PKP1 gene resulting in poorly formed desmosomes and loss of desmosomal and epidermal integrity. We report a case of a 2-year-old Indian male child who presented with palmoplantar hyperkeratosis with fissuring, short, sparse, and easily pluckable scalp hair, nail dystrophy, and multiple erosions over the skin. Skin biopsy showed epidermal hyperplasia with widening of intercellular spaces. His developmental milestones were delayed but intelligence was normal. Echocardiography, X-ray chest, and electrocardiogram were normal. Very few cases of this syndrome have been reported in the literature. We consider this as the first case report from India.

  17. Pathological Plasticity in Fragile X Syndrome

    Directory of Open Access Journals (Sweden)

    Brandon S. Martin

    2012-01-01

    Full Text Available Deficits in neuronal plasticity are common hallmarks of many neurodevelopmental disorders. In the case of fragile-X syndrome (FXS, disruption in the function of a single gene, FMR1, results in a variety of neurological consequences directly related to problems with the development, maintenance, and capacity of plastic neuronal networks. In this paper, we discuss current research illustrating the mechanisms underlying plasticity deficits in FXS. These processes include synaptic, cell intrinsic, and homeostatic mechanisms both dependent on and independent of abnormal metabotropic glutamate receptor transmission. We place particular emphasis on how identified deficits may play a role in developmental critical periods to produce neuronal networks with permanently decreased capacity to dynamically respond to changes in activity central to learning, memory, and cognition in patients with FXS. Characterizing early developmental deficits in plasticity is fundamental to develop therapies that not only treat symptoms but also minimize the developmental pathology of the disease.

  18. Entanglement and decoherence: fragile and robust entanglement

    CERN Document Server

    Novotný, Jaroslav; Jex, Igor

    2011-01-01

    The destruction of entanglement of open quantum systems by decoherence is investigated in the asymptotic long-time limit. Starting from a general and analytically solvable decoherence model which does not involve any weak-coupling or Markovian assumption it is shown that two fundamentally different classes of entangled states can be distinguished. Quantum states of the first class are fragile against decoherence so that they can be disentangled asymptotically even if coherences between pointer states are still present. Quantum states of the second type are robust against decoherence. Asymptotically they can be disentangled only if also decoherence is perfect. A simple criterion for identifying these two classes on the basis of two-qubit entanglement is presented.

  19. Metabolomics reveals metabolic targets and biphasic responses in breast cancer cells treated by curcumin alone and in association with docetaxel.

    Directory of Open Access Journals (Sweden)

    Mathilde Bayet-Robert

    Full Text Available BACKGROUND: Curcumin (CUR has deserved extensive research due to its anti-inflammatory properties, of interest in human diseases including cancer. However, pleiotropic even paradoxical responses of tumor cells have been reported, and the mechanisms of action of CUR remain uncompletely elucidated. METHODOLOGY/PRINCIPAL FINDINGS: (1H-NMR spectroscopy-based metabolomics was applied to get novel insight into responses of MCF7 and MDA-MB-231 breast cancer cells to CUR alone, and MCF7 cells to CUR in cotreatment with docetaxel (DTX. In both cell types, a major target of CUR was glutathione metabolism. Total glutathione (GSx increased at low dose CUR (≤ 10 mg.l(-1-28 µM- (up to +121% in MCF7 cells, P<0.01, and +138% in MDA-MB-231 cells, P<0.01, but decreased at high dose (≥ 25 mg.l(-1 -70 µM- (-49%, in MCF7 cells, P<0.02, and -56% in MDA-MB-231 cells, P<0.025. At high dose, in both cell types, GSx-related metabolites decreased, including homocystein, creatine and taurine (-60 to -80%, all, P<0.05. Together with glutathione-S-transferase actvity, data established that GSx biosynthesis was upregulated at low dose, and GSx consumption activated at high dose. Another major target, in both cell types, was lipid metabolism involving, at high doses, accumulation of polyunsaturated and total free fatty acids (between ×4.5 and ×11, P<0.025, and decrease of glycerophospho-ethanolamine and -choline (about -60%, P<0.025. Multivariate statistical analyses showed a metabolic transition, even a biphasic behavior of some metabolites including GSx, between low and high doses. In addition, CUR at 10 mg.l(-1 in cotreatment with DTX induced modifications in glutathione metabolism, lipid metabolism, and glucose utilization. Some of these changes were biphasic depending on the duration of exposure to CUR. CONCLUSIONS/SIGNIFICANCE: Metabolomics reveals major metabolic targets of CUR in breast cancer cells, and biphasic responses that challenge the widely accepted

  20. Seismic fragility of nuclear power plant components (Phase II)

    International Nuclear Information System (INIS)

    As part of the Component Fragility Program which was initiated in FY 1985, three additional equipment classes have been evaluated. This report contains the fragility results and discussions on these equipment classes which are switchgear, I and C panels and relays. Both low and medium voltage switchgear assemblies have been considered and a separate fragility estimate for each type is provided. Test data on cabinets from the nuclear instrumentation/neutron monitoring system, plant/process protection system, solid state protective system and engineered safeguards test system comprise the BNL data base for I and C panels (NSSS). Fragility levels have been determined for various failure modes of switchgear and I ampersand C panels, and the deterministic results are presented in terms of test response spectra. In addition, the test data have been evaluated for estimating the respective probabilistic fragility levels which are expressed in terms of a median value, an uncertainty coefficient, a randomness coefficient and an HCLPF value. Due to a wide variation of relay design and the fragility level, a generic fragility level cannot be established for relays. 7 refs., 13 figs., 12 tabs

  1. Genes suppressed by DNA methylation in non-small cell lung cancer reveal the epigenetics of epithelial-mesenchymal transition.

    OpenAIRE

    Lin, Steven; Wang, Jing; Saintigny, Pierre; Wu, Chia-Chin; Giri, Uma; Jing ZHANG; Menju, Toshi; Diao, Lixia; Byers, Lauren; Weinstein, John ,; Coombes, Kevin; Girard, Luc; Komaki, Ritsuko; Wistuba, Ignacio; Date, Hiroshi

    2013-01-01

    Background DNA methylation is associated with aberrant gene expression in cancer, and has been shown to correlate with therapeutic response and disease prognosis in some types of cancer. We sought to investigate the biological significance of DNA methylation in lung cancer. Results We integrated the gene expression profiles and data of gene promoter methylation for a large panel of non-small cell lung cancer cell lines, and identified 578 candidate genes with expression levels that were inver...

  2. Seismic fragility analysis of structural components for HFBR facilities

    International Nuclear Information System (INIS)

    The paper presents a summary of recently completed seismic fragility analyses of the HFBR facilities. Based on a detailed review of past PRA studies, various refinements were made regarding the strength and ductility evaluation of structural components. Available laboratory test data were analysed to evaluate the formulations used to predict the ultimate strength and deformation capacities of steel, reinforced concrete and masonry structures. The biasness and uncertainties were evaluated within the framework of the fragility evaluation methods widely accepted in the nuclear industry. A few examples of fragility calculations are also included to illustrate the use of the presented formulations

  3. Modifying fragility and collective motion in polymer melts with nanoparticles.

    Science.gov (United States)

    Starr, Francis W; Douglas, Jack F

    2011-03-18

    We investigate the impact of nanoparticles (NP) on the fragility and cooperative stringlike motion in a model glass-forming polymer melt by molecular dynamics simulation. The NP cause significant changes to both the fragility and the average length of stringlike motion, where the effect depends on the NP-polymer interaction and NP concentration. We interpret these changes via the Adam-Gibbs (AG) theory, assuming the strings can be directly identified with the abstract "cooperatively rearranging regions" of AG. Our findings indicate that fragility is primarily a measure of the temperature dependence of the cooperativity of molecular motion. PMID:21469879

  4. Subsystem fragility: Seismic Safety Margins Research Program (Phase I)

    Energy Technology Data Exchange (ETDEWEB)

    Kennedy, R. P.; Campbell, R. D.; Hardy, G.; Banon, H.

    1981-10-01

    Seismic fragility levels of safety related equipment are developed for use in a seismic oriented Probabilistic Risk Assessment (PRA) being conducted as part of the Seismic Safety Margins Research Program (SSMRP). The Zion Nuclear Power Plant is being utilized as a reference plant and fragility descriptions are developed for specific and generic safety related equipment groups in Zion. Both equipment fragilities and equipment responses are defined in probabilistic terms to be used as input to the SSMRP event tree/fault tree models of the Zion systems. 65 refs., 14 figs., 11 tabs.

  5. Invertible chaotic fragile watermarking for robust image authentication

    International Nuclear Information System (INIS)

    Fragile watermarking is a popular method for image authentication. In such schemes, a fragile signal that is sensitive to manipulations is embedded in the image, so that it becomes undetectable after any modification of the original work. Most algorithms focus either on the ability to retrieve the original work after watermark detection (invertibility) or on detecting which image parts have been altered (localization). Furthermore, the majority of fragile watermarking schemes suffer from robustness flaws. We propose a new technique that combines localization and invertibility. Moreover, watermark dependency on the original image and the non-linear watermark embedding procedure guarantees that no malicious attacks will manage to create information leaks.

  6. Systems biology modeling reveals a possible mechanism of the tumor cell death upon oncogene inactivation in EGFR addicted cancers.

    Directory of Open Access Journals (Sweden)

    Jian-Ping Zhou

    Full Text Available Despite many evidences supporting the concept of "oncogene addiction" and many hypotheses rationalizing it, there is still a lack of detailed understanding to the precise molecular mechanism underlying oncogene addiction. In this account, we developed a mathematic model of epidermal growth factor receptor (EGFR associated signaling network, which involves EGFR-driving proliferation/pro-survival signaling pathways Ras/extracellular-signal-regulated kinase (ERK and phosphoinositol-3 kinase (PI3K/AKT, and pro-apoptotic signaling pathway apoptosis signal-regulating kinase 1 (ASK1/p38. In the setting of sustained EGFR activation, the simulation results show a persistent high level of proliferation/pro-survival effectors phospho-ERK and phospho-AKT, and a basal level of pro-apoptotic effector phospho-p38. The potential of p38 activation (apoptotic potential due to the elevated level of reactive oxygen species (ROS is largely suppressed by the negative crosstalk between PI3K/AKT and ASK1/p38 pathways. Upon acute EGFR inactivation, the survival signals decay rapidly, followed by a fast increase of the apoptotic signal due to the release of apoptotic potential. Overall, our systems biology modeling together with experimental validations reveals that inhibition of survival signals and concomitant release of apoptotic potential jointly contribute to the tumor cell death following the inhibition of addicted oncogene in EGFR addicted cancers.

  7. A novel role for peptidylarginine deiminases in microvesicle release reveals therapeutic potential of PAD inhibition in sensitizing prostate cancer cells to chemotherapy

    Directory of Open Access Journals (Sweden)

    Sharad Kholia

    2015-06-01

    Full Text Available Introduction: Protein deimination, defined as the post-translational conversion of protein-bound arginine to citrulline, is carried out by a family of 5 calcium-dependent enzymes, the peptidylarginine deiminases (PADs and has been linked to various cancers. Cellular microvesicle (MV release, which is involved in cancer progression, and deimination have not been associated before. We hypothesize that elevated PAD expression, observed in cancers, causes increased MV release in cancer cells and contributes to cancer progression. Background: We have previously reported that inhibition of MV release sensitizes cancer cells to chemotherapeutic drugs. PAD2 and PAD4, the isozymes expressed in patients with malignant tumours, can be inhibited with the pan-PAD-inhibitor chloramidine (Cl-am. We sought to investigate whether Cl-am can inhibit MV release and whether this pathway could be utilized to further increase the sensitivity of cancer cells to drug-directed treatment. Methods: Prostate cancer cells (PC3 were induced to release high levels of MVs upon BzATP stimulation of P2X7 receptors. Western blotting with the pan-protein deimination antibody F95 was used to detect a range of deiminated proteins in cells stimulated to microvesiculate. Changes in deiminated proteins during microvesiculation were revealed by immunoprecipitation and immunoblotting, and mass spectrometry identified deiminated target proteins with putative roles in microvesiculation. Conclusion: We report for the first time a novel function of PADs in the biogenesis of MVs in cancer cells. Our results reveal that during the stimulation of prostate cancer cells (PC3 to microvesiculate, PAD2 and PAD4 expression levels and the deimination of cytoskeletal actin are increased. Pharmacological inhibition of PAD enzyme activity using Cl-am significantly reduced MV release and abrogated the deimination of cytoskeletal actin. We demonstrated that combined Cl-am and methotrexate (MTX treatment of

  8. Financial Reforms and Financial Fragility: A Panel Data Analysis

    Directory of Open Access Journals (Sweden)

    Syed Faizan Iftikhar

    2015-04-01

    Full Text Available This paper explores the relationship between financial reforms, financial liberalization and the quality of banking regulation and supervision for financial fragility by applying a dynamic two-step system generalized method of moments GMM panel estimator technique. The finding of this study is that the financial vulnerability of the banking sector could be affected, not only by bank-specific and macro-specific variables; but also by financial liberalization and banking regulations and supervision policies. The empirical results of this study confirm the evidence that financial reforms and financial liberalization significantly enhance the likelihood of financial fragility while strong banking regulations and supervision have an inverse relationship with financial fragility. The results of this study also explain that the lag value of loan growth and unemployment contribute to enhancing financial fragility while equity to assets ratio, natural log of total assets and share of foreign banks reduce financial vulnerability.

  9. Establishing local government in fragile states: experimental evidence from Afghanistan

    NARCIS (Netherlands)

    T. Jochem; I. Murtazashvili; J. Murtazashvili

    2016-01-01

    International and domestic policy makers often promote elections to establish village government in fragile states. However, two additional options are available in such countries: formalization of self-governing village councils and formalization of community development councils (CDCs). We designe

  10. The displaced claiming their rights in fragile states

    OpenAIRE

    Antonia Mulvey

    2013-01-01

    To date, displaced persons in fragile and conflict-affected stateshave had little success in claiming their rights for housing, land andproperty violations. Creative legal thinking and strategic litigation has the potential to change this.

  11. Forests in Fragile and Conflict-Affected States

    OpenAIRE

    Harwell, Emily

    2011-01-01

    Recognizes in failed states or states at risk of becoming failed states the linkages between forests, armed conflict, poverty, and various aspects of state fragility. Forests are valuable for local subsistence livelihoods, timber, and other commercially valuable forest products, as well as ecosystem services including forest carbon and biodiversity. This makes the linkage between forests and fragile states significant to local poverty reduction, national and global trade, and global public go...

  12. Physical activity, bone density, and fragility fractures in women

    OpenAIRE

    Englund, Undis

    2009-01-01

    Scandinavia has among the highest incidence of fragility fractures in the world. The reasons for this are unknown, but might involve differences in genetic and/or environmental factors, such as sunlight exposure and levels of physical activity. Weight-bearing exercise is thought to have a beneficial effect on bone health in the young, but few studies have evaluated whether exercise in older subjects affects bone density and protects against fragility fractures. The initial objective of this t...

  13. On the importance of uncertain factors in seismic fragility assessment

    OpenAIRE

    Borgonovo, Emanuele; Zentner, Irmela; PELLEGRI A; Tarantola, Stefano; DE ROCQUIGNY E

    2012-01-01

    This paper addresses the definition of importance measures for helping the modeller to detect the factors on which to focus modelling activity and data collection in seismic fragility analysis. We study sensitivity measures consistent with the decision-support criteria of interest, namely, the (mean) fragility curve and the ‘‘High Confidence of Low Probability of Failure’’ (HCLPF) value. The importance measures are obtained analytically for the EPRI safety factor method, which is ...

  14. Osmotic fragility test in heterozygotes for alpha and beta thalassaemia.

    OpenAIRE

    Maccioni, L; Cao, A

    1985-01-01

    This study shows that the combination of heterozygous beta thalassaemia and deletion heterozygous (-alpha/alpha alpha) or homozygous (-alpha/-alpha) alpha+ thalassaemia may result in the production of erythrocytes which have normal mean volume and haemoglobinisation but decreased osmotic fragility. Based on this finding and previous studies, which have shown that beta thalassaemia screening by the osmotic fragility test may miss a significant proportion of beta thalassaemia heterozygotes, we ...

  15. Thyroid function in fragile-X syndrome males.

    OpenAIRE

    Bregman, J. D.; Leckman, J. F.; Ort, S. I.

    1990-01-01

    Twelve males with fragile-X syndrome between the ages of three and 28 years underwent assessment of thyroid function. All 12 subjects demonstrated normal baseline values for thyroid stimulating hormone (TSH), thyroxine, thyroid binding globulin (TBG), and estimated free thyroxine (EFT). Relative to a control group reported in the literature, however, the fragile-X subjects exhibited a blunted TSH response to thyrotropin releasing hormone (TRH). This finding suggests the presence of subtle dys...

  16. A Case Report of Fragile X Syndrome with Fingers Anomaly

    OpenAIRE

    F. Ashrafzadeh; Abbaszadegan, M; Ghaemi, N

    2003-01-01

    Fragile X Syndrome, the most common cause of inherited mental retardation, results from mutation in fragile X mental retardation gene (FMR1) on long arm of X chromosome, Xq27.3. Clinical features include moderate to severe mental retardation without neurologic deficit, long face, large ears, prominent jaw, macro-orchidism, attention deficit, behavior disorder and occasionally autistic behavior . Hyperextensible joints may also be seen in these patients. There is no other c...

  17. Fragile Countries and the 2008-2009 Crisis

    OpenAIRE

    Allen, Franklin; Giovannetti, Giorgia

    2010-01-01

    European Report on Development This paper analyses the channels through which the economic and financial crisis of 2008-2009 is transmitted to fragile countries in Sub-Saharan Africa. Trade stands out as the main direct channel, even though intra-Africa remittances play a relevant role, given that most migrants in Sub-Saharan Africa fragile countries cannot afford the cost of migrating to Europe or to the United States and stay close, remaining in the continent. Whether reduced...

  18. Aid to fragile states: Do donors help or hinder?

    OpenAIRE

    Browne, Stephen

    2007-01-01

    he record of aid to fragile and poorly-performing states is the real test of aid effectiveness. Rich countries can justify aid to fragile states both through altruism and self-interest. But, with some exceptions, donors have appeared at the wrong times and with the wrong attitudes, even sometimes undermining development progress. State failure has dimensions of both will and capacity. Failure demands constructive engagement by donors, in some cases to save people in weak states from their lea...

  19. Topic 3: Governance, Fragility, and Failure: Implications for Livelihoods

    OpenAIRE

    Ear, Sophal

    2008-01-01

    Sophal Ear, Ph.D. () http://faculty.nps.edu/sear Assistant Professor Department of National Security Affairs 27 October 2008 1. Common terms of reference 2. Defining “governance”, “fragility”, etc. 3. So what’s governance got to do with it? • Livelihoods • Policies, Institutions, and Processes • Good Governance Matters • Governance in Reality and in Practice 4. From Governance to FragilityFragility and Failed States: Europe in 164...

  20. Operationalizing Experience: Donor Approaches to Service Delivery in Fragile States

    OpenAIRE

    DiCaprio, Alisa

    2013-01-01

    This study explores the different approaches to service delivery in fragile states by surveying donors' own evaluations of their existing fragile states policies. Because there is limited understanding of what works in risky environments, monitoring and evaluation are critical components of effective assistance. By highlighting trends in the strategies that donors have developed to implement acknowledged good practices, we can better understand how these experiences might contribute to future...

  1. Comparative DNA methylome analysis of endometrial carcinoma reveals complex and distinct deregulation of cancer promoters and enhancers

    OpenAIRE

    Zhang, Bo; Xing, Xiaoyun; Li, Jing; Lowdon, Rebecca F; Zhou, Yan; Lin, Nan; Zhang, Baoxue; Sundaram, Vasavi; Chiappinelli, Katherine B.; Hagemann, Ian S.; Mutch, David G.; Goodfellow, Paul J.; Wang, Ting

    2014-01-01

    Background Aberrant DNA methylation is a hallmark of many cancers. Classically there are two types of endometrial cancer, endometrioid adenocarcinoma (EAC), or Type I, and uterine papillary serous carcinoma (UPSC), or Type II. However, the whole genome DNA methylation changes in these two classical types of endometrial cancer is still unknown. Results Here we described complete genome-wide DNA methylome maps of EAC, UPSC, and normal endometrium by applying a combined strategy of methylated DN...

  2. Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden

    OpenAIRE

    Cazier, J.-B.; Rao, S. R.; Mclean, C. M.; A. L. Walker; Wright, B J; Jaeger, E. E. M.; Kartsonaki, C.; Marsden, L.; Yau, C; Camps, C.; Kaisaki, P.; ,; Allan, Christopher; Attar, Moustafa; Bell, John

    2014-01-01

    Bladder cancers are a leading cause of death from malignancy. Molecular markers might predict disease progression and behaviour more accurately than the available prognostic factors. Here we use whole-genome sequencing to identify somatic mutations and chromosomal changes in 14 bladder cancers of different grades and stages. As well as detecting the known bladder cancer driver mutations, we report the identification of recurrent protein-inactivating mutations in CDKN1A and FAT1. The former ar...

  3. Mitochondrial DNA Haplogroup Analysis Reveals no Association between the Common Genetic Lineages and Prostate Cancer in the Korean Population

    OpenAIRE

    Kim, Wook; Yoo, Tag-Keun; Shin, Dong-Jik; Rho, Hyun-Wook; Jin, Han-Jun; Kim, Eun-Tak; Bae, Yoon-Sun

    2008-01-01

    Mitochondrial DNA (mtDNA) variation has recently been suggested to have an association with various cancers, including prostate cancer risk, in human populations. Since mtDNA is haploid and lacks recombination, specific mutations in the mtDNA genome associated with human diseases arise and remain in particular genetic backgrounds referred to as haplogroups. To assess the possible contribution of mtDNA haplogroup-specific mutations to the occurrence of prostate cancer, we have therefore perfor...

  4. The landscape of chromosomal aberrations in breast cancer mouse models reveals driver-specific routes to tumorigenesis

    OpenAIRE

    Ben-David, Uri; Ha, Gavin; Khadka, Prasidda; Jin, Xin; Wong, Bang; Franke, Lude; Golub, Todd R.

    2016-01-01

    Aneuploidy and copy-number alterations (CNAs) are a hallmark of human cancer. Although genetically engineered mouse models (GEMMs) are commonly used to model human cancer, their chromosomal landscapes remain underexplored. Here we use gene expression profiles to infer CNAs in 3,108 samples from 45 mouse models, providing the first comprehensive catalogue of chromosomal aberrations in cancer GEMMs. Mining this resource, we find that most chromosomal aberrations accumulate late during breast tu...

  5. Interim Stabilisation in Fragile Security Situations

    Directory of Open Access Journals (Sweden)

    Nat J. Colletta

    2012-09-01

    Full Text Available For more than two decades a conventional approach to security promotion has been widely applied by multilateral and bilateral agencies during war-to-peace transitions. Advocates of this approach typically recommend a combination of disarmament, demobilisation and reintegration (DDR and security sector reform (SSR to consolidate peace-making and peace-building processes (Colletta et al 2009, Muggah 2006. Notwithstanding the broad acceptance of such activities – and the theory that underlies them – there is little evidence that such interventions have contributed to any enduring solution to conflict and fragility (Muggah 2009. Indeed, analysts have come to recognise that the political, economic and social pre-conditions for DDR and SSR – including a relatively functional government, a reasonably stable labour market and a minimum level of social trust – are seldom in place. Even when these ambitious pre-requisites have been achieved, it is not clear that they are sufficient for DDR and SSR to take hold. Nevertheless, these orthodoxies persist in security promotion policy and practice.

  6. The Brazilian Pampa: A Fragile Biome

    Directory of Open Access Journals (Sweden)

    Valdir Marcos Stefenon

    2009-12-01

    Full Text Available Biodiversity is one of the most fundamental properties of Nature. It underpins the stability of ecosystems, provides vast bioresources for economic use, and has important cultural significance for many people. The Pampa biome, located in the southernmost state of Brazil, Rio Grande do Sul, illustrates the direct and indirect interdependence of humans and biodiversity. The Brazilian Pampa lies within the South Temperate Zone where grasslands scattered with shrubs and trees are the dominant vegetation. The soil, originating from sedimentary rocks, often has an extremely sandy texture that makes them fragile—highly prone to water and wind erosion. Human activities have converted or degraded many areas of this biome. In this review we discuss our state-of-the-art knowledge of the diversity and the major biological features of this regions and the cultural factors that have shaped it. Our aim is to contribute toward a better understanding of the current status of this special biome and to describe how the interaction between human activities and environment affects the region, highlighting the fragility of the Brazilian Pampa.

  7. Fragility curves of concrete bridges retrofitted by column jacketing

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    The Northridge earthquake inflicted various levels of damage upon a large number of Caltrans' bridges not retrofitted by column jacketing. In this respect, this study represents results of fragility curve development for two (2) sample bridges typical in southern California, strengthened for seismic retrofit by means of steel jacketing of bridge columns. Monte Carlo simulation is performed to study nonlinear dynamic responses of the bridges before and after column retrofit. Fragility curves in this study are represented by Iognormal distribution functions with two parameters and developed as a function of PGA. The sixty (60) ground acceleration time histories for the Los Angeles area developed for the Federal Emergency Management Agcncy (FEMA) SAC (SEAOC-ATC-CUREe) steel project are used for the dynamic analysis of the bridges.The improvement in the fiagility with steel jacketing is quantified by comparing fragility curves of the bridge before and after column retrofit. In this first attempt to formulate the problem of fragility enhancement, the quantification is made by comparing the median values of the fragility curves before and after the retrofit. Under the hypothesis that this quantification also applies to empirical fragility curves developed on the basis of Northridge earthquake damage, the enhanced version of the empirical curves is developed for the ensuing analysis to determine the enhancement of transportation network performance due to the retrofit.

  8. Monoclonal Antibodies Specific for STAT3β Reveal Its Contribution to Constitutive STAT3 Phosphorylation in Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Bharadwaj, Uddalak; Kasembeli, Moses M.; Eckols, T. Kris; Kolosov, Mikhail; Lang, Paul [Section of Infectious Disease, Department of Medicine, Baylor College of Medicine, Houston, TX 77030 (United States); Christensen, Kurt [Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030 (United States); Edwards, Dean P. [Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030 (United States); Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030 (United States); Tweardy, David J., E-mail: dtweardy@bcm.edu [Section of Infectious Disease, Department of Medicine, Baylor College of Medicine, Houston, TX 77030 (United States); Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030 (United States); Department of Biochemistry & Molecular Biology, BCM 286, Room N-1319, Baylor College of Medicine, Houston, TX 77030 (United States)

    2014-09-29

    Since its discovery in mice and humans 19 years ago, the contribution of alternatively spliced Stat3, Stat3β, to the overall functions of Stat3 has been controversial. Tyrosine-phosphorylated (p) Stat3β homodimers are more stable, bind DNA more avidly, are less susceptible to dephosphorylation, and exhibit distinct intracellular dynamics, most notably markedly prolonged nuclear retention, compared to pStat3α homodimers. Overexpression of one or the other isoform in cell lines demonstrated that Stat3β acted as a dominant-negative of Stat3α in transformation assays; however, studies with mouse strains deficient in one or the other isoform indicated distinct contributions of Stat3 isoforms to inflammation. Current immunological reagents cannot differentiate Stat3β proteins derived from alternative splicing vs. proteolytic cleavage of Stat3α. We developed monoclonal antibodies that recognize the 7 C-terminal amino acids unique to Stat3β (CT7) and do not cross-react with Stat3α. Immunoblotting studies revealed that levels of Stat3β protein, but not Stat3α, in breast cancer cell lines positively correlated with overall pStat3 levels, suggesting that Stat3β may contribute to constitutive Stat3 activation in this tumor system. The ability to unambiguously discriminate splice alternative Stat3β from proteolytic Stat3β and Stat3α will provide new insights into the contribution of Stat3β vs. Stat3α to oncogenesis, as well as other biological and pathological processes.

  9. Monoclonal Antibodies Specific for STAT3β Reveal Its Contribution to Constitutive STAT3 Phosphorylation in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Uddalak Bharadwaj

    2014-09-01

    Full Text Available Since its discovery in mice and humans 19 years ago, the contribution of alternatively spliced Stat3, Stat3β, to the overall functions of Stat3 has been controversial. Tyrosine-phosphorylated (p Stat3β homodimers are more stable, bind DNA more avidly, are less susceptible to dephosphorylation, and exhibit distinct intracellular dynamics, most notably markedly prolonged nuclear retention, compared to pStat3α homodimers. Overexpression of one or the other isoform in cell lines demonstrated that Stat3β acted as a dominant-negative of Stat3α in transformation assays; however, studies with mouse strains deficient in one or the other isoform indicated distinct contributions of Stat3 isoforms to inflammation. Current immunological reagents cannot differentiate Stat3β proteins derived from alternative splicing vs. proteolytic cleavage of Stat3α. We developed monoclonal antibodies that recognize the 7 C-terminal amino acids unique to Stat3β (CT7 and do not cross-react with Stat3α. Immunoblotting studies revealed that levels of Stat3β protein, but not Stat3α, in breast cancer cell lines positively correlated with overall pStat3 levels, suggesting that Stat3β may contribute to constitutive Stat3 activation in this tumor system. The ability to unambiguously discriminate splice alternative Stat3β from proteolytic Stat3β and Stat3α will provide new insights into the contribution of Stat3β vs. Stat3α to oncogenesis, as well as other biological and pathological processes.

  10. Monoclonal Antibodies Specific for STAT3β Reveal Its Contribution to Constitutive STAT3 Phosphorylation in Breast Cancer

    International Nuclear Information System (INIS)

    Since its discovery in mice and humans 19 years ago, the contribution of alternatively spliced Stat3, Stat3β, to the overall functions of Stat3 has been controversial. Tyrosine-phosphorylated (p) Stat3β homodimers are more stable, bind DNA more avidly, are less susceptible to dephosphorylation, and exhibit distinct intracellular dynamics, most notably markedly prolonged nuclear retention, compared to pStat3α homodimers. Overexpression of one or the other isoform in cell lines demonstrated that Stat3β acted as a dominant-negative of Stat3α in transformation assays; however, studies with mouse strains deficient in one or the other isoform indicated distinct contributions of Stat3 isoforms to inflammation. Current immunological reagents cannot differentiate Stat3β proteins derived from alternative splicing vs. proteolytic cleavage of Stat3α. We developed monoclonal antibodies that recognize the 7 C-terminal amino acids unique to Stat3β (CT7) and do not cross-react with Stat3α. Immunoblotting studies revealed that levels of Stat3β protein, but not Stat3α, in breast cancer cell lines positively correlated with overall pStat3 levels, suggesting that Stat3β may contribute to constitutive Stat3 activation in this tumor system. The ability to unambiguously discriminate splice alternative Stat3β from proteolytic Stat3β and Stat3α will provide new insights into the contribution of Stat3β vs. Stat3α to oncogenesis, as well as other biological and pathological processes

  11. Variability in the incidence of miRNAs and genes in fragile sites and the role of repeats and CpG islands in the distribution of genetic material.

    Directory of Open Access Journals (Sweden)

    Alessandro Laganà

    Full Text Available BACKGROUND: Chromosomal fragile sites are heritable specific loci especially prone to breakage. Some of them are associated with human genetic disorders and several studies have demonstrated their importance in genome instability in cancer. MicroRNAs (miRNAs are small non-coding RNAs responsible of post-transcriptional gene regulation and their involvement in several diseases such as cancer has been widely demonstrated. The altered expression of miRNAs is sometimes due to chromosomal rearrangements and epigenetic events, thus it is essential to study miRNAs in the context of their genomic locations, in order to find significant correlations between their aberrant expression and the phenotype. PRINCIPAL FINDINGS: Here we use statistical models to study the incidence of human miRNA genes on fragile sites and their association with cancer-specific translocation breakpoints, repetitive elements, and CpG islands. Our results show that, on average, fragile sites are denser in miRNAs and also in protein coding genes. However, the distribution of miRNAs and protein coding genes in fragile versus non-fragile sites depends on chromosome. We find also a positive correlation between fragility and repeats, and between miRNAs and CpG islands. CONCLUSION: Our results show that the relationship between site fragility and miRNA density is far more complex than previously thought. For example, we find that protein coding genes seem to be following similar patterns as miRNAs, if considered their overall distribution. However, once we allow for differences at the chromosome level in our statistical analysis, we find that distribution of miRNA and protein coding genes in fragile sites is very different from that of miRNA. This is a novel result that we believe may help discover new potential correlations between the localization of miRNAs and their crucial role in biological processes and in the development of diseases.

  12. Cellular Metabolism and Dose Reveal Carnitine-Dependent and -Independent Mechanisms of Butyrate Oxidation in Colorectal Cancer Cells.

    Science.gov (United States)

    Han, Anna; Bennett, Natalie; MacDonald, Amber; Johnstone, Megan; Whelan, Jay; Donohoe, Dallas R

    2016-08-01

    Dietary fiber has been suggested to suppress colorectal cancer development, although the mechanisms contributing to this beneficial effect remain elusive. Butyrate, a fermentation product of fiber, has been shown to have anti-proliferative and pro-apoptotic effects on colorectal cancer cells. The metabolic fate of butyrate in the cell is important in determining whether, it acts as an HDAC inhibitor or is consumed as a short-chain fatty acid. Non-cancerous colonocytes utilize butyrate as the primary energy source whereas cancerous colonocytes increase glucose utilization through the Warburg effect. In this study, we show that butyrate oxidation is decreased in cancerous colonocytes compared to non-cancerous colonocytes. We demonstrate that colorectal cancer cells utilize both a carnitine-dependent and carnitine-independent mechanism that contributes to butyrate oxidation. The carnitine-dependent mechanism is contingent on butyrate concentration. Knockdown of CPT1A in colorectal cancer cells abolishes butyrate oxidation. In terms of selectivity, the carnitine-dependent mechanism only regulated butyrate oxidation, as acetate and propionate oxidation were carnitine-independent. Carnitine decreased the action of butyrate as an HDAC inhibitor and suppressed induction of H3 acetylation by butyrate in colorectal cancer cells. Thus, diminished oxidation of butyrate is associated with decreased HDAC inhibition and histone acetylation. In relation to the mechanism, we find that dichloroacetate, which decreases phosphorylation of pyruvate dehydrogenase, increased butyrate oxidation and that this effect was carnitine-dependent. In conclusion, these data suggest that colorectal cancer cells decrease butyrate oxidation through inhibition of pyruvate dehydrogenase, which is carnitine-dependent, and provide insight into why butyrate shows selective effects toward colorectal cancer cells. J. Cell. Physiol. 231: 1804-1813, 2016. © 2015 Wiley Periodicals, Inc. PMID:26661480

  13. Genome-wide DNA methylation profiling in triple-negative breast cancer reveals epigenetic signatures with important clinical value

    Science.gov (United States)

    Stirzaker, Clare; Zotenko, Elena; Clark, Susan J

    2016-01-01

    abstract Analysis of cancer methylomes has dramatically changed our concept of the potential of diagnostic and prognostic methylation biomarkers in disease stratification. Through whole-genome methylation capture sequencing of triple-negative breast cancers (TNBCs) we recently identified differentially methylated regions with diagnostic and prognostic value that promise to stratify TNBCs for more personalized management. PMID:27308556

  14. Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer

    DEFF Research Database (Denmark)

    Weischenfeldt, Joachim; Simon, Ronald; Feuerbach, Lars; Schlangen, Karin; Weichenhan, Dieter; Minner, Sarah; Wuttig, Daniela; Warnatz, Hans-Jörg; Stehr, Henning; Rausch, Tobias; Jäger, Natalie; Gu, Lei; Bogatyrova, Olga; Stütz, Adrian M; Claus, Rainer; Eils, Jürgen; Eils, Roland; Gerhäuser, Clarissa; Huang, Po-Hsien; Hutter, Barbara; Kabbe, Rolf; Lawerenz, Christian; Radomski, Sylwester; Bartholomae, Cynthia C; Fälth, Maria; Gade, Stephan; Schmidt, Manfred; Amschler, Nina; Haß, Thomas; Galal, Rami; Gjoni, Jovisa; Kuner, Ruprecht; Baer, Constance; Masser, Sawinee; von Kalle, Christof; Zichner, Thomas; Benes, Vladimir; Raeder, Benjamin; Mader, Malte; Amstislavskiy, Vyacheslav; Avci, Meryem; Lehrach, Hans; Parkhomchuk, Dmitri; Sultan, Marc; Burkhardt, Lia; Graefen, Markus; Huland, Hartwig; Kluth, Martina; Krohn, Antje; Sirma, Hüseyin; Stumm, Laura; Steurer, Stefan; Grupp, Katharina; Sültmann, Holger; Sauter, Guido; Plass, Christoph; Brors, Benedikt; Yaspo, Marie-Laure; Korbel, Jan O; Schlomm, Thorsten

    2013-01-01

    Early-onset prostate cancer (EO-PCA) represents the earliest clinical manifestation of prostate cancer. To compare the genomic alteration landscapes of EO-PCA with "classical" (elderly-onset) PCA, we performed deep sequencing-based genomics analyses in 11 tumors diagnosed at young age, and pursue...

  15. Mitochondrial DNA haplogroup analysis reveals no association between the common genetic lineages and prostate cancer in the Korean population.

    Directory of Open Access Journals (Sweden)

    Wook Kim

    Full Text Available Mitochondrial DNA (mtDNA variation has recently been suggested to have an association with various cancers, including prostate cancer risk, in human populations. Since mtDNA is haploid and lacks recombination, specific mutations in the mtDNA genome associated with human diseases arise and remain in particular genetic backgrounds referred to as haplogroups. To assess the possible contribution of mtDNA haplogroup-specific mutations to the occurrence of prostate cancer, we have therefore performed a population-based study of a prostate cancer cases and corresponding controls from the Korean population. No statistically significant difference in the distribution of mtDNA haplogroup frequencies was observed between the case and control groups of Koreans. Thus, our data imply that specific mtDNA mutations/lineages did not appear to have a significant effect on a predisposition to prostate cancer in the Korean population, although larger sample sizes are necessary to validate our results.

  16. Differential profiling of breast cancer plasma proteome by isotope-coded affinity tagging method reveals biotinidase as a breast cancer biomarker

    International Nuclear Information System (INIS)

    Breast cancer is one of the leading causes of women's death worldwide. It is important to discover a reliable biomarker for the detection of breast cancer. Plasma is the most ideal source for cancer biomarker discovery since many cells cross-communicate through the secretion of soluble proteins into blood. Plasma proteomes obtained from 6 breast cancer patients and 6 normal healthy women were analyzed by using the isotope-coded affinity tag (ICAT) labeling approach and tandem mass spectrometry. All the plasma samples used were depleted of highly abundant 6 plasma proteins by immune-affinity column chromatography before ICAT labeling. Several proteins showing differential abundance level were selected based on literature searches and their specificity to the commercially available antibodies, and then verified by immunoblot assays. A total of 155 proteins were identified and quantified by ICAT method. Among them, 33 proteins showed abundance changes by more than 1.5-fold between the plasmas of breast cancer patients and healthy women. We chose 5 proteins for the follow-up confirmation in the individual plasma samples using immunoblot assay. Four proteins, α1-acid glycoprotein 2, monocyte differentiation antigen CD14, biotinidase (BTD), and glutathione peroxidase 3, showed similar abundance ratio to ICAT result. Using a blind set of plasmas obtained from 21 breast cancer patients and 21 normal healthy controls, we confirmed that BTD was significantly down-regulated in breast cancer plasma (Wilcoxon rank-sum test, p = 0.002). BTD levels were lowered in all cancer grades (I-IV) except cancer grade zero. The area under the receiver operating characteristic curve of BTD was 0.78. Estrogen receptor status (p = 0.940) and progesterone receptor status (p = 0.440) were not associated with the plasma BTD levels. Our study suggests that BTD is a potential serological biomarker for the detection of breast cancer

  17. Advances in research on the fragile X syndrome.

    Science.gov (United States)

    Mazzocco, M M

    2000-01-01

    Fragile X syndrome is a neurodevelopmental disorder that results from a single gene mutation on the X chromosome. The purpose of this review is to summarize key advances made in understanding the fragile X premutation gene seen in carriers and the full mutation gene seen in persons with the syndrome. DNA testing has replaced cytogenetic testing as the primary method for identification of fragile X, although the efficacy of protein level screening is being explored. The premutation is associated with no effects, although there is evidence of physical effects-primarily premature menopause and mild outward features of the fragile X syndrome-among premutation carriers. There is much controversy regarding premutation effects on psychological development. The few experimental studies carried out to date do not suggest noticeable or significant effects. One challenge in addressing this controversy is the sometimes ambiguous differentiation between premutation and full mutation genes. There is a well-established yet highly variable phenotype of the full mutation. Research from this decade has helped to address specific aspects of this phenotype, including the early course of its development in males, the influence of home and family environments, the nature of social difficulties and autistic features seen in boys and girls with fragile X, and the potential role of hyperarousal or hyper-reactivity. Studies in these areas, and on the role of FMR protein, will contribute towards ongoing advances in our understanding of fragile X syndrome and its mechanisms. The variability in physical, social, and cognitive features, as described in this review, is one that prohibits clear-cut screening guidelines designed to avoid high rates of both false positives and false negatives. Results from recent studies indicate the need to consider behavioral features in selecting candidates for fragile X screening. MRDD Research Reviews 2000;6:96-106. PMID:10899802

  18. Observation and Characterization of Fragile Organometallic Molecules Encapsulated in Single-Wall Carbon Nanotubes

    Directory of Open Access Journals (Sweden)

    Daisuke Ogawa

    2014-01-01

    Full Text Available Thermally fragile tris(η5-cyclopentadienylerbium (ErCp3 molecules are encapsulated in single-wall carbon nanotubes (SWCNTs with high yield. We realized the encapsulation of ErCp3 with high filling ratio by using high quality SWCNTs at an optimized temperature under higher vacuum. Structure determination based on high-resolution transmission electron microscope observations together with the image simulations reveals the presence of almost free rotation of each ErCp3 molecule in SWCNTs. The encapsulation is also confirmed by X-ray diffraction. Trivalent character of Er ions (i.e., Er3+ is confirmed by X-ray absorption spectrum.

  19. Study on model of seismic fragility analysis for nuclear power plant

    International Nuclear Information System (INIS)

    After the Fukushima nuclear accident, the impact evaluation of nuclear power plants resulted from external events is required in China, and the 12th Five-Year Plan for Nuclear Safety also demands that the probability safety assessment of external events shall be developed before 2015. The earthquake is one of the most important external events which are essentially evaluated, and the seismic fragility is a key element in seismic PSA, while the fragility model is the basis of seismic fragility analysis. In this paper, the concept of seismic fragility was introduced, the seismic fragility model recommended by NRC and EPRI was studied, and the fragility model was derived. Then, the application example of the fragility model was given, and the effects of fragility due to randomness and uncertainty were discussed. The results show that a wealth of knowledge and experience is useful for the fragility analysis, which would reduce the uncertainty and gain access to practice. (authors)

  20. Functional and structural deficits at accumbens synapses in a mouse model of Fragile X.

    Science.gov (United States)

    Neuhofer, Daniela; Henstridge, Christopher M; Dudok, Barna; Sepers, Marja; Lassalle, Olivier; Katona, István; Manzoni, Olivier J

    2015-01-01

    together reveal new structural and functional synaptic deficits in Fragile X. PMID:25859182

  1. Genetic diagnosis in clinical psychiatry: A case report of a woman with a 47, XXX karyotype and Fragile X syndrome

    Directory of Open Access Journals (Sweden)

    Anthony M. Vandersteen

    2009-03-01

    Full Text Available Background and Objectives: A recent report highlighted the importance of considering a chromosomal abnormality in the differential diagnosis of adult clinical psychiatry. This case report illustrates the importance of considering Fragile X syndrome, an X-linked genetic disorder associated with psychiatric morbidities. Methods: A 45 years old woman was referred to the clinical genetics department by her psychiatrist for investigation of her gross obesity, hyperphagia, learning difficulties and affective disorder. Results: Cytogenetic analysis revealed a 47,XXX karyotype. Molecular testing identified an expansion of approximately 580 repeats in the FRAXA gene carried on two of her three copies of the X chromosome. Clinical evaluation revealed features consistent with the Prader-Willi like phenotype of Fragile X syndrome. Conclusions: It is important to consider molecular and cytogenetic testing in patients with dysmorphic features, complex neuro-behavioural profile and/or psychotic disorders in order to establish a causative diagnosis, provide adequate counselling and initiate cascade screening where applicable.

  2. Metabolomics Reveals Metabolic Targets and Biphasic Responses in Breast Cancer Cells Treated by Curcumin Alone and in Association with Docetaxel

    OpenAIRE

    Bayet-Robert, Mathilde; Morvan, Daniel

    2013-01-01

    Background Curcumin (CUR) has deserved extensive research due to its anti-inflammatory properties, of interest in human diseases including cancer. However, pleiotropic even paradoxical responses of tumor cells have been reported, and the mechanisms of action of CUR remain uncompletely elucidated. Methodology/Principal Findings 1H-NMR spectroscopy-based metabolomics was applied to get novel insight into responses of MCF7 and MDA-MB-231 breast cancer cells to CUR alone, and MCF7 cells to CUR in...

  3. Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies

    Institute of Scientific and Technical Information of China (English)

    Michael Steckel; Julian Downward; David C Hancock; Miriam Molina-Arcas; Britta Weigelt; Michaela Marani; Patricia H Warne; Hanna Kuznetsov; Gavin Kelly; Becky Saunders; Michael Howell

    2012-01-01

    Oneogenic mutations in RAS genes are very common in human cancer,resulting in cells with well-characterized selective advantages,but also less well-understood vulnerabilities.We have carried out a large-scale loss-of-function screen to identify genes that are required by KRAS-transformed colon cancer cells,but not by derivatives lacking this oncogene.Top-scoring genes were then tested in a larger panel of KRAS mutant and wild-type cancer cells.Cancer cells expressing oncogenic KRAS were found to be highly dependent on the transcription factor GATA2 and the DNA replication initiation regulator CDC6.Extending this analysis using a collection of drugs with known targets,we found that cancer cells with mutant KRAS showed selective addiction to proteasome function,as well as synthetic lethality with topoisomerase inhibition.Combination targeting of these functions caused improved killing of KRAS mutant cells relative to wild-type cells.These observations suggest novel targets and new ways of combining existing therapies for optimal effect in RAS mutant cancers,which are traditionally seen as being highly refractory to therapy.

  4. Fragility estimates of smart structures with sensor faults

    International Nuclear Information System (INIS)

    In this paper, the impact of sensor faults within smart structures is investigated using seismic fragility analysis techniques. Seismic fragility analysis is one of the methods used to evaluate the vulnerability of structural systems under a broad range of earthquake events. It would play an important role in estimating seismic losses and in the decision making process based on vibration control performance of the smart structures during seismic events. In this study, a three-story building employing a highly nonlinear hysteretic magnetorheological (MR) damper is analyzed to estimate the seismic fragility of the smart control system. Different levels of sensor damage scenarios for smart structures are considered to provide a better understanding of the expected fragility estimates due to the impact of sensor failures. Probabilistic demand models are constructed with a Bayesian updating approach while the seismic capacity of smart structures is estimated based on the approximate structural performance of semi-actively controlled structures. Peak ground acceleration (PGA) of ground motion is used as a measure of earthquake intensity. Then the fragility curves for the smart structures are developed and compared with those for the semi-active control systems with different levels of sensor damage scenarios. The responses of an uncontrolled structure are used as a baseline. It is shown from the simulations that the proposed methodology is effective in quantifying the impact of sensor faults within smart structures. (paper)

  5. Developing empirical collapse fragility functions for global building types

    Science.gov (United States)

    Jaiswal, K.; Wald, D.; D'Ayala, D.

    2011-01-01

    Building collapse is the dominant cause of casualties during earthquakes. In order to better predict human fatalities, the U.S. Geological Survey’s Prompt Assessment of Global Earthquakes for Response (PAGER) program requires collapse fragility functions for global building types. The collapse fragility is expressed as the probability of collapse at discrete levels of the input hazard defined in terms of macroseismic intensity. This article provides a simple procedure for quantifying collapse fragility using vulnerability criteria based on the European Macroseismic Scale (1998) for selected European building types. In addition, the collapse fragility functions are developed for global building types by fitting the beta distribution to the multiple experts’ estimates for the same building type (obtained from EERI’s World Housing Encyclopedia (WHE)-PAGER survey). Finally, using the collapse probability distributions at each shaking intensity level as a prior and field-based collapse-rate observations as likelihood, it is possible to update the collapse fragility functions for global building types using the Bayesian procedure.

  6. AB053. MicroRNA expression profile in penile cancer revealed by next-generation small RNA sequencing

    Science.gov (United States)

    Zhang, Li; Wei, Pengfei

    2016-01-01

    Objective Penile cancer (PeCa) is a relatively rare tumor entity but possesses higher morbidity and mortality rates especially in developing countries. To date, the concrete pathogenic signaling pathways and core machineries involved in tumorigenesis and progression of PeCa remain to be elucidated. Several studies suggested miRNAs, which modulate gene expression at posttranscriptional level, were frequently mis-regulated and aberrantly expressed in human cancers. However, the miRNA profile in human PeCa has not been reported before. Methods In this present study, the miRNA profile was obtained from 10 fresh penile cancerous tissues and matched adjacent non-cancerous tissues via next-generation sequencing. Results As a result, a total of 751 and 806 annotated miRNAs were identified in normal and cancerous penile tissues, respectively. Among which, 56 miRNAs with significantly different expression levels between paired tissues were identified. Subsequently, several annotated miRNAs were randomly and validated using quantitative real-time PCR. Compared with the previous publications regarding to the altered miRNAs expression in various cancers and especially genitourinary (prostate, bladder, kidney, testis) cancers, the most majority of deregulated miRNAs showed the similar expression pattern in penile cancer. Moreover, the bioinformatics analyses suggested that the putative target genes of differentially expressed miRNAs between cancerous and matched normal penile tissues were tightly associated with cell junction, proliferation, growth as well as genomic instability and so on, by modulating Wnt, MAPK, p53, PI3K-Akt, Notch and TGF-β signaling pathways, which were all well-established to participate in cancer initiation and progression. Conclusions Our work presents a global view of the differentially expressed miRNAs and potentially regulatory networks of their target genes for clarifying the pathogenic transformation of normal penis to PeCa, which research resource

  7. Touch and massage for medically fragile infants.

    Science.gov (United States)

    Livingston, Karen; Beider, Shay; Kant, Alexis J; Gallardo, Constance C; Joseph, Michael H; Gold, Jeffrey I

    2009-12-01

    of the infants receiving massage. Massage in a tertiary urban academic NICU continues to be an area of needed study. Future studies examining infant health outcomes, such as weight gain, decreased length of hospitalization and caregiver-infant bonding, would provide greater insight into the impact of massage for medically fragile infants. PMID:18955228

  8. Chemogenetic evaluation of the mitotic kinesin CENP-E reveals a critical role in triple-negative breast cancer.

    Science.gov (United States)

    Kung, Pei-Pei; Martinez, Ricardo; Zhu, Zhou; Zager, Michael; Blasina, Alessandra; Rymer, Isha; Hallin, Jill; Xu, Meirong; Carroll, Christopher; Chionis, John; Wells, Peter; Kozminski, Kirk; Fan, Jeffery; Guicherit, Oivin; Huang, Buwen; Cui, Mei; Liu, Chaoting; Huang, Zhongdong; Sistla, Anand; Yang, Jennifer; Murray, Brion W

    2014-08-01

    Breast cancer patients with tumors lacking the three diagnostic markers (ER, PR, and HER2) are classified as triple-negative (primarily basal-like) and have poor prognosis because there is no disease-specific therapy available. To address this unmet medical need, gene expression analyses using more than a thousand breast cancer samples were conducted, which identified elevated centromere protein E (CENP-E) expression in the basal-a molecular subtype relative to other subtypes. CENP-E, a mitotic kinesin component of the spindle assembly checkpoint, is shown to be induced in basal-a tumor cell lines by the mitotic spindle inhibitor drug docetaxel. CENP-E knockdown by inducible shRNA reduces basal-a breast cancer cell viability. A potent, selective CENP-E inhibitor (PF-2771) was used to define the contribution of CENP-E motor function to basal-like breast cancer. Mechanistic evaluation of PF-2771 in basal-a tumor cells links CENP-E-dependent molecular events (e.g., phosphorylation of histone H3 Ser-10; phospho-HH3-Ser10) to functional outcomes (e.g., chromosomal congression defects). Across a diverse panel of breast cell lines, CENP-E inhibition by PF-2771 selectively inhibits proliferation of basal breast cancer cell lines relative to premalignant ones and its response correlates with the degree of chromosomal instability. Pharmacokinetic-pharmacodynamic efficacy analysis in a basal-a xenograft tumor model shows that PF-2771 exposure is well correlated with increased phospho-HH3-Ser10 levels and tumor growth regression. Complete tumor regression is observed in a patient-derived, basal-a breast cancer xenograft tumor model treated with PF-2771. Tumor regression is also observed with PF-2771 in a taxane-resistant basal-a model. Taken together, CENP-E may be an effective therapeutic target for patients with triple-negative/basal-a breast cancer. PMID:24928852

  9. Systems analysis of ATF3 in stress response and cancer reveals opposing effects on pro-apoptotic genes in p53 pathway.

    Directory of Open Access Journals (Sweden)

    Yujiro Tanaka

    Full Text Available Stress-inducible transcription factors play a pivotal role in cellular adaptation to environment to maintain homeostasis and integrity of the genome. Activating transcription factor 3 (ATF3 is induced by a variety of stress and inflammatory conditions and is over-expressed in many kinds of cancer cells. However, molecular mechanisms underlying pleiotropic functions of ATF3 have remained elusive. Here we employed systems analysis to identify genome-wide targets of ATF3 that is either induced by an alkylating agent methyl methanesulfonate (MMS or over-expressed in a prostate tumour cell line LNCaP. We show that stress-induced and cancer-associated ATF3 is recruited to 5,984 and 1,423 targets, respectively, in the human genome, 89% of which are common. Notably, ATF3 targets are highly enriched for not only ATF/CRE motifs but also binding sites of several other stress-inducible transcription factors indicating an extensive network of stress response factors in transcriptional regulation of target genes. Further analysis of effects of ATF3 knockdown on these targets revealed that stress-induced ATF3 regulates genes in metabolic pathways, cell cycle, apoptosis, cell adhesion, and signalling including insulin, p53, Wnt, and VEGF pathways. Cancer-associated ATF3 is involved in regulation of distinct sets of genes in processes such as calcium signalling, Wnt, p53 and diabetes pathways. Notably, stress-induced ATF3 binds to 40% of p53 targets and activates pro-apoptotic genes such as TNFRSF10B/DR5 and BBC3/PUMA. Cancer-associated ATF3, by contrast, represses these pro-apoptotic genes in addition to CDKN1A/p21. Taken together, our data reveal an extensive network of stress-inducible transcription factors and demonstrate that ATF3 has opposing, cell context-dependent effects on p53 target genes in DNA damage response and cancer development.

  10. Fragility in the 14q21q translocation region

    Directory of Open Access Journals (Sweden)

    Stacy R. Denison

    2002-01-01

    Full Text Available Aphidicolin (APC-induced chromosomal breakage was analyzed for women representing three generations of a single family and carrying a Robertsonian translocation rob(14q21q. Fluorescence in situ hybridization (FISH analysis confirmed the dicentric constitution of the derived chromosome and indicated the absence of beta-satellite signal at the translocation region. Per-individual analysis of metaphases from APC-treated peripheral blood lymphocyte cultures identified significantly nonrandom chromosomal breakage at the translocation region in all three individuals examined. The APC-inducible fragility at the 14q21q translocation region suggests that this rearrangement was the result of chromosomal mutation at fragile site(s in the progenitor chromosomes, or that this fragility was the result of the fusion of nonfragile progenitor chromosomes.

  11. Fabrication and transfer of fragile 3D PDMS microstructures

    International Nuclear Information System (INIS)

    We present a method for PDMS microfabrication of fragile membranes and 3D fluidic networks, using a surface modified water-dissolvable release material, poly(vinyl alcohol), as a tool for handling, transfer and release of fragile polymer microstructures. The method is well suited for the fabrication of complex multilayer microfluidic devices, here shown for a PDMS device with a thin gas permeable membrane and closely spaced holes for vertical interlayer connections fabricated in a single layer. To the authors’ knowledge, this constitutes the most advanced PDMS fabrication method for the combination of thin, fragile structures and 3D fluidics networks, and hence a considerable step in the direction of making PDMS fabrication of complex microfluidic devices a routine endeavour. (paper)

  12. Fragile X syndrome in two siblings with major congenital malformations

    Energy Technology Data Exchange (ETDEWEB)

    Giampietro, P.F.; Haas, B.R.; Lipper, E. [Cornell Univ. Medical Center, New York, NY (United States)] [and others

    1996-05-17

    We report on 2 brothers with both fragile X and VACTERL-H syndrome. The first sibling, age 5, had bilateral cleft lip and palate, ventricular septal defect, and a hypoplastic thumb. The second sibling, age 2{1/2}, had a trachesophageal fistula, esophageal atresia, and vertebral abnormality. High-resolution chromosome analysis showed a 46,XY chromosome constitution in both siblings. By PCR and Southern blot analysis, the siblings were found to have large triplet repeat expansions in the fragile X gene (FMR 1) and both had methylation mosaicism. Enzyme kinetic studies of iduronate sulfatase demonstrated a two-fold increase in activity in the first sib as compared to the second. Possible mechanisms through which the fragile X mutation can cause down-regulation of adjacent loci are discussed. 24 refs., 4 figs.

  13. The robust-yet-fragile nature of interdependent networks

    CERN Document Server

    Tan, Fei

    2014-01-01

    Interdependent networks have been shown to be extremely vulnerable based on the percolation model. Parshani et. al further indicated that the more inter-similar networks are, the more robust they are to random failure. Our understanding of how coupling patterns shape and impact the cascading failures of loads in interdependent networks is limited, but is essential for the design and optimization of the real-world interdependent networked systems. This question, however, is largely unexplored. In this paper, we address this question by investigating the robustness of interdependent ER random graphs and BA scale-free networks under both random failure and intentional attack. It is found that interdependent ER random graphs are robust-yet-fragile under both random failures and intentional attack. Interdependent BA scale-free networks, however, are only robust-yet-fragile under random failure but fragile under intentional attack. These results advance our understanding of the robustness of interdependent networks...

  14. Fabrication and transfer of fragile 3D PDMS microstructures

    Science.gov (United States)

    Mikael Karlsson, J.; Haraldsson, Tommy; Carlborg, Carl Fredrik; Hansson, Jonas; Russom, Aman; van der Wijngaart, Wouter

    2012-08-01

    We present a method for PDMS microfabrication of fragile membranes and 3D fluidic networks, using a surface modified water-dissolvable release material, poly(vinyl alcohol), as a tool for handling, transfer and release of fragile polymer microstructures. The method is well suited for the fabrication of complex multilayer microfluidic devices, here shown for a PDMS device with a thin gas permeable membrane and closely spaced holes for vertical interlayer connections fabricated in a single layer. To the authors’ knowledge, this constitutes the most advanced PDMS fabrication method for the combination of thin, fragile structures and 3D fluidics networks, and hence a considerable step in the direction of making PDMS fabrication of complex microfluidic devices a routine endeavour.

  15. Seismic fragilities for nuclear power plant risk studies

    International Nuclear Information System (INIS)

    Seismic fragilities of critical structures and equipment are developed as families of conditional failure frequency curves plotted against peak ground acceleration. The procedure is based on available data combined with judicious extrapolation of design information on plant structures and equipment. Representative values of fragility parameters for typical modern nuclear power plants are provided. Based on the fragility evaluation for about a dozen nuclear power plants, it is proposed that unnecessary conservatism existing in current seismic design practice could be removed by properly accounting for inelastic energy absorption capabilities of structures. The paper discusses the key contributors to seismic risk and the significance of possible correlation between component failures and potential design and construction errors. (orig.)

  16. Seismic fragilities for nuclear power plant risk studies

    International Nuclear Information System (INIS)

    Seismic fragilities of critical structures and equipment are developed as families of conditional failure frequency curves plotted against peak ground acceleration. The procedure is based on available data combined with judicious extrapolation of design information on plant structures and equipment. Representative values of fragility parameters for typical modern nuclear power plants are provided. Based on the fragility evaluation for about a dozen nuclear power plants, it is proposed that unnecessary conservatism existing in current seismic design practice could be removed by properly accounting for inelastic energy absorption capabilities of structures. The paper discusses the key contributors to seismic risk and the significance of possible correlation between component failures and potential design and construction errors

  17. A nonsense mutation in FMR1 causing fragile X syndrome

    DEFF Research Database (Denmark)

    Grønskov, Karen; Brøndum-Nielsen, Karen; Dedic, Alma;

    2011-01-01

    Fragile X syndrome is a common cause of inherited intellectual disability. It is caused by lack of the FMR1 gene product FMRP. The most frequent cause is the expansion of a CGG repeat located in the 5'UTR of FMR1. Alleles with 200 or more repeats become hypermethylated and transcriptionally silent....... Only few patients with intragenic point mutations in FMR1 have been reported and, currently, routine analysis of patients referred for fragile X syndrome includes solely analysis for repeat expansion and methylation status. We identified a substitution in exon 2 of FMR1, c.80C>A, causing a nonsense...... mutation p.Ser27X, in a patient with classical clinical symptoms of fragile X syndrome. The mother who carried the mutation in heterozygous form presented with mild intellectual impairment. We conclude that further studies including western blot and DNA sequence analysis of the FMR1 gene should be...

  18. Normal RNAi response in human fragile x fibroblasts

    DEFF Research Database (Denmark)

    Madsen, Charlotte; Grønskov, Karen; Brøndum-Nielsen, Karen;

    2009-01-01

    BACKGROUND: Fragile x syndrome is caused by loss of expression of the FMRP protein involved in the control of a large number of mRNA targets. The Drosophila ortholog dFXR interacts with a protein complex that includes Argonaute2, an essential component of the RNA-induced silencing complex (RISC......). Furthermore dFXR associates with Dicer, another essential processing enzyme of the RNAi pathway. Both microRNA and microRNA precursors can co-immunoprecipitate with dFXR. Consequently it has been suggested that the Fragile x syndrome may be due to a defect in an RNAi-related apparatus. FINDINGS: We have...... investigated the RNAi response in Fragile x patient cells lacking FMRP compared with normal controls. RNAi responses were successfully detected, but no statistically significant difference between the response in normal cells compared to patients cells was found - neither one nor two days after transfection...

  19. RNA profiling reveals familial aggregation of molecular subtypes in non-BRCA1/2 breast cancer families

    DEFF Research Database (Denmark)

    Larsen, Martin J; Thomassen, Mads; Tan, Qihua;

    2014-01-01

    BACKGROUND: In more than 70% of families with a strong history of breast and ovarian cancers, pathogenic mutation in BRCA1 or BRCA2 cannot be identified, even though hereditary factors are expected to be involved. It has been proposed that tumors with similar molecular phenotypes also share similar...... and provide evidence for epigenetic inactivation of BRCA1 in three of the tumors. In addition, 7 BRCA2-like tumors were found. CONCLUSIONS: Our finding indicates involvement of hereditary factors in non-BRCA1/2 breast cancer families in which family members may carry genetic susceptibility not just to...... underlying pathophysiological mechanisms. In the current study, the aim was to investigate if global RNA profiling can be used to identify functional subgroups within breast tumors from families tested negative for BRCA1/2 germline mutations and how these subgroupings relate to different breast cancer...

  20. Multi-variant pathway association analysis reveals the importance of genetic determinants of estrogen metabolism in breast and endometrial cancer susceptibility.

    Directory of Open Access Journals (Sweden)

    Yen Ling Low

    2010-07-01

    Full Text Available Despite the central role of estrogen exposure in breast and endometrial cancer development and numerous studies of genes in the estrogen metabolic pathway, polymorphisms within the pathway have not been consistently associated with these cancers. We posit that this is due to the complexity of multiple weak genetic effects within the metabolic pathway that can only be effectively detected through multi-variant analysis. We conducted a comprehensive association analysis of the estrogen metabolic pathway by interrogating 239 tagSNPs within 35 genes of the pathway in three tumor samples. The discovery sample consisted of 1,596 breast cancer cases, 719 endometrial cancer cases, and 1,730 controls from Sweden; and the validation sample included 2,245 breast cancer cases and 1,287 controls from Finland. We performed admixture maximum likelihood (AML-based global tests to evaluate the cumulative effect from multiple SNPs within the whole metabolic pathway and three sub-pathways for androgen synthesis, androgen-to-estrogen conversion, and estrogen removal. In the discovery sample, although no single polymorphism was significant after correction for multiple testing, the pathway-based AML global test suggested association with both breast (p(global = 0.034 and endometrial (p(global = 0.052 cancers. Further testing revealed the association to be focused on polymorphisms within the androgen-to-estrogen conversion sub-pathway, for both breast (p(global = 0.008 and endometrial cancer (p(global = 0.014. The sub-pathway association was validated in the Finnish sample of breast cancer (p(global = 0.015. Further tumor subtype analysis demonstrated that the association of the androgen-to-estrogen conversion sub-pathway was confined to postmenopausal women with sporadic estrogen receptor positive tumors (p(global = 0.0003. Gene-based AML analysis suggested CYP19A1 and UGT2B4 to be the major players within the sub-pathway. Our study indicates that the composite

  1. Plasma Proteomic Profiling in Hereditary Breast Cancer Reveals a BRCA1-Specific Signature: Diagnostic and Functional Implications

    OpenAIRE

    Domenica Scumaci; Laura Tammè; Claudia Vincenza Fiumara; Giusi Pappaianni; Antonio Concolino; Emanuela Leone; Maria Concetta Faniello; Barbara Quaresima; Enrico Ricevuto; Francesco Saverio Costanzo; Giovanni Cuda

    2015-01-01

    Background Breast cancer (BC) is a leading cause of death among women. Among the major risk factors, an important role is played by familial history of BC. Germ-line mutations in BRCA1/2 genes account for most of the hereditary breast and/or ovarian cancers. Gene expression profiling studies have disclosed specific molecular signatures for BRCA1/2-related breast tumors as compared to sporadic cases, which might help diagnosis and clinical follow-up. Even though, a clear hallmark of BRCA1/2-po...

  2. Whole-of-Government Approaches to Fragile States in Africa

    DEFF Research Database (Denmark)

    Olsen, Gorm Rye

    2013-01-01

    For a number of years fragile states have been high on the foreign policy agendas of the USA and the EU. Both actors look upon fragile states with great concern and consider them as security threats. Officially they give priority to ‘whole-of-government approaches’ (wga) when addressing the threats...... from these states. However, there is a gap between the policy declarations and the policies implemented by the two actors. The missing link in the implementation of wga in Africa is explained by two variables: on the one hand, material interests in the continent and, on the other hand, the institutions...

  3. BONE FRAGILITY IN TURNER SYNDROME: MECHANISMS AND PREVENTION STRATEGIES

    Directory of Open Access Journals (Sweden)

    Maria Felicia Faienza

    2016-04-01

    Full Text Available Bone fragility is recognized as one of major comorbidities in Turner Syndrome (TS. The mechanisms underlying bone impairment in affected patients are not clearly elucidated, but estrogen deficiency and X-chromosomal abnormalities represent important factors. Moreover, although many girls with TS undergo recombinant growth hormone (rGH therapy to treat short stature, the efficacy of this treatment on BMD is controversial. The present review will focus on bone fragility in subjects with TS, providing an overview on the pathogenic mechanisms and some prevention strategies.

  4. Bone Fragility in Turner Syndrome: Mechanisms and Prevention Strategies.

    Science.gov (United States)

    Faienza, Maria Felicia; Ventura, Annamaria; Colucci, Silvia; Cavallo, Luciano; Grano, Maria; Brunetti, Giacomina

    2016-01-01

    Bone fragility is recognized as one of the major comorbidities in Turner syndrome (TS). The mechanisms underlying bone impairment in affected patients are not clearly elucidated, but estrogen deficiency and X-chromosomal abnormalities represent important factors. Moreover, although many girls with TS undergo recombinant growth hormone therapy to treat short stature, the efficacy of this treatment on bone mineral density is controversial. The present review will focus on bone fragility in subjects with TS, providing an overview on the pathogenic mechanisms and some prevention strategies. PMID:27199891

  5. Bone Fragility in Turner Syndrome: Mechanisms and Prevention Strategies

    Science.gov (United States)

    Faienza, Maria Felicia; Ventura, Annamaria; Colucci, Silvia; Cavallo, Luciano; Grano, Maria; Brunetti, Giacomina

    2016-01-01

    Bone fragility is recognized as one of the major comorbidities in Turner syndrome (TS). The mechanisms underlying bone impairment in affected patients are not clearly elucidated, but estrogen deficiency and X-chromosomal abnormalities represent important factors. Moreover, although many girls with TS undergo recombinant growth hormone therapy to treat short stature, the efficacy of this treatment on bone mineral density is controversial. The present review will focus on bone fragility in subjects with TS, providing an overview on the pathogenic mechanisms and some prevention strategies. PMID:27199891

  6. Semi-Fragile Watermarking for Copyright Protection and Image Authentication

    Institute of Scientific and Technical Information of China (English)

    HUANG Ji-feng

    2005-01-01

    In this paper, we propose a semi-fragile watermarking technology for copyright protection and image authentication. We transform the image into wavelet domain and group the four adjacent wavelet coefficients. Utilizing the characteristics of the human visual system, we embed a digital signal into the average of the four adjacent wavelet coefficients since the mean has better stability than single wavelet coefficient. This method needn't original image when extracts the watermark. Experimental results show the effectiveness of this method which is robust to common image process and fragile to malicious attack.

  7. Fragile X syndrome. Molecular and clinical insights and treatment issues.

    OpenAIRE

    Hagerman, R.J.

    1997-01-01

    The fragile X syndrome is the most common inherited cause of mental retardation that is known. The prevalence of mental retardation from this syndrome ranges from 1 in 1,250 to 1 in 4,000 in the general population, although the prevalence of female carriers has been reported to be as high as 1 in 259. The discovery of the FMR1 gene mutation in 1991 has simplified diagnosis, enhanced our understanding of the spectrum of involvement in the fragile X syndrome, and stimulated research regarding t...

  8. FRAGILE COUNTRIES AND THE 2008-2009 CRISIS.

    OpenAIRE

    Franklin Allen and Giorgia Giovannetti

    2010-01-01

    This paper analyses the channels through which the economic and financial crisis of 2008-2009 is transmitted to fragile countries in Sub-Saharan Africa. Trade stands out as the main direct channel, even though intra-Africa remittances play a relevant role, given that most migrants in Sub-Saharan Africa fragile countries cannot afford the cost of mi-grating to Europe or to the United States and stay close, remaining in the continent. Whether reduced aid flows also act as a crisis transmission ...

  9. Robust and fragile Werner states in the collective dephasing

    OpenAIRE

    Li, Shang-Bin; Xu, Jing-Bo

    2005-01-01

    We investigate the concurrence and Bell violation of the standard Werner state or Werner-like states in the presence of collective dephasing. It is shown that the standard Werner state and certain kinds of Werner-like states are robust against the collective dephasing, and some kinds of Werner-like states is fragile and becomes completely disentangled in a finite-time. The threshold time of complete disentanglement of the fragile Werner-like states is given. The influence of external driving ...

  10. Fine-Scale Mapping of the 5q11.2 Breast Cancer Locus Reveals at Least Three Independent Risk Variants Regulating MAP3K1

    Science.gov (United States)

    Glubb, Dylan M.; Maranian, Mel J.; Michailidou, Kyriaki; Pooley, Karen A.; Meyer, Kerstin B.; Kar, Siddhartha; Carlebur, Saskia; O’Reilly, Martin; Betts, Joshua A.; Hillman, Kristine M.; Kaufmann, Susanne; Beesley, Jonathan; Canisius, Sander; Hopper, John L.; Southey, Melissa C.; Tsimiklis, Helen; Apicella, Carmel; Schmidt, Marjanka K.; Broeks, Annegien; Hogervorst, Frans B.; van der Schoot, C. Ellen; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Fasching, Peter A.; Ruebner, Matthias; Ekici, Arif B.; Beckmann, Matthias W.; Peto, Julian; dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Pharoah, Paul D.P.; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Burwinkel, Barbara; Marme, Frederik; Yang, Rongxi; Surowy, Harald; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; González-Neira, Anna; Benitez, Javier; Zamora, M. Pilar; Arias Perez, Jose Ignacio; Anton-Culver, Hoda; Neuhausen, Susan L.; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Ko, Yon-Dschun; Brüning, Thomas; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tanaka, Hideo; Dörk, Thilo; Bogdanova, Natalia V.; Helbig, Sonja; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Wu, Anna H.; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O.; Lambrechts, Diether; Zhao, Hui; Weltens, Caroline; van Limbergen, Erik; Chang-Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Seibold, Petra; Radice, Paolo; Peterlongo, Paolo; Barile, Monica; Capra, Fabio; Couch, Fergus J.; Olson, Janet E.; Hallberg, Emily; Vachon, Celine; Giles, Graham G.; Milne, Roger L.; McLean, Catriona; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Teo, Soo Hwang; Yip, Cheng Har; See, Mee-Hoong; Cornes, Belinda; Cheng, Ching-Yu; Ikram, M. Kamran; Kristensen, Vessela; Zheng, Wei; Halverson, Sandra L.; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robert A.E.M.; Seynaeve, Caroline; Van Asperen, Christi J.; García-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J.; Lissowska, Jolanta; Czene, Kamila; Klevebring, Daniel; Darabi, Hatef; Eriksson, Mikael; Hooning, Maartje J.; Hollestelle, Antoinette; Martens, John W.M.; Collée, J. Margriet; Hall, Per; Li, Jingmei; Humphreys, Keith; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Cross, Simon S.; Reed, Malcolm W.R.; Blot, William; Signorello, Lisa B.; Cai, Qiuyin; Shah, Mitul; Ghoussaini, Maya; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.; Noh, Dong-Young; Hartman, Mikael; Miao, Hui; Lim, Wei Yen; Tang, Anthony; Hamann, Ute; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Olswold, Curtis; Slager, Susan; Toland, Amanda E.; Yannoukakos, Drakoulis; Shen, Chen-Yang; Wu, Pei-Ei; Yu, Jyh-Cherng; Hou, Ming-Feng; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael; Pita, Guillermo; Alonso, M. Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Healey, Catherine S.; Brown, Melissa A.; Ponder, Bruce A.J.; Chenevix-Trench, Georgia; Thompson, Deborah J.; Edwards, Stacey L.; Easton, Douglas F.; Dunning, Alison M.; French, Juliet D.

    2015-01-01

    Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER+: odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21–1.27, ptrend = 5.7 × 10−44) and estrogen-receptor-negative (ER−: OR = 1.10, 95% CI = 1.05–1.15, ptrend = 3.0 × 10−4) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10−5]) and five variants composing iCHAV3 (lead rs11949391; ER+: OR = 0.90, 95% CI = 0.87–0.93, pcond = 1.4 × 10−4). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival. PMID:25529635

  11. Transcriptome Analysis of Piperlongumine-Treated Human Pancreatic Cancer Cells Reveals Involvement of Oxidative Stress and Endoplasmic Reticulum Stress Pathways.

    Science.gov (United States)

    Dhillon, Harsharan; Mamidi, Sujan; McClean, Phillip; Reindl, Katie M

    2016-06-01

    Piperlongumine (PL), an alkaloid obtained from long peppers, displays antitumorigenic properties for a variety of human cell- and animal-based models. The aim of this study was to identify the underlying molecular mechanisms for PL anticancer effects on human pancreatic cancer cells. RNA sequencing (RNA-seq) was used to identify the effects of PL on the transcriptome of MIA PaCa-2 human pancreatic cancer cells. PL treatment of pancreatic cancer cells resulted in differential expression of 683 mRNA transcripts with known protein functions, 351 of which were upregulated and 332 of which were downregulated compared to control-treated cells. Transcripts associated with oxidative stress, endoplasmic reticulum (ER) stress, and unfolded protein response pathways were significantly overexpressed with PL treatment. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to validate the RNA-seq results, which included upregulation of HO-1, IRE1α, cytochrome c, and ASNS. The results provide key insight into the mechanisms by which PL alters cancer cell physiology and identify that activation of oxidative stress and ER stress pathways is a critical avenue for PL anticancer effects. PMID:27119744

  12. The low-abundance transcriptome reveals novel biomarkers, specific intracellular pathways and targetable genes associated with advanced gastric cancer.

    Science.gov (United States)

    Bizama, Carolina; Benavente, Felipe; Salvatierra, Edgardo; Gutiérrez-Moraga, Ana; Espinoza, Jaime A; Fernández, Elmer A; Roa, Iván; Mazzolini, Guillermo; Sagredo, Eduardo A; Gidekel, Manuel; Podhajcer, Osvaldo L

    2014-02-15

    Studies on the low-abundance transcriptome are of paramount importance for identifying the intimate mechanisms of tumor progression that can lead to novel therapies. The aim of the present study was to identify novel markers and targetable genes and pathways in advanced human gastric cancer through analyses of the low-abundance transcriptome. The procedure involved an initial subtractive hybridization step, followed by global gene expression analysis using microarrays. We observed profound differences, both at the single gene and gene ontology levels, between the low-abundance transcriptome and the whole transcriptome. Analysis of the low-abundance transcriptome led to the identification and validation by tissue microarrays of novel biomarkers, such as LAMA3 and TTN; moreover, we identified cancer type-specific intracellular pathways and targetable genes, such as IRS2, IL17, IFNγ, VEGF-C, WISP1, FZD5 and CTBP1 that were not detectable by whole transcriptome analyses. We also demonstrated that knocking down the expression of CTBP1 sensitized gastric cancer cells to mainstay chemotherapeutic drugs. We conclude that the analysis of the low-abundance transcriptome provides useful insights into the molecular basis and treatment of cancer. PMID:23907728

  13. Meta-analysis of several gene lists for distinct types of cancer: A simple way to reveal common prognostic markers

    Directory of Open Access Journals (Sweden)

    Sun Xiao

    2007-04-01

    Full Text Available Abstract Background Although prognostic biomarkers specific for particular cancers have been discovered, microarray analysis of gene expression profiles, supported by integrative analysis algorithms, helps to identify common factors in molecular oncology. Similarities of Ordered Gene Lists (SOGL is a recently proposed approach to meta-analysis suitable for identifying features shared by two data sets. Here we extend the idea of SOGL to the detection of significant prognostic marker genes from microarrays of multiple data sets. Three data sets for leukemia and the other six for different solid tumors are used to demonstrate our method, using established statistical techniques. Results We describe a set of significantly similar ordered gene lists, representing outcome comparisons for distinct types of cancer. This kind of similarity could improve the diagnostic accuracies of individual studies when SOGL is incorporated into the support vector machine algorithm. In particular, we investigate the similarities among three ordered gene lists pertaining to mesothelioma survival, prostate recurrence and glioma survival. The similarity-driving genes are related to the outcomes of patients with lung cancer with a hazard ratio of 4.47 (p = 0.035. Many of these genes are involved in breakdown of EMC proteins regulating angiogenesis, and may be used for further research on prognostic markers and molecular targets of gene therapy for cancers. Conclusion The proposed method and its application show the potential of such meta-analyses in clinical studies of gene expression profiles.

  14. Genetics Home Reference: fragile X-associated tremor/ataxia syndrome

    Science.gov (United States)

    ... Home Health Conditions FXTAS fragile X-associated tremor/ataxia syndrome Enable Javascript to view the expand/collapse ... All Close All Description Fragile X-associated tremor/ataxia syndrome ( FXTAS ) is characterized by problems with movement ...

  15. Fragile X Syndrome: Keys to the Molecular Genetics of Synaptic Plasticity

    Science.gov (United States)

    Lombroso, Paul J.; Ogren, Marilee P.

    2008-01-01

    Fragile X syndrome, the most common form of inherited mental retardation is discussed. The relationship between specific impairments in synaptic plasticity and Fragile X syndrome is investigated as it strengthens synaptic contacts between neurons.

  16. Structure and management of tuberculosis control programs in fragile states-Afghanistan, DR Congo, Haiti, Somalia

    NARCIS (Netherlands)

    V. Mauch; D. Weil; A. Munim; F. Boillot; R. Coninx; S. Huseynova; C. Powell; A. Seita; H. Wembanyama; S. van den Hof

    2010-01-01

    Objectives: Health care delivery is particularly problematic in fragile states often connected with increased incidence of communicable diseases, among them tuberculosis. This article draws upon experiences in tuberculosis control in four fragile states from which four lessons learned were derived.

  17. Pim-selective inhibitor DHPCC-9 reveals Pim kinases as potent stimulators of cancer cell migration and invasion

    Directory of Open Access Journals (Sweden)

    Prudhomme Michelle

    2010-10-01

    Full Text Available Abstract Background Pim family kinases are small constitutively active serine/threonine-specific kinases, elevated levels of which have been detected in human hematopoietic malignancies as well as in solid tumours. While we and others have previously shown that the oncogenic Pim kinases stimulate survival of hematopoietic cells, we now examined their putative role in regulating motility of adherent cancer cells. For this purpose, we inhibited Pim kinase activity using a small molecule compound, 1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde (DHPCC-9, which we had recently identified as a potent and selective inhibitor for all Pim family members. Results We now demonstrate that the Pim kinase inhibitor DHPCC-9 is very effective also in cell-based assays. DHPCC-9 impairs the anti-apoptotic effects of Pim-1 in cytokine-deprived myeloid cells and inhibits intracellular phosphorylation of Pim substrates such as Bad. Moreover, DHPCC-9 slows down migration and invasion of cancer cells derived from either prostate cancer or squamocellular carcinoma patients. Silencing of Pim expression reduces cell motility, while Pim overexpression enhances it, strongly suggesting that the observed effects of DHPCC-9 are dependent on Pim kinase activity. Interestingly, DHPCC-9 also abrogates NFATc-dependent migration of cancer cells, implying that NFATc factors mediate at least part of the pro-migratory effects of Pim kinases. Conclusions Altogether, our data indicate that DHPCC-9 is not only a powerful tool to investigate physiological effects of the oncogenic Pim family kinases, but also an attractive molecule for drug development to inhibit invasiveness of Pim-overexpressing cancer cells.

  18. The effect of methionine and 5-azacytidine on fragile X expression.

    OpenAIRE

    Abruzzo, M A; Mayer, M.; Jacobs, P A

    1985-01-01

    The cellular mechanism for the expression of the fragile site at Xq28 is unknown. We tested the effect of 5-azacytidine and methionine on fragile X expression in lymphocytes and lymphoblastoid cells in an attempt to determine if DNA methylation was involved. We were unable to demonstrate a consistent dosage effect of methionine on fragile X expression. While 5-azacytidine was found to inhibit the fragile X in both males and females, it did so only at relatively high concentrations. We conclud...

  19. Cholinergic Dysfunction in Fragile X Syndrome and Potential Intervention: A Preliminary 1H MRS Study

    OpenAIRE

    Kesler, Shelli R.; Lightbody, Amy A.; Reiss, Allan L.

    2009-01-01

    Males with fragile X syndrome are at risk for significant cognitive and behavioral deficits, particularly those involving executive prefrontal systems. Disruption of the cholinergic system secondary to fragile X mental retardation protein deficiency may contribute to the cognitive-behavioral impairments associated with fragile X. We measured choline in the dorsolateral prefrontal cortex of 9 males with fragile X syndrome and 9 age-matched typically developing controls using 1H magnetic resona...

  20. Heart Activity and Autistic Behavior in Infants and Toddlers with Fragile X Syndrome

    OpenAIRE

    Roberts, Jane E.; Tonnsen, Bridgette; Robinson, Ashley; Svetlana V Shinkareva

    2012-01-01

    The present study contrasted physiological arousal in infants and toddlers with fragile X syndrome to typically developing control participants and examined physiological predictors early in development to autism severity later in development in fragile X syndrome. Thirty-one males with fragile X syndrome (ages 8–40 months) and 25 age-matched control participants were included. The group with fragile X syndrome showed shorter interbeat intervals (IBIs), lower vagal tone (VT), and less modulat...

  1. Transcriptome analysis of copper homeostasis genes reveals coordinated upregulation of SLC31A1,SCO1, and COX11 in colorectal cancer.

    Science.gov (United States)

    Barresi, Vincenza; Trovato-Salinaro, Angela; Spampinato, Giorgia; Musso, Nicolò; Castorina, Sergio; Rizzarelli, Enrico; Condorelli, Daniele Filippo

    2016-08-01

    Copper homeostasis and distribution is strictly regulated by a network of transporters and intracellular chaperones encoded by a group of genes collectively known as copper homeostasis genes (CHGs). In this work, analysis of The Cancer Genome Atlas database for somatic point mutations in colorectal cancer revealed that inactivating mutations are absent or extremely rare in CHGs. Using oligonucleotide microarrays, we found a strong increase in mRNA levels of the membrane copper transporter 1 protein [CTR1; encoded by the solute carrier family 31 member 1 gene (SLC31A1 gene)] in our series of colorectal carcinoma samples. CTR1 is the main copper influx transporter and changes in its expression are able to induce modifications of cellular copper accumulation. The increased SLC31A1 mRNA level is accompanied by a parallel increase in transcript levels for copper efflux pump ATP7A, copper metabolism Murr1 domain containing 1 (COMMD1), the cytochrome C oxidase assembly factors [synthesis of cytochrome c oxidase 1 (SCO1) and cytochrome c oxidase copper chaperone 11 (COX11)], the cupric reductase six transmembrane epithelial antigen of the prostate (STEAP3), and the metal-regulatory transcription factors (MTF1, MTF2) and specificity protein 1 (SP1). The significant correlation between SLC31A1,SCO1, and COX11 mRNA levels suggests that this transcriptional upregulation might be part of a coordinated program of gene regulation. Transcript-level upregulation of SLC31A1,SCO1, and COX11 was also confirmed by the analysis of different colon carcinoma cell lines (Caco-2, HT116, HT29) and cancer cell lines of different tissue origin (MCF7, PC3). Finally, exon-level expression analysis of SLC31A1 reveals differential expression of alternative transcripts in colorectal cancer and normal colonic mucosa. PMID:27516958

  2. Development of a highly metastatic model that reveals a crucial role of fibronectin in lung cancer cell migration and invasion

    International Nuclear Information System (INIS)

    The formation of metastasis is the most common cause of death in patients with lung cancer. A major implement to understand the molecular mechanisms involved in lung cancer metastasis has been the lack of suitable models to address it. In this study, we aimed at establishing a highly metastatic model of human lung cancer and characterizing its metastatic properties and underlying mechanisms. The human lung adeno-carcinoma SPC-A-1 cell line was used as parental cells for developing of highly metastatic cells by in vivo selection in NOD/SCID mice. After three rounds of selection, a new SPC-A-1sci cell line was established from pulmonary metastatic lesions. Subsequently, the metastatic properties of this cell line were analyzed, including optical imaging of in vivo metastasis, immunofluorescence and immunohistochemical analysis of several epithelial mesenchymal transition (EMT) makers and trans-well migration and invasion assays. Finally, the functional roles of fibronectin in the invasive and metastatic potentials of SPC-A-1sci cells were determined by shRNA analysis. A spontaneously pulmonary metastatic model of human lung adeno-carcinoma was established in NOD/SCID mice, from which a new lung cancer cell line, designated SPC-A-1sci, was isolated. Initially, the highly metastatic behavior of this cell line was validated by optical imaging in mice models. Further analyses showed that this cell line exhibit phenotypic and molecular alterations consistent with EMT. Compared with its parent cell line SPC-A-1, SPC-A-1sci was more aggressive in vitro, including increased potentials for cell spreading, migration and invasion. Importantly, fibronectin, a mesenchymal maker of EMT, was found to be highly expressed in SPC-A-1sci cells and down-regulation of it can decrease the in vitro and in vivo metastatic abilities of this cell line. We have successfully established a new human lung cancer cell line with highly metastatic potentials, which is subject to EMT and possibly

  3. Biomedical Advances in Developmental Psychology: The Case of Fragile X Syndrome.

    Science.gov (United States)

    Hagerman, Randi J.

    1996-01-01

    Discusses the Human Genome Project and the identification of Fragile X Syndrome, the most common inherited cause of mental retardation. Fragile X Syndrome is caused by an abnormal gene on the bottom of the X chromosome. Examined the phenotype of Fragile X Syndrome in males and females and the spectrum of learning difficulties caused by the…

  4. Family Environment and Behavior Problems in Children, Adolescents, and Adults with Fragile X Syndrome

    Science.gov (United States)

    Greenberg, Jan S.; Seltzer, Marsha Mailick; Baker, Jason K.; Smith, Leann E.; Warren, Steven F.; Brady, Nancy; Hong, Jinkuk

    2012-01-01

    We examine how the family environment is associated with aspects of the Fragile X syndrome phenotype during childhood, adolescence, and adulthood. Mothers of children (n = 48), adolescents (n = 85), and adults (n = 34) with Fragile X syndrome participated in a multisite study. For children and adults with Fragile X syndrome, the presence of warmth…

  5. Heart Activity and Autistic Behavior in Infants and Toddlers with Fragile X Syndrome

    Science.gov (United States)

    Roberts, Jane E.; Tonnsen, Bridgette; Robinson, Ashley; Shinkareva, Svetlana V.

    2012-01-01

    The present study contrasted physiological arousal in infants and toddlers with fragile X syndrome to typically developing control participants and examined physiological predictors early in development to autism severity later in development in fragile X syndrome. Thirty-one males with fragile X syndrome (ages 8-40 months) and 25 age-matched…

  6. Side Effects of Minocycline Treatment in Patients with Fragile X Syndrome and Exploration of Outcome Measures

    Science.gov (United States)

    Utari, Agustini; Chonchaiya, Weerasak; Rivera, Susan M.; Schneider, Andrea; Hagerman, Randi J.; Faradz, Sultana M. H.; Ethell, Iryna M.; Nguyen, Danh V.

    2010-01-01

    Minocycline can rescue the dendritic spine and synaptic structural abnormalities in the fragile X knock-out mouse. This is a review and preliminary survey to document side effects and potential outcome measures for minocycline use in the treatment of individuals with fragile X syndrome. We surveyed 50 patients with fragile X syndrome who received…

  7. Obesity, Food Selectivity, and Physical Activity in Individuals with Fragile X Syndrome

    Science.gov (United States)

    Raspa, Melissa; Bailey, Donald B., Jr.; Bishop, Ellen; Holiday, David; Olmsted, Murrey

    2010-01-01

    National survey data from 884 families were used to examine the overall health of children and adults with fragile X syndrome. Results indicate the rate of obesity in adults with fragile X syndrome is similar to the general population (30%). Male children with fragile X syndrome, however, had higher rates of obesity (31%) when compared with…

  8. Between Development and Security: The European Union, Governance and Fragile States

    NARCIS (Netherlands)

    W. Hout (Wil)

    2009-01-01

    textabstractOver the past five to seven years, most international aid donors have started to pay attention to so-called ‘fragile states’. Generally, the interest in state fragility was spurred by security considerations in the wake of the terrorist attacks of ‘9/11’. Fragile states came to be seen a

  9. Seismic fragility of ventilation stack of nuclear power plant

    International Nuclear Information System (INIS)

    Fragility study of safety related elements is necessary step in seismic PSA of nuclear power plant (NPP). In present work fragility was analyzed after the example of the ventilation stack of NPP. Ventilation stack, considered in present work, is a separately erected construction with height of 100 m made of cast-in-place reinforced concrete. In accordance with IAEA terminology fragility of element is defined as conditional probability of its failure at given level of seismic loading. Failure of a ventilation stack was considered as development of the plastic hinge in some section of a shaft. Seismic ground acceleration a, which corresponds to failure, could be defined as limit seismic acceleration of ventilation stack [a]. Limit seismic acceleration [a] was considered as random value. Sources of its variation are connected with stochastic nature of factors determining it (properties of construction materials, soils etc.), and also with uncertainties of existing analytical techniques. Random value [a] was assumed to be distributed lognormally. Median m[a] and logarithmically standard deviation β of this distribution were defined by 'scaling method' developed by R.P. Kennedy et al. Using this values fragility curves were plotted for different levels of confidence probability. (author)

  10. Arousal Modulation in Females with Fragile X or Turner Syndrome

    Science.gov (United States)

    Roberts, Jane; Mazzocco, Michele M. M.; Murphy, Melissa M.; Hoehn-Saric, Rudolf

    2008-01-01

    The present study was carried out to examine physiological arousal modulation (heart activity and skin conductance), across baseline and cognitive tasks, in females with fragile X or Turner syndrome and a comparison group of females with neither syndrome. Relative to the comparison group, for whom a greater increase in skin conductance was…

  11. Seismic fragility capacity of equipment--horizontal shaft pump test

    International Nuclear Information System (INIS)

    The current seismic fragility capacity of horizontal shaft pump is 1.6 x 9.8 m/s2(1.6 g), which was decided from previous vibration tests and we believe that it must have sufficient margin. The purpose of fragility capacity test is to obtain realistic seismic fragility capacity of horizontal shaft pump by vibration tests. Reactor Building Closed Cooling Water (RCW) Pump was tested as a typical horizontal shaft pump, and then bearings and liner rings were tested as important parts to evaluate critical acceleration and dispersion. Regarding RCW pump test, no damage was found, though maximum input acceleration level was 6 x 9.8 m/s2 (6 g). Some kinds of bearings and liner rings were tested on the element test. Input load was based on seismic motion which was same with the RCW pump test, and maximum load was equivalent to over 20 times of design seismic acceleration. There was not significant damage that caused emergency stop of pump but degradation of surface roughness was found on some kinds of bearings. It would cause reduction of pump life, but such damage on bearings occurred under large seismic load condition that was equivalent to over 10 to 20 g force. Test results show that realistic fragility capacity of horizontal shaft pump would be at least four times as higher as current value which has been used for our seismic PSA. (authors)

  12. The quest for targeted therapy in fragile X syndrome

    NARCIS (Netherlands)

    S. Zeidler; R.K. Hukema (Renate); R. Willemsen (Rob)

    2015-01-01

    textabstractFragile X syndrome (FXS) is the most common, monogenetic cause of intellectual disability and autism-spectrum disorders. Although there is no effective therapy, greater understanding of disturbed neuronal pathways has introduced options for targeted therapy. But whereas many FXS phenotyp

  13. Clinical assessment tools identify functional deficits in fragility fracture patients

    Science.gov (United States)

    Ames, Tyler D; Wee, Corinne E; Le, Khoi M; Wang, Tiffany L; Bishop, Julie Y; Phieffer, Laura S; Quatman, Carmen E

    2016-01-01

    Purpose To identify inexpensive, noninvasive, portable, clinical assessment tools that can be used to assess functional performance measures that may put older patients at risk for falls such as balance, handgrip strength, and lumbopelvic control. Patients and methods Twenty fragility fracture patients and 21 healthy control subjects were evaluated using clinical assessment tools (Nintendo Wii Balance Board [WBB], a handheld dynamometer, and an application for the Apple iPod Touch, the Level Belt) that measure functional performance during activity of daily living tasks. The main outcome measurements were balance (WBB), handgrip strength (handheld dynamometer), and lumbopelvic control (iPod Touch Level Belt), which were compared between fragility fracture patients and healthy controls. Results Fragility fracture patients had lower scores on the vertical component of the WBB Torso Twist task (P=0.042) and greater medial–lateral lumbopelvic sway during a 40 m walk (P=0.026) when compared to healthy controls. Unexpectedly, the fracture patients had significantly higher scores on the left leg (P=0.020) and total components (P=0.010) of the WBB Single Leg Stand task as well as less faults during the left Single Leg Stand task (P=0.003). Conclusion The clinical assessment tools utilized in this study are relatively inexpensive and portable tools of performance measures capable of detecting differences in postural sway between fragility fracture patients and controls.

  14. Auditory Brainstem Responses in Young Males with Fragile X Syndrome

    Science.gov (United States)

    Roberts, Joanne; Hennon, Elizabeth A.; Anderson, Kathleen; Roush, Jackson; Gravel, Judith; Skinner, Martie; Misenheimer, Jan; Reitz, Patricia

    2005-01-01

    Fragile X syndrome (FXS) is the most common inherited cause of mental retardation resulting in developmental delays in males. Atypical outer ear morphology is characteristic of FXS and may serve as a marker for abnormal auditory function. Despite this abnormality, studies of the hearing of young males with FXS are generally lacking. A few studies…

  15. Rethinking Youth, Livelihoods, and Fragility in West Africa

    OpenAIRE

    Fortune, Francis; Ismail, Olawale; Stephen, Monica

    2015-01-01

    Africa’s population is young and growing at twice the pace of other continents. A youth bulge presents a series of development policy opportunities and challenges. In this context, simplistic linkages between the youth bulge, high unemployment, and fragility have gained traction and given rise to a youth policy agenda that targets urban male youth as the problem and emphasizes formal secto...

  16. Developmental Trajectories of Young Girls with Fragile X Syndrome

    Science.gov (United States)

    Hatton, Deborah D.; Wheeler, Anne; Sideris, John; Sullivan, Kelly; Reichardt, Alison; Roberts, Jane; Clark, Renee; Bailey, Donald B., Jr.

    2009-01-01

    To describe the early phenotype of girls with full mutation fragile X, we used 54 observations of 15 girls between the ages of 6 months and 9 years to examine developmental trajectories as measured by the Battelle Development Inventory. In this sample, autistic behavior was associated with poorer developmental outcomes, primarily due to…

  17. Phonological Awareness and Reading in Boys with Fragile X Syndrome

    Science.gov (United States)

    Adlof, Suzanne M.; Klusek, Jessica; Shinkareva, Svetlana V.; Robinson, Marissa L.; Roberts, Jane E.

    2015-01-01

    Background: Reading delays are well documented in children with fragile X syndrome (FXS), but few studies have examined linguistic precursors of reading in this population. This study examined the longitudinal development of phonological awareness and its relationship with basic reading in boys with FXS. Individual differences in genetic,…

  18. Seizures in Fragile X Syndrome: Characteristics and Comorbid Diagnoses

    Science.gov (United States)

    Berry-Kravis, Elizabeth; Raspa, Melissa; Loggin-Hester, Lisa; Bishop, Ellen; Holiday, David; Bailey, Donald B., Jr.

    2010-01-01

    A national survey of caregivers of individuals with fragile X syndrome addressed characteristics of epilepsy and co-occurring conditions. Of the 1,394 individuals (1,090 males and 304 females) with the full mutation, 14% of males and 6% of females reported seizures. Seizures were more often partial, began between ages 4 and 10 years, and were…

  19. Social Cognition in Adolescent Girls with Fragile X Syndrome

    Science.gov (United States)

    Turkstra, Lyn S.; Abbeduto, Leonard; Meulenbroek, Peter

    2014-01-01

    This study aimed to characterize social cognition, executive functions (EFs), and everyday social functioning in adolescent girls with fragile X syndrome, and identify relationships among these variables. Participants were 20 girls with FXS and 20 age-matched typically developing peers. Results showed significant between-groups differences in…

  20. Fragile X mental retardation protein and synaptic plasticity

    OpenAIRE

    Sidorov, Michael S.; Auerbach, Benjamin D.; Bear, Mark F.

    2013-01-01

    Loss of the translational repressor FMRP causes Fragile X syndrome. In healthy neurons, FMRP modulates the local translation of numerous synaptic proteins. Synthesis of these proteins is required for the maintenance and regulation of long-lasting changes in synaptic strength. In this role as a translational inhibitor, FMRP exerts profound effects on synaptic plasticity.

  1. Gender Differences in Repetitive Language in Fragile X Syndrome

    Science.gov (United States)

    Murphy, M. M.; Abbeduto, L.

    2007-01-01

    Background: Verbal perseveration (i.e. excessive self-repetition) is a characteristic of male individuals with fragile X syndrome; however, little is known about its occurrence among females or its underlying causes. This project examined the relationship between perseveration and (1) gender, (2) cognitive and linguistic ability, and (3) language…

  2. Reading and Phonological Skills in Boys with Fragile X Syndrome

    Science.gov (United States)

    Klusek, Jessica; Hunt, Anna W.; Mirrett, Penny L.; Hatton, Deborah D.; Hooper, Stephen R.; Roberts, Jane E.; Bailey, Donald B.

    2015-01-01

    Although reading skills are critical for the success of individuals with intellectual disabilities, literacy has received little attention in fragile X syndrome (FXS). This study examined the literacy profile of FXS. Boys with FXS (n = 51; mean age 10.2 years) and mental age-matched boys with typical development (n = 35) participated in…

  3. Social Approach and Emotion Recognition in Fragile X Syndrome

    Science.gov (United States)

    Williams, Tracey A.; Porter, Melanie A.; Langdon, Robyn

    2014-01-01

    Evidence is emerging that individuals with Fragile X syndrome (FXS) display emotion recognition deficits, which may contribute to their significant social difficulties. The current study investigated the emotion recognition abilities, and social approachability judgments, of FXS individuals when processing emotional stimuli. Relative to…

  4. Implicit Procedural Learning in Fragile X and Down Syndrome

    Science.gov (United States)

    Bussy, G.; Charrin, E.; Brun, A.; Curie, A.; des Portes, V.

    2011-01-01

    Background: Procedural learning refers to rule-based motor skill learning and storage. It involves the cerebellum, striatum and motor areas of the frontal lobe network. Fragile X syndrome, which has been linked with anatomical abnormalities within the striatum, may result in implicit procedural learning deficit. Methods: To address this issue, a…

  5. Fragile ′X′ syndrome. A case study.

    OpenAIRE

    Mittal S; Rawal Y

    1996-01-01

    Fragile ′X′ syndrome also known as the Martin-Bell syndrome or the marker ′X′ syndrome is an ′X′-linked disorder with connective tissue dysplasia and varying degree of mental retardation. A case of this syndrome with characteristic Martin-Bell phenotype is presented. Oral features as yet unmentioned are added.

  6. Parenting Young Children with and without Fragile X Syndrome

    Science.gov (United States)

    Sterling, Audra; Barnum, Leah; Skinner, Debra; Warren, Steven F.; Fleming, Kandace

    2012-01-01

    The purpose of this study was to examine maternal parenting styles across age-matched siblings using a within-family design, in which one child has Fragile X syndrome. Thirteen families participated; children were aged 16 to 71 months. Mothers completed several videotaped activities with each child separately as well as an interview. Mothers used…

  7. Obtaining reliable quality data from fragility seismic tests

    International Nuclear Information System (INIS)

    The parameters discussed in this paper are the same as those present in normal seismic qualification testing. These parameters behave differently in high level acceleration tests and their contribution in providing unreliable data is of major concern since there is a significant difference. These parameters need to be considered in developing methodology guidelines for future fragility standards

  8. Identity in Fragile States: Social cohesion and state building

    OpenAIRE

    Seth Kaplan

    2009-01-01

    Seth Kaplan describes how understanding the relationship between identities, institutions, social cohesion, and state legitimacy is vital to spurring economic and political development in fragile states. The international community needs to stop imposing inflexible formulas for development and to start helping weak countries build on their own people's capacities for good governance.

  9. What Are the Symptoms of Fragile X Syndrome?

    Science.gov (United States)

    ... body language. Girls usually do not have severe problems with speech or language. Some children with Fragile X begin talking later than typically developing children. Most will talk eventually, but a few might stay nonverbal throughout their lives. Sensory. Many children with ...

  10. Development of hazard-compatible building fragility and vulnerability models

    Science.gov (United States)

    Karaca, E.; Luco, N.

    2008-01-01

    We present a methodology for transforming the structural and non-structural fragility functions in HAZUS into a format that is compatible with conventional seismic hazard analysis information. The methodology makes use of the building capacity (or pushover) curves and related building parameters provided in HAZUS. Instead of the capacity spectrum method applied in HAZUS, building response is estimated by inelastic response history analysis of corresponding single-degree-of-freedom systems under a large number of earthquake records. Statistics of the building response are used with the damage state definitions from HAZUS to derive fragility models conditioned on spectral acceleration values. Using the developed fragility models for structural and nonstructural building components, with corresponding damage state loss ratios from HAZUS, we also derive building vulnerability models relating spectral acceleration to repair costs. Whereas in HAZUS the structural and nonstructural damage states are treated as if they are independent, our vulnerability models are derived assuming "complete" nonstructural damage whenever the structural damage state is complete. We show the effects of considering this dependence on the final vulnerability models. The use of spectral acceleration (at selected vibration periods) as the ground motion intensity parameter, coupled with the careful treatment of uncertainty, makes the new fragility and vulnerability models compatible with conventional seismic hazard curves and hence useful for extensions to probabilistic damage and loss assessment.

  11. Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer.

    Science.gov (United States)

    Weischenfeldt, Joachim; Simon, Ronald; Feuerbach, Lars; Schlangen, Karin; Weichenhan, Dieter; Minner, Sarah; Wuttig, Daniela; Warnatz, Hans-Jörg; Stehr, Henning; Rausch, Tobias; Jäger, Natalie; Gu, Lei; Bogatyrova, Olga; Stütz, Adrian M; Claus, Rainer; Eils, Jürgen; Eils, Roland; Gerhäuser, Clarissa; Huang, Po-Hsien; Hutter, Barbara; Kabbe, Rolf; Lawerenz, Christian; Radomski, Sylwester; Bartholomae, Cynthia C; Fälth, Maria; Gade, Stephan; Schmidt, Manfred; Amschler, Nina; Haß, Thomas; Galal, Rami; Gjoni, Jovisa; Kuner, Ruprecht; Baer, Constance; Masser, Sawinee; von Kalle, Christof; Zichner, Thomas; Benes, Vladimir; Raeder, Benjamin; Mader, Malte; Amstislavskiy, Vyacheslav; Avci, Meryem; Lehrach, Hans; Parkhomchuk, Dmitri; Sultan, Marc; Burkhardt, Lia; Graefen, Markus; Huland, Hartwig; Kluth, Martina; Krohn, Antje; Sirma, Hüseyin; Stumm, Laura; Steurer, Stefan; Grupp, Katharina; Sültmann, Holger; Sauter, Guido; Plass, Christoph; Brors, Benedikt; Yaspo, Marie-Laure; Korbel, Jan O; Schlomm, Thorsten

    2013-02-11

    Early-onset prostate cancer (EO-PCA) represents the earliest clinical manifestation of prostate cancer. To compare the genomic alteration landscapes of EO-PCA with "classical" (elderly-onset) PCA, we performed deep sequencing-based genomics analyses in 11 tumors diagnosed at young age, and pursued comparative assessments with seven elderly-onset PCA genomes. Remarkable age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. Whereas EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG, elderly-onset PCAs displayed primarily non-androgen-associated SRs. Data from a validation cohort of > 10,000 patients showed age-dependent androgen receptor levels and a prevalence of SRs affecting androgen-regulated genes, further substantiating the activity of a characteristic "androgen-type" pathomechanism in EO-PCA. PMID:23410972

  12. Monoclonal antibodies to murine thrombospondin-1 and thrombospondin-2 reveal differential expression patterns in cancer and low antigen expression in normal tissues

    International Nuclear Information System (INIS)

    There is a considerable interest for the discovery and characterization of tumor-associated antigens, which may facilitate antibody-based pharmacodelivery strategies. Thrombospondin-1 and thrombospondin-2 are homologous secreted proteins, which have previously been reported to be overexpressed during remodeling typical for wound healing and tumor progression and to possibly play a functional role in cell proliferation, migration and apoptosis. To our knowledge, a complete immunohistochemical characterization of thrombospondins levels in normal rodent tissues has not been reported so far. Using antibody phage technology, we have generated and characterized monoclonal antibodies specific to murine thrombospondin-1 and thrombospondin-2, two antigens which share 62% aminoacid identity. An immunofluorescence analysis revealed that both antigens are virtually undetectable in normal mouse tissues, except for a weak staining of heart tissue by antibodies specific to thrombospondin-1. The analysis also showed that thrombospondin-1 was strongly expressed in 5/7 human tumors xenografted in nude mice, while it was only barely detectable in 3/8 murine tumors grafted in immunocompetent mice. By contrast, a high-affinity antibody to thrombospondin-2 revealed a much lower level of expression of this antigen in cancer specimens. Our analysis resolves ambiguities related to conflicting reports on thrombosponding expression in health and disease. Based on our findings, thrombospondin-1 (and not thrombospondin-2) may be considered as a target for antibody-based pharmacodelivery strategies, in consideration of its low expression in normal tissues and its upregulation in cancer. - Highlights: • High affinity monoclonal antibodies to murine and human TSP1 and 2 were raised. • Both antigens are virtually undetectable in normal mouse tissues. • Strong positivity of human tumor xenografts for TSP1 was detected. • Study revealed much lower level of TSP2 expression in cancer specimens

  13. Monoclonal antibodies to murine thrombospondin-1 and thrombospondin-2 reveal differential expression patterns in cancer and low antigen expression in normal tissues

    Energy Technology Data Exchange (ETDEWEB)

    Bujak, Emil [Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 2, CH-8093 Zurich (Switzerland); Pretto, Francesca; Ritz, Danilo; Gualandi, Laura; Wulhfard, Sarah [Philochem AG, Libernstrasse 3, CH-8112 Otelfingen (Switzerland); Neri, Dario, E-mail: neri@pharma.ethz.ch [Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 2, CH-8093 Zurich (Switzerland)

    2014-09-10

    There is a considerable interest for the discovery and characterization of tumor-associated antigens, which may facilitate antibody-based pharmacodelivery strategies. Thrombospondin-1 and thrombospondin-2 are homologous secreted proteins, which have previously been reported to be overexpressed during remodeling typical for wound healing and tumor progression and to possibly play a functional role in cell proliferation, migration and apoptosis. To our knowledge, a complete immunohistochemical characterization of thrombospondins levels in normal rodent tissues has not been reported so far. Using antibody phage technology, we have generated and characterized monoclonal antibodies specific to murine thrombospondin-1 and thrombospondin-2, two antigens which share 62% aminoacid identity. An immunofluorescence analysis revealed that both antigens are virtually undetectable in normal mouse tissues, except for a weak staining of heart tissue by antibodies specific to thrombospondin-1. The analysis also showed that thrombospondin-1 was strongly expressed in 5/7 human tumors xenografted in nude mice, while it was only barely detectable in 3/8 murine tumors grafted in immunocompetent mice. By contrast, a high-affinity antibody to thrombospondin-2 revealed a much lower level of expression of this antigen in cancer specimens. Our analysis resolves ambiguities related to conflicting reports on thrombosponding expression in health and disease. Based on our findings, thrombospondin-1 (and not thrombospondin-2) may be considered as a target for antibody-based pharmacodelivery strategies, in consideration of its low expression in normal tissues and its upregulation in cancer. - Highlights: • High affinity monoclonal antibodies to murine and human TSP1 and 2 were raised. • Both antigens are virtually undetectable in normal mouse tissues. • Strong positivity of human tumor xenografts for TSP1 was detected. • Study revealed much lower level of TSP2 expression in cancer specimens

  14. Plasma Proteomic Profiling in Hereditary Breast Cancer Reveals a BRCA1-Specific Signature: Diagnostic and Functional Implications

    Science.gov (United States)

    Scumaci, Domenica; Tammè, Laura; Fiumara, Claudia Vincenza; Pappaianni, Giusi; Concolino, Antonio; Leone, Emanuela; Faniello, Maria Concetta; Quaresima, Barbara; Ricevuto, Enrico; Costanzo, Francesco Saverio; Cuda, Giovanni

    2015-01-01

    Background Breast cancer (BC) is a leading cause of death among women. Among the major risk factors, an important role is played by familial history of BC. Germ-line mutations in BRCA1/2 genes account for most of the hereditary breast and/or ovarian cancers. Gene expression profiling studies have disclosed specific molecular signatures for BRCA1/2-related breast tumors as compared to sporadic cases, which might help diagnosis and clinical follow-up. Even though, a clear hallmark of BRCA1/2-positive BC is still lacking. Many diseases are correlated with quantitative changes of proteins in body fluids. Plasma potentially carries important information whose knowledge could help to improve early disease detection, prognosis, and response to therapeutic treatments. The aim of this study was to develop a comprehensive approach finalized to improve the recovery of specific biomarkers from plasma samples of subjects affected by hereditary BC. Methods To perform this analysis, we used samples from patients belonging to highly homogeneous population previously reported. Depletion of high abundant plasma proteins, 2D gel analysis, liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics analysis were used into an integrated approach to investigate tumor-specific changes in the plasma proteome of BC patients and healthy family members sharing the same BRCA1 gene founder mutation (5083del19), previously reported by our group, with the aim to identify specific signatures. Results The comparative analysis of the experimental results led to the identification of gelsolin as the most promising biomarker. Conclusions Further analyses, performed using a panel of breast cancer cell lines, allowed us to further elucidate the signaling network that might modulate the expression of gelsolin in breast cancer. PMID:26061043

  15. Proteomic profiling reveals that resveratrol inhibits HSP27 expression and sensitizes breast cancer cells to doxorubicin therapy.

    Directory of Open Access Journals (Sweden)

    José Díaz-Chávez

    Full Text Available The use of chemopreventive natural compounds represents a promising strategy in the search for novel therapeutic agents in cancer. Resveratrol (3,4',5-trans-trihydroxystilbilene is a dietary polyphenol found in fruits, vegetables and medicinal plants that exhibits chemopreventive and antitumor effects. In this study, we searched for modulated proteins with preventive or therapeutic potential in MCF-7 breast cancer cells exposed to resveratrol. Using two-dimensional electrophoresis we found significant changes (FC >2.0; p≤0.05 in the expression of 16 proteins in resveratrol-treated MCF-7 cells. Six down-regulated proteins were identified by tandem mass spectrometry (ESI-MS/MS as heat shock protein 27 (HSP27, translationally-controlled tumor protein, peroxiredoxin-6, stress-induced-phosphoprotein-1, pyridoxine-5'-phosphate oxidase-1 and hypoxanthine-guanine phosphoribosyl transferase; whereas one up-regulated protein was identified as triosephosphate isomerase. Particularly, HSP27 overexpression has been associated to apoptosis inhibition and resistance of human cancer cells to therapy. Consistently, we demonstrated that resveratrol induces apoptosis in MCF-7 cells. Apoptosis was associated with a significant increase in mitochondrial permeability transition, cytochrome c release in cytoplasm, and caspases -3 and -9 independent cell death. Then, we evaluated the chemosensitization effect of increasing concentrations of resveratrol in combination with doxorubicin anti-neoplastic agent in vitro. We found that resveratrol effectively sensitize MCF-7 cells to cytotoxic therapy. Next, we evaluated the relevance of HSP27 targeted inhibition in therapy effectiveness. Results evidenced that HSP27 inhibition using RNA interference enhances the cytotoxicity of doxorubicin. In conclusion, our data indicate that resveratrol may improve the therapeutic effects of doxorubicin in part by cell death induction. We propose that potential modulation of HSP27

  16. Importance of revealing a rare case of breast cancer in a female to male transsexual after bilateral mastectomy

    OpenAIRE

    Nikolic Dejan V; Djordjevic Miroslav L; Granic Miroslav; Nikolic Aleksandra T; Stanimirovic Violeta V; Zdravkovic Darko; Jelic Svetlana

    2012-01-01

    Abstract The incidence of breast carcinoma following prophylactic mastectomy is probably less than 2%. We present a 43-year-old female to male transsexual who developed breast cancer 1 year after bilateral nipple- sparing subcutaneous mastectomy as part of female to male gender reassignment surgery. In addition to gender reassignment surgery, total abdominal hysterectomy with bilateral salpingo-oophorectomy (to avoid the patient from entering menopause and to eliminate any subsequent risk of ...

  17. Proteomic analysis of media from lung cancer cells reveals role of 14-3-3 proteins in cachexia

    OpenAIRE

    Julie B. McLean; Moylan, Jennifer S.; Horrell, Erin M. W.; Andrade, Francisco H.

    2015-01-01

    Aims: At the time of diagnosis, 60% of lung cancer patients present with cachexia, a severe wasting syndrome that increases morbidity and mortality. Tumors secrete multiple factors that contribute to cachectic muscle wasting, and not all of these factors have been identified. We used Orbitrap electrospray ionization mass spectrometry to identify novel cachexia-inducing candidates in media conditioned with Lewis lung carcinoma cells (LCM). Results: One-hundred and 58 proteins were confirmed in...

  18. Meta-analysis of several gene lists for distinct types of cancer: A simple way to reveal common prognostic markers

    OpenAIRE

    Sun Xiao; Yang Xinan

    2007-01-01

    Abstract Background Although prognostic biomarkers specific for particular cancers have been discovered, microarray analysis of gene expression profiles, supported by integrative analysis algorithms, helps to identify common factors in molecular oncology. Similarities of Ordered Gene Lists (SOGL) is a recently proposed approach to meta-analysis suitable for identifying features shared by two data sets. Here we extend the idea of SOGL to the detection of significant prognostic marker genes fro...

  19. Cationic Antimicrobial Peptides Derived from Crocodylus siamensis Leukocyte Extract, Revealing Anticancer Activity and Apoptotic Induction on Human Cervical Cancer Cells.

    Science.gov (United States)

    Theansungnoen, Tinnakorn; Maijaroen, Surachai; Jangpromma, Nisachon; Yaraksa, Nualyai; Daduang, Sakda; Temsiripong, Theeranan; Daduang, Jureerut; Klaynongsruang, Sompong

    2016-06-01

    Known antimicrobial peptides KT2 and RT2 as well as the novel RP9 derived from the leukocyte extract of the freshwater crocodile (Crocodylus siamensis) were used to evaluate the ability in killing human cervical cancer cells. RP9 in the extract was purified by a combination of anion exchange column and reversed-phase HPLC, and its sequence was analyzed by mass spectrometry. The novel peptide could inhibit Gram-negative Vibrio cholerae (clinical isolation) and Gram-positive Bacillus pumilus TISTR 905, and its MIC values were 61.2 µM. From scanning electron microscopy, the peptide was seen to affect bacterial surfaces directly. KT2 and RT2, which are designed antimicrobial peptides using the C. siamensis Leucrocin I template, as well as RP9 were chemically synthesized for investigation of anticancer activity. By Sulforhodamine B colorimetric assay, these antimicrobial peptides could inhibit both HeLa and CaSki cancer cell lines. The IC50 values of KT2 and RT2 for HeLa and CaSki cells showed 28.7-53.4 and 17.3-30.8 µM, while those of RP9 were 126.2 and 168.3 µM, respectively. Additionally, the best candidate peptides KT2 and RT2 were used to determine the apoptotic induction on cancer cells by human apoptosis array assay. As a result, KT2 and RT2 were observed to induce apoptotic cell death in HeLa cells. Therefore, these results indicate that KT2 and RT2 with antimicrobial activity have a highly potent ability to kill human cervical cancer cells. PMID:27129462

  20. CGCI Investigators Reveal Comprehensive Landscape of Diffuse Large B-Cell Lymphoma (DLBCL) Genomes | Office of Cancer Genomics

    Science.gov (United States)

    Researchers from British Columbia Cancer Agency used whole genome sequencing to analyze 40 DLBCL cases and 13 cell lines in order to fill in the gaps of the complex landscape of DLBCL genomes. Their analysis, “Mutational and structural analysis of diffuse large B-cell lymphoma using whole genome sequencing,” was published online in Blood on May 22. The authors are Ryan Morin, Marco Marra, and colleagues.  

  1. Plasma Proteomic Profiling in Hereditary Breast Cancer Reveals a BRCA1-Specific Signature: Diagnostic and Functional Implications.

    Directory of Open Access Journals (Sweden)

    Domenica Scumaci

    Full Text Available Breast cancer (BC is a leading cause of death among women. Among the major risk factors, an important role is played by familial history of BC. Germ-line mutations in BRCA1/2 genes account for most of the hereditary breast and/or ovarian cancers. Gene expression profiling studies have disclosed specific molecular signatures for BRCA1/2-related breast tumors as compared to sporadic cases, which might help diagnosis and clinical follow-up. Even though, a clear hallmark of BRCA1/2-positive BC is still lacking. Many diseases are correlated with quantitative changes of proteins in body fluids. Plasma potentially carries important information whose knowledge could help to improve early disease detection, prognosis, and response to therapeutic treatments. The aim of this study was to develop a comprehensive approach finalized to improve the recovery of specific biomarkers from plasma samples of subjects affected by hereditary BC.To perform this analysis, we used samples from patients belonging to highly homogeneous population previously reported. Depletion of high abundant plasma proteins, 2D gel analysis, liquid chromatography-tandem mass spectrometry (LC-MS/MS and bioinformatics analysis were used into an integrated approach to investigate tumor-specific changes in the plasma proteome of BC patients and healthy family members sharing the same BRCA1 gene founder mutation (5083del19, previously reported by our group, with the aim to identify specific signatures.The comparative analysis of the experimental results led to the identification of gelsolin as the most promising biomarker.Further analyses, performed using a panel of breast cancer cell lines, allowed us to further elucidate the signaling network that might modulate the expression of gelsolin in breast cancer.

  2. Comparative Proteomics of Ovarian Cancer Aggregate Formation Reveals an Increased Expression of Calcium-activated Chloride Channel Regulator 1 (CLCA1).

    Science.gov (United States)

    Musrap, Natasha; Tuccitto, Alessandra; Karagiannis, George S; Saraon, Punit; Batruch, Ihor; Diamandis, Eleftherios P

    2015-07-10

    Ovarian cancer is a lethal gynecological disease that is characterized by peritoneal metastasis and increased resistance to conventional chemotherapies. This increased resistance and the ability to spread is often attributed to the formation of multicellular aggregates or spheroids in the peritoneal cavity, which seed abdominal surfaces and organs. Given that the presence of metastatic implants is a predictor of poor survival, a better understanding of how spheroids form is critical to improving patient outcome, and may result in the identification of novel therapeutic targets. Thus, we attempted to gain insight into the proteomic changes that occur during anchorage-independent cancer cell aggregation. As such, an ovarian cancer cell line, OV-90, was cultured in adherent and non-adherent conditions using stable isotope labeling with amino acids in cell culture (SILAC). Anchorage-dependent cells (OV-90AD) were grown in tissue culture flasks, whereas anchorage-independent cells (OV-90AI) were grown in suspension using the hanging-drop method. Cellular proteins from both conditions were then identified using LC-MS/MS, which resulted in the quantification of 1533 proteins. Of these, 13 and 6 proteins were up-regulated and down-regulated, respectively, in aggregate-forming cells compared with cells grown as monolayers. Relative gene expression and protein expression of candidates were examined in other cell line models of aggregate formation (TOV-112D and ES-2), which revealed an increased expression of calcium-activated chloride channel regulator 1 (CLCA1). Moreover, inhibitor and siRNA transfection studies demonstrated an apparent effect of CLCA1 on cancer cell aggregation. Further elucidation of the role of CLCA1 in the pathogenesis of ovarian cancer is warranted. PMID:26004777

  3. Importance of revealing a rare case of breast cancer in a female to male transsexual after bilateral mastectomy

    Science.gov (United States)

    2012-01-01

    The incidence of breast carcinoma following prophylactic mastectomy is probably less than 2%. We present a 43-year-old female to male transsexual who developed breast cancer 1 year after bilateral nipple- sparing subcutaneous mastectomy as part of female to male gender reassignment surgery. In addition to gender reassignment surgery, total abdominal hysterectomy with bilateral salpingo-oophorectomy (to avoid the patient from entering menopause and to eliminate any subsequent risk of iatrogenic endometrial carcinoma), colpocleisys, metoidioplasty, phalloplasty, urethroplasty together with scrotoplasty/placement of testicular prosthesis and perineoplasty were also performed. Before the sex change surgery, the following diagnostic procedures were performed: breast ultrasound and mammography (which were normal), lung radiography (also normal) together with abdominal ultrasound examination, biochemical analysis of the blood and hormonal status. According to medical literature, in the last 50 years only three papers have been published with four cases of breast cancer in transsexual female to male patients. All hormonal pathways included in this complex hormonal and surgical procedure of transgender surgery have important implications for women undergoing prophylactic mastectomy because of a high risk of possible breast cancer. PMID:23273269

  4. Importance of revealing a rare case of breast cancer in a female to male transsexual after bilateral mastectomy

    Directory of Open Access Journals (Sweden)

    Nikolic Dejan V

    2012-12-01

    Full Text Available Abstract The incidence of breast carcinoma following prophylactic mastectomy is probably less than 2%. We present a 43-year-old female to male transsexual who developed breast cancer 1 year after bilateral nipple- sparing subcutaneous mastectomy as part of female to male gender reassignment surgery. In addition to gender reassignment surgery, total abdominal hysterectomy with bilateral salpingo-oophorectomy (to avoid the patient from entering menopause and to eliminate any subsequent risk of iatrogenic endometrial carcinoma, colpocleisys, metoidioplasty, phalloplasty, urethroplasty together with scrotoplasty/placement of testicular prosthesis and perineoplasty were also performed. Before the sex change surgery, the following diagnostic procedures were performed: breast ultrasound and mammography (which were normal, lung radiography (also normal together with abdominal ultrasound examination, biochemical analysis of the blood and hormonal status. According to medical literature, in the last 50 years only three papers have been published with four cases of breast cancer in transsexual female to male patients. All hormonal pathways included in this complex hormonal and surgical procedure of transgender surgery have important implications for women undergoing prophylactic mastectomy because of a high risk of possible breast cancer.

  5. Agricultural Fragility Estimates Subjected to Volcanic Ash Fall Hazards

    Science.gov (United States)

    Ham, H. J.; Lee, S.; Choi, S. H.; Yun, W. S.

    2015-12-01

    Agricultural Fragility Estimates Subjected to Volcanic Ash Fall Hazards Hee Jung Ham1, Seung-Hun Choi1, Woo-Seok Yun1, Sungsu Lee2 1Department of Architectural Engineering, Kangwon National University, Korea 2Division of Civil Engineering, Chungbuk National University, Korea ABSTRACT In this study, fragility functions are developed to estimate expected volcanic ash damages of the agricultural sector in Korea. The fragility functions are derived from two approaches: 1) empirical approach based on field observations of impacts to agriculture from the 2006 eruption of Merapi volcano in Indonesia and 2) the FOSM (first-order second-moment) analytical approach based on distribution and thickness of volcanic ash observed from the 1980 eruption of Mt. Saint Helens and agricultural facility specifications in Korea. Fragility function to each agricultural commodity class is presented by a cumulative distribution function of the generalized extreme value distribution. Different functions are developed to estimate production losses from outdoor and greenhouse farming. Seasonal climate influences vulnerability of each agricultural crop and is found to be a crucial component in determining fragility of agricultural commodities to an ash fall. In the study, the seasonality coefficient is established as a multiplier of fragility function to consider the seasonal vulnerability. Yields of the different agricultural commodities are obtained from Korean Statistical Information Service to create a baseline for future agricultural volcanic loss estimation. Numerically simulated examples of scenario ash fall events at Mt. Baekdu volcano are utilized to illustrate the application of the developed fragility functions. Acknowledgements This research was supported by a grant 'Development of Advanced Volcanic Disaster Response System considering Potential Volcanic Risk around Korea' [MPSS-NH-2015-81] from the Natural Hazard Mitigation Research Group, Ministry of Public Safety and Security of

  6. Integrated Proteomic and Glycoproteomic Analyses of Prostate Cancer Cells Reveal Glycoprotein Alteration in Protein Abundance and Glycosylation.

    Science.gov (United States)

    Shah, Punit; Wang, Xiangchun; Yang, Weiming; Toghi Eshghi, Shadi; Sun, Shisheng; Hoti, Naseruddin; Chen, Lijun; Yang, Shuang; Pasay, Jered; Rubin, Abby; Zhang, Hui

    2015-10-01

    Prostate cancer is the most common cancer among men in the U.S. and worldwide, and androgen-deprivation therapy remains the principal treatment for patients. Although a majority of patients initially respond to androgen-deprivation therapy, most will eventually develop castration resistance. An increased understanding of the mechanisms that underline the pathogenesis of castration resistance is therefore needed to develop novel therapeutics. LNCaP and PC3 prostate cancer cell lines are models for androgen-dependence and androgen-independence, respectively. Herein, we report the comparative analysis of these two prostate cancer cell lines using integrated global proteomics and glycoproteomics. Global proteome profiling of the cell lines using isobaric tags for relative and absolute quantitation (iTRAQ) labeling and two- dimensional (2D) liquid chromatography-tandem MS (LC-MS/MS) led to the quantification of 8063 proteins. To analyze the glycoproteins, glycosite-containing peptides were isolated from the same iTRAQ-labeled peptides from the cell lines using solid phase extraction followed by LC-MS/MS analysis. Among the 1810 unique N-linked glycosite-containing peptides from 653 identified N-glycoproteins, 176 glycoproteins were observed to be different between the two cell lines. A majority of the altered glycoproteins were also observed with changes in their global protein expression levels. However, alterations in 21 differentially expressed glycoproteins showed no change at the protein abundance level, indicating that the glycosylation site occupancy was different between the two cell lines. To determine the glycosylation heterogeneity at specific glycosylation sites, we further identified and quantified 1145 N-linked glycopeptides with attached glycans in the same iTRAQ-labeled samples. These intact glycopeptides contained 67 glycan compositions and showed increased fucosylation in PC3 cells in several of the examined glycosylation sites. The increase in

  7. Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1

    DEFF Research Database (Denmark)

    Glubb, Dylan M; Maranian, Mel J; Michailidou, Kyriaki;

    2015-01-01

    Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals an...

  8. Clinical assessment tools identify functional deficits in fragility fracture patients

    Directory of Open Access Journals (Sweden)

    Ames TD

    2016-05-01

    Full Text Available Tyler D Ames,1 Corinne E Wee,1 Khoi M Le,1 Tiffany L Wang,1 Julie Y Bishop,2 Laura S Phieffer,2 Carmen E Quatman2 1The Ohio State University College of Medicine, 2Department of Orthopaedics, The Ohio State University Wexner Medical Center, Columbus, OH, USA Purpose: To identify inexpensive, noninvasive, portable, clinical assessment tools that can be used to assess functional performance measures that may put older patients at risk for falls such as balance, handgrip strength, and lumbopelvic control.Patients and methods: Twenty fragility fracture patients and 21 healthy control subjects were evaluated using clinical assessment tools (Nintendo Wii Balance Board [WBB], a handheld dynamometer, and an application for the Apple iPod Touch, the Level Belt that measure functional performance during activity of daily living tasks. The main outcome measurements were balance (WBB, handgrip strength (handheld dynamometer, and lumbopelvic control (iPod Touch Level Belt, which were compared between fragility fracture patients and healthy controls.Results: Fragility fracture patients had lower scores on the vertical component of the WBB Torso Twist task (P=0.042 and greater medial–lateral lumbopelvic sway during a 40 m walk (P=0.026 when compared to healthy controls. Unexpectedly, the fracture patients had significantly higher scores on the left leg (P=0.020 and total components (P=0.010 of the WBB Single Leg Stand task as well as less faults during the left Single Leg Stand task (P=0.003.Conclusion: The clinical assessment tools utilized in this study are relatively inexpensive and portable tools of performance measures capable of detecting differences in postural sway between fragility fracture patients and controls. Keywords: fall risk, geriatric fracture, Nintendo Wii Balance Board, Level Belt, fragility fracture

  9. Structural Studies of the Tandem Tudor Domains of Fragile X Mental Retardation Related Proteins FXR1 and FXR2

    Energy Technology Data Exchange (ETDEWEB)

    Adams-Cioaba, Melanie A.; Guo, Yahong; Bian, ChuanBing; Amaya, Maria F.; Lam, Robert; Wasney, Gregory A.; Vedadi, Masoud; Xu, Chao; Min, Jinrong (Toronto)

    2011-11-23

    Expansion of the CGG trinucleotide repeat in the 5'-untranslated region of the FMR1, fragile X mental retardation 1, gene results in suppression of protein expression for this gene and is the underlying cause of Fragile X syndrome. In unaffected individuals, the FMRP protein, together with two additional paralogues (Fragile X Mental Retardation Syndrome-related Protein 1 and 2), associates with mRNA to form a ribonucleoprotein complex in the nucleus that is transported to dendrites and spines of neuronal cells. It is thought that the fragile X family of proteins contributes to the regulation of protein synthesis at sites where mRNAs are locally translated in response to stimuli. Here, we report the X-ray crystal structures of the non-canonical nuclear localization signals of the FXR1 and FXR2 autosomal paralogues of FMRP, which were determined at 2.50 and 1.92 {angstrom}, respectively. The nuclear localization signals of the FXR1 and FXR2 comprise tandem Tudor domain architectures, closely resembling that of UHRF1, which is proposed to bind methylated histone H3K9. The FMRP, FXR1 and FXR2 proteins comprise a small family of highly conserved proteins that appear to be important in translational regulation, particularly in neuronal cells. The crystal structures of the N-terminal tandem Tudor domains of FXR1 and FXR2 revealed a conserved architecture with that of FMRP. Biochemical analysis of the tandem Tudor doamins reveals their ability to preferentially recognize trimethylated peptides in a sequence-specific manner.

  10. The RBBP6/ZBTB38/MCM10 Axis Regulates DNA Replication and Common Fragile Site Stability

    Directory of Open Access Journals (Sweden)

    Benoit Miotto

    2014-04-01

    Full Text Available Faithful DNA replication is essential for the maintenance of genome integrity. Incomplete genome replication leads to DNA breaks and chromosomal rearrangements, which are causal factors in cancer and other human diseases. Despite their importance, the molecular mechanisms that control human genome stability are incompletely understood. Here, we report a pathway that is required for human genome replication and stability. This pathway has three components: an E3 ubiquitin ligase, a transcriptional repressor, and a replication protein. The E3 ubiquitin ligase RBBP6 ubiquitinates and destabilizes the transcriptional repressor ZBTB38. This repressor negatively regulates transcription and levels of the MCM10 replication factor on chromatin. Cells lacking RBBP6 experience reduced replication fork progression and increased damage at common fragile sites due to ZBTB38 accumulation and MCM10 downregulation. Our results uncover a pathway that ensures genome-wide DNA replication and chromosomal stability.

  11. Integrating analysis reveals microRNA-mediated pathway crosstalk among Crohn's disease, ulcerative colitis and colorectal cancer.

    Science.gov (United States)

    Bai, Jing; Li, Yongsheng; Shao, Tingting; Zhao, Zheng; Wang, Yuan; Wu, Aiwei; Chen, Hong; Li, Shengli; Jiang, Chunjie; Xu, Juan; Li, Xia

    2014-07-29

    Inflammatory bowel disease (IBD), which can increase the risk of colorectal cancer (CRC), includes two primary subtypes, ulcerative colitis (UC) and Crohn's disease (CD). Although several individual genes involved in inflammation or cancer characterization have been identified, it is still difficult to elucidate functional relationship details between the molecules underlying pathogenesis at the system level. The global effect of miRNAs on genes or their involved functions is also poorly understood. We first integrated genome-wide gene expression profiles and biological pathway information to explore the underlying associations among UC, CD and CRC at the function and gene level. After identifying the pathways regulated by miRNAs, a global map of miRNA-mediated pathway crosstalk shared by the three diseases was further constructed to vertically explain the links of three level alterations. The three types of diseases have close associations with each other at the levels of function, gene and miRNA regulation. Several key biological pathways are involved in the three diseases, related to the immune system and inflammation, metabolism, or cell proliferation and apoptosis etc. Moreover, miRNAs exhibit dominant effects on multiple pathways. It is worth noting that UC shows relatively close associations with CD and CRC at the three levels. Finally, the miRNAs could mediate the crosstalk within or between pathways. For example, hsa-miR-125b, hsa-miR-335 and hsa-miR-155 mediated the crosstalk between three metabolic pathways. The crosstalk within the Toll-like receptor signaling pathway could be mediated by hsa-miR-124, hsa-miR-146a and hsa-mir-221/222. Our results make sense for the prevention and treatment of intestinal-related chronic inflammation or cancer. PMID:24949825

  12. A high-resolution transcriptome map of cell cycle reveals novel connections between periodic genes and cancer.

    Science.gov (United States)

    Dominguez, Daniel; Tsai, Yi-Hsuan; Gomez, Nicholas; Jha, Deepak Kumar; Davis, Ian; Wang, Zefeng

    2016-08-01

    Progression through the cell cycle is largely dependent on waves of periodic gene expression, and the regulatory networks for these transcriptome dynamics have emerged as critical points of vulnerability in various aspects of tumor biology. Through RNA-sequencing of human cells during two continuous cell cycles (>2.3 billion paired reads), we identified over 1 000 mRNAs, non-coding RNAs and pseudogenes with periodic expression. Periodic transcripts are enriched in functions related to DNA metabolism, mitosis, and DNA damage response, indicating these genes likely represent putative cell cycle regulators. Using our set of periodic genes, we developed a new approach termed "mitotic trait" that can classify primary tumors and normal tissues by their transcriptome similarity to different cell cycle stages. By analyzing >4 000 tumor samples in The Cancer Genome Atlas (TCGA) and other expression data sets, we found that mitotic trait significantly correlates with genetic alterations, tumor subtype and, notably, patient survival. We further defined a core set of 67 genes with robust periodic expression in multiple cell types. Proteins encoded by these genes function as major hubs of protein-protein interaction and are mostly required for cell cycle progression. The core genes also have unique chromatin features including increased levels of CTCF/RAD21 binding and H3K36me3. Loss of these features in uterine and kidney cancers is associated with altered expression of the core 67 genes. Our study suggests new chromatin-associated mechanisms for periodic gene regulation and offers a predictor of cancer patient outcomes. PMID:27364684

  13. Fragile X mental retardation protein stimulates ribonucleoprotein assembly of influenza A virus

    Science.gov (United States)

    Zhou, Zhuo; Cao, Mengmeng; Guo, Yang; Zhao, Lili; Wang, Jingfeng; Jia, Xue; Li, Jianguo; Wang, Conghui; Gabriel, Gülsah; Xue, Qinghua; Yi, Yonghong; Cui, Sheng; Jin, Qi; Wang, Jianwei; Deng, Tao

    2014-02-01

    The ribonucleoprotein (RNP) of the influenza A virus is responsible for the transcription and replication of viral RNA in the nucleus. These processes require interplay between host factors and RNP components. Here, we report that the Fragile X mental retardation protein (FMRP) targets influenza virus RNA synthesis machinery and facilitates virus replication both in cell culture and in mice. We demonstrate that FMRP transiently associates with viral RNP and stimulates viral RNP assembly through RNA-mediated interaction with the nucleoprotein. Furthermore, the KH2 domain of FMRP mediates its association with the nucleoprotein. A point mutation (I304N) in the KH2 domain, identified from a Fragile X syndrome patient, disrupts the FMRP-nucleoprotein association and abolishes the ability of FMRP to participate in viral RNP assembly. We conclude that FMRP is a critical host factor used by influenza viruses to facilitate viral RNP assembly. Our observation reveals a mechanism of influenza virus RNA synthesis and provides insights into FMRP functions.

  14. Fragile imperceptible digital watermark with privacy control

    Science.gov (United States)

    Coppersmith, Don; Mintzer, Frederick C.; Tresser, Charles P.; Wu, Chai W.; Yeung, Minerva M.

    1999-04-01

    We propose a watermarking scheme which allows the watermarked image to be authenticated by an authentication agent without revealing to the authentication agent the human-readable content of the image by combining privacy control with watermarking and authentication mechanisms. This watermarking scheme has universal applicability to data sets such as image, video and audio bit streams. The watermark can be made to be imperceptible to humans. Usage of public key cryptography allows the authentication agent to authenticate without the capabilities to watermark an image.

  15. Characterization of global microRNA expression reveals oncogenic potential of miR-145 in metastatic colorectal cancer

    International Nuclear Information System (INIS)

    MicroRNAs (MiRNAs) are short non-coding RNAs that control protein expression through various mechanisms. Their altered expression has been shown to be associated with various cancers. The aim of this study was to profile miRNA expression in colorectal cancer (CRC) and to analyze the function of specific miRNAs in CRC cells. MirVana miRNA Bioarrays were used to determine the miRNA expression profile in eight CRC cell line models, 45 human CRC samples of different stages, and four matched normal colon tissue samples. SW620 CRC cells were stably transduced with miR-143 or miR-145 expression vectors and analyzed in vitro for cell proliferation, cell differentiation and anchorage-independent growth. Signalling pathways associated with differentially expressed miRNAs were identified using a gene set enrichment analysis. The expression analysis of clinical CRC samples identified 37 miRNAs that were differentially expressed between CRC and normal tissue. Furthermore, several of these miRNAs were associated with CRC tumor progression including loss of miR-133a and gain of miR-224. We identified 11 common miRNAs that were differentially expressed between normal colon and CRC in both the cell line models and clinical samples. In vitro functional studies indicated that miR-143 and miR-145 appear to function in opposing manners to either inhibit or augment cell proliferation in a metastatic CRC model. The pathways targeted by miR-143 and miR-145 showed no significant overlap. Furthermore, gene expression analysis of metastatic versus non-metastatic isogenic cell lines indicated that miR-145 targets involved in cell cycle and neuregulin pathways were significantly down-regulated in the metastatic context. MiRNAs showing altered expression at different stages of CRC could be targets for CRC therapies and be further developed as potential diagnostic and prognostic analytes. The identified biological processes and signalling pathways collectively targeted by co-expressed miRNAs in

  16. Meta-analysis of human cancer microarrays reveals GATA3 is integral to the estrogen receptor alpha pathway

    Directory of Open Access Journals (Sweden)

    Giguère Vincent

    2008-06-01

    Full Text Available Abstract Background The transcription factor GATA3 has recently been shown to be necessary for mammary gland morphogenesis and luminal cell differentiation. There is also an increasing body of data linking GATA3 to the estrogen receptor α (ERα pathway. Among these it was shown that GATA3 associates with the promoter of the ERα gene and ERα can reciprocally associate with the GATA3 gene. GATA3 has also been directly implicated in a differentiated phenotype in mouse models of mammary tumourigenesis. The purpose of our study was to compare coexpressed genes, by meta-analysis, of GATA3 and relate these to a similar analysis for ERα to determine the depth of overlap. Results We have used a newly described method of meta-analysis of multiple cancer studies within the Oncomine database, focusing here predominantly upon breast cancer studies. We demonstrate that ERα and GATA3 reciprocally have the highest overlap with one another. Furthermore, we show that when both coexpression meta-analysis lists for ERα and GATA3 are compared there is a significant overlap between both and, like ERα, GATA3 coexpresses with ERα pathway partners such as pS2 (TFF1, TFF3, FOXA1, BCL2, ERBB4, XBP1, NRIP1, IL6ST, keratin 18(KRT18 and cyclin D1 (CCND1. Moreover, as these data are derived from human tumour samples this adds credence to previous cell-culture or murine based studies. Conclusion GATA3 is hypothesized to be integral to the ERα pathway given the following: (1 The large overlap of coexpressed genes as seen by meta-analysis, between GATA3 and ERα, (2 The highest coexpressing gene for GATA3 was ERα and vice-versa, (3 GATA3, like ERα, coexpresses with many well-known ERα pathway partners such as pS2.

  17. Prevalence of Sarcopenia and Its Relationship with Sites of Fragility Fractures in Elderly Chinese Men and Women.

    Directory of Open Access Journals (Sweden)

    Wei Hong

    Full Text Available Sarcopenia might be associated with bone fragility in elderly individuals. This study aimed to investigate the prevalence of sarcopenia and its association with fragility fracture sites in elderly Chinese patients.Patients (322 men and 435 women aged 65-94 years and with a history of fragility fractures in the ankle, wrist, vertebrae or hip, and healthy men (n = 1263 and women (n = 1057 aged 65-92 years without a history of fractures were enrolled. Whole-body dual energy X-ray absorptiometry was used to analyze skeletal muscle mass index (SMI, fat mass and bone mineral density. Sarcopenia was defined as SMI less than two standard deviations below the mean of a young reference group.Sarcopenia occurrence varied with fracture location. Sarcopenia was more common in females with vertebral and hip fractures and in men with hip and ankle fractures than in the non-fracture group. Sarcopenia was significantly more prevalent in men with wrist, hip and ankle fractures than in women. SMI was correlated with BMD in different fracture groups. Logistic regression analyses revealed that lower SMI was associated with an increased risk of hip fracture both in men and women and ankle fracture in men.Sarcopenia may be an independent risk factor for hip and ankle fractures in men, and for hip fractures in women.

  18. Fragility: The Next Wave in Critical Infrastructure Protection

    Directory of Open Access Journals (Sweden)

    Allan McDougall

    2009-01-01

    Full Text Available In North America today, we are about to embark on a significant effort to repair, or even upgrade, many aspects of our infrastructure. Many of these efforts are linked to economic recovery packages. Others are based on sheer need. The challenge for decision makers and planners involves ensuring that scarce economic resources are put to their best use. Understanding the concept of fragility plays a pivotal part in reaching that understanding.Fragility, like many other systems—particularly Information Technology (IT systems—works on the concept of subjects and objects. Subjects are those entities that seek to exploit the services (or capacity offered by the object. Objects, on the other hand, are those entities that deliver some good or service to the overall system. Of course, something may act as the object in one pairing and the subject in another pairing—they are not exclusive in nature.

  19. Fragility and structure of Al-Cu alloy melts

    Energy Technology Data Exchange (ETDEWEB)

    Lv Xiaoqian [Key Laboratory of Liquid Structure and Heredity of Material, Education Ministry of China, Shandong University, Jingshi Road 73, Jinan 250061 (China); Bian Xiufang [Key Laboratory of Liquid Structure and Heredity of Material, Education Ministry of China, Shandong University, Jingshi Road 73, Jinan 250061 (China)]. E-mail: xfbian@sdu.edu.cn; Mao Tan [Key Laboratory of Liquid Structure and Heredity of Material, Education Ministry of China, Shandong University, Jingshi Road 73, Jinan 250061 (China); Li Zhenkuan [Key Laboratory of Liquid Structure and Heredity of Material, Education Ministry of China, Shandong University, Jingshi Road 73, Jinan 250061 (China); Guo Jing [Key Laboratory of Liquid Structure and Heredity of Material, Education Ministry of China, Shandong University, Jingshi Road 73, Jinan 250061 (China); Zhao Yan [Key Laboratory of Liquid Structure and Heredity of Material, Education Ministry of China, Shandong University, Jingshi Road 73, Jinan 250061 (China)

    2007-04-15

    The dynamic viscosity measurements are performed for Al-Cu alloy melts with different compositions using an oscillating-cup viscometer. The results show that the viscosities of Al-Cu alloy melts increase with the copper content increasing, and also have a correlation with the correlation radius of clusters, which is measured by the high-temperature X-ray diffractometer. It has also been found that the fragilities of superheated melts (M) of hypereutectic Al-Cu alloys increase with the copper content increasing. There exists a relationship between the fragility and the structure in Al-Cu alloy melts. The value of the M reflects the variation of activation energy for viscous flow.

  20. Parenting young children with and without Fragile X syndrome.

    Science.gov (United States)

    Sterling, Audra; Barnum, Leah; Skinner, Debra; Warren, Steven F; Fleming, Kandace

    2012-05-01

    The purpose of this study was to examine maternal parenting styles across age-matched siblings using a within-family design, in which one child has Fragile X syndrome. Thirteen families participated; children were aged 16 to 71 months. Mothers completed several videotaped activities with each child separately as well as an interview. Mothers used a consistent, responsive style with both children, using the same degree of positive affect and warmth. Differences included using more behavior management strategies with the child with Fragile X and a conversational style of interaction with the sibling. Differences in approaches suggest the mothers adapted to the developmental differences between the children. The interview data supported these findings; mothers were aware of the changes made to accommodate the developmental differences. PMID:22716262

  1. Molecular analysis of fragile X syndrome in Antalya Province

    OpenAIRE

    Bilgen T; Keser I; Mihci E; Haspolat S; Tacoy S; Luleci G

    2005-01-01

    Background: Detection of the (CGG)n repeats in the FMR1 gene that cause the fragile X syndrome (FXS), has become a milestone for phenotype-genotype correlation in FXS. Aims: To screen the FMR1 gene CGG repeats in index cases with FXS and their family members in the Antalya Province. Setting and design: This study was prospectively conducted between January 200and March 2005 in Department of Medical Biology and Genetics, Faculty of Medicine, Akdeniz University, Antalya. Materials and Method...

  2. Matrix Metalloproteinases and Minocycline: Therapeutic Avenues for Fragile X Syndrome

    OpenAIRE

    Siller, Saul S.; Kendal Broadie

    2012-01-01

    Fragile X syndrome (FXS) is the most common known genetic form of intellectual disability and autism spectrum disorders. FXS patients suffer a broad range of other neurological symptoms, including hyperactivity, disrupted circadian activity cycles, obsessive-compulsive behavior, and childhood seizures. The high incidence and devastating effects of this disease state make finding effective pharmacological treatments imperative. Recently, reports in both mouse and Drosophila FXS disease models ...

  3. The quest for targeted therapy in fragile X syndrome

    OpenAIRE

    Zeidler, S.; Hukema, Renate; Willemsen, Rob

    2015-01-01

    textabstractFragile X syndrome (FXS) is the most common, monogenetic cause of intellectual disability and autism-spectrum disorders. Although there is no effective therapy, greater understanding of disturbed neuronal pathways has introduced options for targeted therapy. But whereas many FXS phenotypes were improved in preclinical studies with drugs targeting these pathways in the FXS mouse model, attempts to translate these animal-model success stories into treatment of patients in clinical t...

  4. Extreme genetic fragility of the HIV-1 capsid

    OpenAIRE

    Rihn, S.J.; Wilson, S. J.; Loman, N. J.; Alim, M.; Bakker, S.E.; Bhella, D.; Gifford, R.J.; Rixon, F J; Bieniasz, P D

    2013-01-01

    Genetic robustness, or fragility, is defined as the ability, or lack thereof, of a biological entity to maintain function in the face of mutations. Viruses that replicate via RNA intermediates exhibit high mutation rates, and robustness should be particularly advantageous to them. The capsid (CA) domain of the HIV-1 Gag protein is under strong pressure to conserve functional roles in viral assembly, maturation, uncoating, and nuclear import. However, CA is also under strong immunological pres...

  5. Characterization of ultrasonic vocalizations of Fragile X mice.

    Science.gov (United States)

    Belagodu, Amogh P; Johnson, Aaron M; Galvez, Roberto

    2016-09-01

    Fragile X Syndrome (FXS) is the leading form of inherited intellectual disability. It is caused by the transcriptional silencing of FMR1, the gene which codes for the Fragile X Mental Retardation Protein (FMRP). Patients who have FXS exhibit numerous behavioral and cognitive impairments, such as attention-deficit/hyperactivity disorder, obsessive compulsive disorder, and autistic-like behaviors. In addition to these behavioral abnormalities, FXS patients have also been shown to exhibit various deficits in communication such as abnormal sentence structures, increased utterances, repetition of sounds and words, and reduced articulation. These deficits can dramatically hinder communication for FXS patients, exacerbating learning and cognition impairments while decreasing their quality of life. To examine the biological underpinnings of these communication abnormalities, studies have used a mouse model of the Fragile X Syndrome; however, these vocalization studies have resulted in inconsistent findings that often do not correlate with abnormalities observed in FXS patients. Interestingly, a detailed examination of frequency modulated vocalizations that are believed to be a better assessment of rodent communication has never been conducted. The following study used courtship separation to conduct a detailed examination of frequency modulated ultrasonic vocalizations (USV) in FXS mice. Our analyses of frequency modulated USVs demonstrated that adult FXS mice exhibited longer phrases and more motifs. Phrases are vocalizations consisting of multiple frequency modulated ultrasonic vocalizations, while motifs are repeated frequency modulated USV patterns. Fragile X mice had a higher proportion of "u" syllables in all USVs and phrases while their wildtype counterparts preferred isolated "h" syllables. Although the specific importance of these syllables towards communication deficits still needs to be evaluated, these findings in production of USVs are consistent with the

  6. Financial Reforms and Financial Fragility: A Panel Data Analysis

    OpenAIRE

    Syed Faizan Iftikhar

    2015-01-01

    This paper explores the relationship between financial reforms, financial liberalization and the quality of banking regulation and supervision for financial fragility by applying a dynamic two-step system generalized method of moments GMM panel estimator technique. The finding of this study is that the financial vulnerability of the banking sector could be affected, not only by bank-specific and macro-specific variables; but also by financial liberalization and banking regulations and supervi...

  7. Systematic review of pharmacological treatments in fragile X syndrome

    OpenAIRE

    Tejada Maria-Isabel; Ballesteros Javier; Rueda Jose-Ramon

    2009-01-01

    Abstract Background Fragile X syndrome (FXS) is considered the most common cause of inherited mental retardation. Affected people have mental impairment that can include Attention Deficit and/or Hyperactivity Disorder (ADHD), autism disorder, and speech and behavioural disorders. Several pharmacological interventions have been proposed to treat those impairments. Methods Systematic review of the literature and summary of the evidence from clinical controlled trials that compared at least one ...

  8. A Contribution to the Theory of Financial Fragility and Crisis

    OpenAIRE

    Bhaduri, Amit

    2010-01-01

    Three interrelated aspects typical of most financial crisis of domestic origin are brought together in a model in this paper. The first aspect is debt financed consumption boom supported by rising asset prices which ultimately leads to credit crunch and debt deflation as lenders lose confidence in borrowers. This is related to the second aspect tracing gradual evolution towards Ponzi finance. This is accompanied by fragility of the financial sector itself and its insolvency as an inevitable o...

  9. The State of Synapses in Fragile X Syndrome

    OpenAIRE

    Pfeiffer, Brad E.; Huber, Kimberly M.

    2009-01-01

    Fragile X Syndrome is the most common inherited form of mental retardation and a leading genetic cause of autism. There is increasing evidence in both FXS and other forms of autism that alterations in synapse number, structure and function are associated and contribute to these prevalent diseases. FXS is caused by loss of function of the Fmr1 gene which encodes the RNA binding protein, FMRP. Therefore, FXS is a tractable model to understand synaptic dysfunction in cognitive disorders. FMRP is...

  10. On the Effect of State fragility on Corruption

    OpenAIRE

    Asongu, Simplice

    2014-01-01

    The Kodila-Tedika & Bolito-Losembe (2014, ADR) finding on no evidence of causality flowing from State fragility to classical corruption or extreme corruption could have an important influence on academic and policy debates. Using updated data (1996-2010) from 53 African countries, we provide evidence of a positive (negative) nexus between political stability/no violence and corruption-control (corruption). As a policy implication, the finding of the underlying paper maybe more expositional th...

  11. Bone fragility in postmenopausa women: a preliminar study

    OpenAIRE

    Fonseca, E.M.M.; Pereira, Ana I.; Rocha, D.F.S.; Noronha, J.K.

    2012-01-01

    The aim of this work is to identify the prevalence of risks factors for bone fragility in postmenopausal women with hormonal replacement therapy (HRT) within two groups (with bone fracture history and without bone fracture history) and to evaluate the effect of modifiable risk factors on bone mineral density (BMD). The overall prevalence of osteoporosis in postmenopausal Portuguese women is high. A pattern identification of occurrences, in a group of patients submitted to this analysis, will ...

  12. Modeling Fragility in Rapidly Evolving Disaster Response Systems

    OpenAIRE

    Comfort, Louise K.; Ko, Kilkon; Zagorecki, Adam

    2003-01-01

    Assessing the changing dynamic between the demand that is placed upon a community by cumulative exposure to hazards and the capacity of the community to mitigate or respond to that risk represents a central problem in estimating the community's resilience to disaster. This paper presents an initial effort to simulate the dynamic between increasing demand and decreasing capacity in an actual disaster response system to determine the point at which the system fails, or the fragility of the syst...

  13. Decentralized Local Governance In Fragile States: Learning From Iraq

    OpenAIRE

    Brinkerhoff, Derick W.; Johnson, Ronald W.

    2009-01-01

    This article examines the role that local governance plays in creating an effective state and in building constructive state—society relations. Reconstruction efforts in fragile, post-conflict states have focused largely on central government, yet decentralized local authorities offer a number of positive features. Looking at the governance reconstruction experience in Iraq, the analysis explores the extent to which these positive features have characterized Iraqi sub-national government. The...

  14. The Importance of Migration to Small Fragile Economies

    OpenAIRE

    Luthria, Manjula

    2009-01-01

    Most small fragile states have their own unique circumstances that predispose them to social conflict or frequent economic disruptions. These disruptions end up imposing a large cost on regional neighbours and on the international community more broadly. Therefore the development community is in search of ways to reduce the risk of conflict but this search has proved elusive thus far. This paper explores the potential for migration to serve as a safety valve as well as a medium...

  15. On the route to shear jamming, are fragile states real?

    OpenAIRE

    Zhang, Ling; Zheng, Jie; Jie ZHANG

    2015-01-01

    Starting from an unjammed initial state, applying shear to a granular material of a fixed packing fraction below $\\phi_J$, i.e. the isotropic jamming density of frictionless spheres can produce shear jamming states, as have been discovered recently. In addition, it has also been discovered that the system will first experience a bulk fragile state before evolving into a shear jammed state. Due to the existence of friction between the system and the third dimension in the previous studies, it ...

  16. Measuring the business environment for entrepreneurship in fragile states

    OpenAIRE

    Guglielmetti, Chiara

    2010-01-01

    This paper aims towards better understanding the role of entrepreneurship in fragile states, which despite the practical interest and relevance has been somewhat disregarded in academic research. Given the necessity to support policy formulation with appropriate and relevant measurement of entrepreneurship and the business environment, the primary focus in this paper is to scrutinize existing international indicators, in particular the World Bank's Doing Business (DB) indicators and ask wheth...

  17. Parenting Young Children with and without Fragile X Syndrome

    OpenAIRE

    Sterling, Audra M.; Barnum, Leah; Skinner, Debra; Warren, Steven F.; Fleming, Kandace

    2012-01-01

    The purpose of this study was to examine maternal parenting styles across age-matched siblings using a within-family design, in which one child has Fragile X syndrome. Thirteen families participated; children were aged 16 to 71 months. Mothers completed several videotaped activities with each child separately as well as an interview. Mothers used a consistent, responsive style with both children, using the same degree of positive affect and warmth. Differences included using more behavior man...

  18. Highly sensitive proximity mediated immunoassay reveals HER2 status conversion in the circulating tumor cells of metastatic breast cancer patients

    Directory of Open Access Journals (Sweden)

    Kim Phillip

    2011-12-01

    Full Text Available Abstract Background The clinical benefits associated with targeted oncology agents are generally limited to subsets of patients. Even with favorable biomarker profiles, many patients do not respond or acquire resistance. Existing technologies are ineffective for treatment monitoring as they provide only static and limited information and require substantial amounts of tissue. Therefore, there is an urgent need to develop methods that can profile potential therapeutic targets with limited clinical specimens during the course of treatment. Methods We have developed a novel proteomics-based assay, Collaborative Enzyme Enhanced Reactive-immunoassay (CEER that can be used for analyzing clinical samples. CEER utilizes the formation of unique immuno-complex between capture-antibodies and two additional detector-Abs on a microarray surface. One of the detector-Abs is conjugated to glucose oxidase (GO, and the other is conjugated to Horse Radish Peroxidase (HRP. Target detection requires the presence of both detector-Abs because the enzyme channeling event between GO and HRP will not occur unless both Abs are in close proximity. Results CEER was able to detect single-cell level expression and phosphorylation of human epidermal growth factor receptor 2 (HER2 and human epidermal growth factor receptor 1 (HER1 in breast cancer (BCa systems. The shift in phosphorylation profiles of receptor tyrosine kinases (RTKs and other signal transduction proteins upon differential ligand stimulation further demonstrated extreme assay specificity in a multiplexed array format. HER2 analysis by CEER in 227 BCa tissues showed superior accuracy when compared to the outcome from immunohistochemistry (IHC (83% vs. 96%. A significant incidence of HER2 status alteration with recurrent disease was observed via circulating tumor cell (CTC analysis, suggesting an evolving and dynamic disease progression. HER2-positive CTCs were found in 41% (7/17 while CTCs with significant HER2

  19. Determinants of state fragility and implications for aid allocation: An assessment based on the country indicators for foreign policy project

    OpenAIRE

    Carment, David; Prest, Stewart; Samy, Yiagadeesen

    2008-01-01

    This paper is derived from our ongoing research on fragile states funded by the Canadian International Development Agency (CIDA) to help policymakers and analysts make decisions on where and how to allocate aid, especially in fragile state environments. In order for development assistance to have a measurable and positive impact on fragile states, it is necessary to understand both how and why they become fragile. First, we reconceptualize the meaning of state fragility with equal attention g...

  20. Fragility Modeling of Aging Containment Metallic Pressure Boundaries

    International Nuclear Information System (INIS)

    The containment in a nuclear power plant (NPP) provides a barrier against the release of radioactivity in the event of an accident. Corrosion that has been observed in some steel containments and liners of reinforced concrete containments has raised questions about their ability to perform this function. The performance of corroded containments during events at or beyond the design basis is impacted by numerous sources of uncertainty. A fragility model of the containment provides a relatively simple depiction of the impact of uncertainties on structural performance and a basis for decision-making in the presence of uncertainty. Moreover, it is a necessary ingredient of any time-dependent structural reliability analysis. A nonlinear finite element analysis of containment response furnishes the necessary platform to perform numerical experiments to determine containment fragility. A statistically-based sampling plan minimizes the finite element computations required to develop the fragility curve. The -percentile (or other fractile) then gives a statistically based indication of the lower bound on containment capacity, and can be used as a screening tool to determine whether more refined further analysis or tests to support service life evaluations are warranted

  1. Screening and diagnosis for the fragile X syndrome among the mentally retarded: an epidemiological and psychological survey. Collaborative Fragile X Study Group

    NARCIS (Netherlands)

    B.B.A. de Vries (Bert); B.A. Oostra (Ben); M.F. Niermeijer (Martinus); A. Tibben (Arend); A.M.W. van den Ouweland (Ans); S. Mohkamsing; H.J. Duivenvoorden (Hugo); E. Mol; K. Gelsema; M. van Rijn; D.J.J. Halley (Dicky); L.A. Sandkuijl (Lodewijk)

    1997-01-01

    textabstractThe fragile X syndrome is an X-linked mental retardation disorder caused by an expanded CGG repeat in the first exon of the fragile X mental retardation (FMR1) gene. Its frequency, X-linked inheritance, and consequences for relatives all prompt for diagnosis

  2. Do Individuals with Fragile X Syndrome Show Developmental Stuttering or Not? Comment on "Speech Fluency in Fragile X Syndrome" by Van Borsel, Dor and Rondal

    Science.gov (United States)

    Howell, Peter

    2008-01-01

    Van Borsel, Dor, and Rondal (2007) examined the speech of seven boys and two young male adults with fragile X syndrome and considered whether their speech was comparable to that reported in the developmental stuttering literature. They listed five criteria which led them to conclude that the speech patterns of speakers with fragile X syndrome…

  3. Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts

    Directory of Open Access Journals (Sweden)

    Shunqiang Li

    2013-09-01

    Full Text Available To characterize patient-derived xenografts (PDXs for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation.

  4. Delivery-corrected imaging of fluorescently-labeled glucose reveals distinct metabolic phenotypes in murine breast cancer.

    Directory of Open Access Journals (Sweden)

    Amy E Frees

    Full Text Available When monitoring response to cancer therapy, it is important to differentiate changes in glucose tracer uptake caused by altered delivery versus a true metabolic shift. Here, we propose an optical imaging method to quantify glucose uptake and correct for in vivo delivery effects. Glucose uptake was measured using a fluorescent D-glucose derivative 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-ylAmino-2-deoxy-D-glucose (2-NBDG in mice implanted with dorsal skin flap window chambers. Additionally, vascular oxygenation (SO2 was calculated using only endogenous hemoglobin contrast. Results showed that the delivery factor proposed for correction, "RD", reported on red blood cell velocity and injected 2-NBDG dose. Delivery-corrected 2-NBDG uptake (2-NBDG60/RD inversely correlated with blood glucose in normal tissue, indicating sensitivity to glucose demand. We further applied our method in metastatic 4T1 and nonmetastatic 4T07 murine mammary adenocarcinomas. The ratio 2-NBDG60/RD was increased in 4T1 tumors relative to 4T07 tumors yet average SO2 was comparable, suggesting a shift toward a "Warburgian" (aerobic glycolysis metabolism in the metastatic 4T1 line. In heterogeneous regions of both 4T1 and 4T07, 2-NBDG60/RD increased slightly but significantly as vascular oxygenation decreased, indicative of the Pasteur effect in both tumors. These data demonstrate the utility of delivery-corrected 2-NBDG and vascular oxygenation imaging for differentiating metabolic phenotypes in vivo.

  5. Gene Set−Based Integrative Analysis Revealing Two Distinct Functional Regulation Patterns in Four Common Subtypes of Epithelial Ovarian Cancer

    Science.gov (United States)

    Chang, Chia-Ming; Chuang, Chi-Mu; Wang, Mong-Lien; Yang, Yi-Ping; Chuang, Jen-Hua; Yang, Ming-Jie; Yen, Ming-Shyen; Chiou, Shih-Hwa; Chang, Cheng-Chang

    2016-01-01

    Clear cell (CCC), endometrioid (EC), mucinous (MC) and high-grade serous carcinoma (SC) are the four most common subtypes of epithelial ovarian carcinoma (EOC). The widely accepted dualistic model of ovarian carcinogenesis divided EOCs into type I and II categories based on the molecular features. However, this hypothesis has not been experimentally demonstrated. We carried out a gene set-based analysis by integrating the microarray gene expression profiles downloaded from the publicly available databases. These quantified biological functions of EOCs were defined by 1454 Gene Ontology (GO) term and 674 Reactome pathway gene sets. The pathogenesis of the four EOC subtypes was investigated by hierarchical clustering and exploratory factor analysis. The patterns of functional regulation among the four subtypes containing 1316 cases could be accurately classified by machine learning. The results revealed that the ERBB and PI3K-related pathways played important roles in the carcinogenesis of CCC, EC and MC; while deregulation of cell cycle was more predominant in SC. The study revealed that two different functional regulation patterns exist among the four EOC subtypes, which were compatible with the type I and II classifications proposed by the dualistic model of ovarian carcinogenesis. PMID:27527159

  6. Cancer

    Science.gov (United States)

    ... Blood tests (which look for chemicals such as tumor markers) Bone marrow biopsy (for lymphoma or leukemia) Chest ... the case with skin cancers , as well as cancers of the lung, breast, and colon. If the tumor has spread ...

  7. Cancer

    Science.gov (United States)

    Cancer begins in your cells, which are the building blocks of your body. Normally, your body forms ... be benign or malignant. Benign tumors aren't cancer while malignant ones are. Cells from malignant tumors ...

  8. Investigation and treatment of osteoporosis in patients with fragility fractures

    Science.gov (United States)

    Hajcsar, Ernest E.; Hawker, Gillian; Bogoch, Earl R.

    2000-01-01

    Background Many patients who have undiagnosed osteoporosis and a recent fragility fracture present to fracture clinics in Canadian hospitals, where the focus of management is on fracture care. The rate of diagnosis and treatment of osteoporosis in this patient group is unknown. Methods Patients who presented with fractures at sites consistent with fragility-type fractures were identified through a retrospective chart review of fracture clinic visits in 3 Ontario community hospitals in selected weeks in February and November 1996 and August and May 1997. These patients were contacted by mail and telephone follow-up to obtain consent to participate in a telephone interview. Patients were excluded if the index fracture had been traumatic, if they were younger than 18 years, or if they had medical conditions known to be associated with secondary bone loss. Eligible patients were questioned about their history of prior fractures, diagnosis of osteoporosis, and investigation and treatment of osteoporosis before or after the index fracture. Results Among 2694 fracture clinic visits, we identified 228 patients (8.4%) with fragility-type fractures. Of the 228, 128 (56.1%) were contacted and agreed to participate in an interview about 1 year from the date of the index fracture. Of the 128 patients, 108 (83 postmenopausal and 13 premenopausal women and 12 men) were confirmed as eligible. Of the 108, 43 had experienced 53 fractures in addition to the index fracture in the preceding 10 years, of which 71% were of the fragility type. At interview, only 20 (18.5%) (all postmenopausal women) of the 108 patients reported that they had received a diagnosis of osteoporosis. Of the 20, 90% and 45% respectively had been advised to take calcium and vitamin D supplements; 8 (40%) were receiving hormone replacement therapy (HRT), and 8 (40%) were taking bisphosphonates. Of the 88 patients who had not received a diagnosis of osteoporosis, 4 (4.5%) were receiving HRT, none was taking

  9. High resolution mass spectrometry coupled with multivariate data analysis revealing plasma lipidomic alteration in ovarian cancer in Asian women.

    Science.gov (United States)

    Zhang, Yangyang; Liu, Yingying; Li, Lin; Wei, Jinchao; Xiong, Shaoxiang; Zhao, Zhenwen

    2016-04-01

    Ovarian cancer (OC) is the most common cause of death from gynecologic malignancies in women. The identification of reliable diagnostic biomarkers for the early detection of this deadly disease is critical for reducing the mortality rate of OC. Plasma lysophosphatidic acid (LPA) levels were increased from OC patients vs. healthy controls. Therefore, lipidomics may represent an excellent developing prospect for the discovery of diagnostic biomarkers of OC. In this study, a nontargeted lipidomics approach based on ultra performance liquid chromatography-electrospray ionization-QTOF-mass spectrometry (UPLC-ESI-QTOF-MS) combined with multivariate data analysis, including principal component analysis (PCA) and (orthogonal) partial least squared discriminant analysis [(O)PLS-DA] was applied for the investigation of potential diagnostic biomarkers in plasma of OC patients. Patients with OC could be distinguished from healthy individuals and patients with benign gynecological tumor disease by this method, which shows a significant lipid perturbation in this disease. With the assistance of high resolution and high accuracy of MS and MS/MS data, the potential markers including lysophosphatidylcholines (LPCs), phosphatidylcholines (PCs) and triacylglycerols (TGs) with specific fatty acid chains, were identified. Interestingly, LPCs were up-regulated and PCs and TGs were down-regulated, compared OC group with benign tumor and normal control groups, and the glycerophospholipid metabolism emerged as a key pathway, in particular, the phospholipase A2 (PLA2) enzyme activity, that was disregulated in the disease. This study may provide new insight into underlying mechanisms for OC and proves that MS-based lipidomics is a powerful method in discovering new potential clinical biomarkers for diseases. PMID:26838385

  10. Brief-exposure to preoperative bevacizumab reveals a TGF-β signature predictive of response in HER2-negative breast cancers.

    Science.gov (United States)

    Varadan, Vinay; Kamalakaran, Sitharthan; Gilmore, Hannah; Banerjee, Nilanjana; Janevski, Angel; Miskimen, Kristy L S; Williams, Nicole; Basavanhalli, Ajay; Madabhushi, Anant; Lezon-Geyda, Kimberly; Bossuyt, Veerle; Lannin, Donald R; Abu-Khalaf, Maysa; Sikov, William; Dimitrova, Nevenka; Harris, Lyndsay N

    2016-02-01

    To best define biomarkers of response, and to shed insight on mechanism of action of certain clinically important agents for early breast cancer, we used a brief-exposure paradigm in the preoperative setting to study transcriptional changes in patient tumors that occur with one dose of therapy prior to combination chemotherapy. Tumor biopsies from breast cancer patients enrolled in two preoperative clinical trials were obtained at baseline and after one dose of bevacizumab (HER2-negative), trastuzumab (HER2-positive) or nab-paclitaxel, followed by treatment with combination chemo-biologic therapy. RNA-Sequencing based PAM50 subtyping at baseline of 46 HER2-negative patients revealed a strong association between the basal-like subtype and pathologic complete response (pCR) to chemotherapy plus bevacizumab (p ≤ 0.0027), but did not provide sufficient specificity to predict response. However, a single dose of bevacizumab resulted in down-regulation of a well-characterized TGF-β activity signature in every single breast tumor that achieved pCR (p ≤ 0.004). The TGF-β signature was confirmed to be a tumor-specific read-out of the canonical TGF-β pathway using pSMAD2 (p ≤ 0.04), with predictive power unique to brief-exposure to bevacizumab (p ≤ 0.016), but not trastuzumab or nab-paclitaxel. Down-regulation of TGF-β activity was associated with reduction in tumor hypoxia by transcription and protein levels, suggesting therapy-induced disruption of an autocrine-loop between tumor stroma and malignant cells. Modulation of the TGF-β pathway upon brief-exposure to bevacizumab may provide an early functional readout of pCR to preoperative anti-angiogenic therapy in HER2-negative breast cancer, thus providing additional avenues for exploration in both preclinical and clinical settings with these agents. PMID:26284485

  11. Genome Wide Expression Profiling of Cancer Cell Lines Cultured in Microgravity Reveals Significant Dysregulation of Cell Cycle and MicroRNA Gene Networks.

    Science.gov (United States)

    Vidyasekar, Prasanna; Shyamsunder, Pavithra; Arun, Rajpranap; Santhakumar, Rajalakshmi; Kapadia, Nand Kishore; Kumar, Ravi; Verma, Rama Shanker

    2015-01-01

    Zero gravity causes several changes in metabolic and functional aspects of the human body and experiments in space flight have demonstrated alterations in cancer growth and progression. This study reports the genome wide expression profiling of a colorectal cancer cell line-DLD-1, and a lymphoblast leukemic cell line-MOLT-4, under simulated microgravity in an effort to understand central processes and cellular functions that are dysregulated among both cell lines. Altered cell morphology, reduced cell viability and an aberrant cell cycle profile in comparison to their static controls were observed in both cell lines under microgravity. The process of cell cycle in DLD-1 cells was markedly affected with reduced viability, reduced colony forming ability, an apoptotic population and dysregulation of cell cycle genes, oncogenes, and cancer progression and prognostic markers. DNA microarray analysis revealed 1801 (upregulated) and 2542 (downregulated) genes (>2 fold) in DLD-1 cultures under microgravity while MOLT-4 cultures differentially expressed 349 (upregulated) and 444 (downregulated) genes (>2 fold) under microgravity. The loss in cell proliferative capacity was corroborated with the downregulation of the cell cycle process as demonstrated by functional clustering of DNA microarray data using gene ontology terms. The genome wide expression profile also showed significant dysregulation of post transcriptional gene silencing machinery and multiple microRNA host genes that are potential tumor suppressors and proto-oncogenes including MIR22HG, MIR17HG and MIR21HG. The MIR22HG, a tumor-suppressor gene was one of the highest upregulated genes in the microarray data showing a 4.4 log fold upregulation under microgravity. Real time PCR validated the dysregulation in the host gene by demonstrating a 4.18 log fold upregulation of the miR-22 microRNA. Microarray data also showed dysregulation of direct targets of miR-22, SP1, CDK6 and CCNA2. PMID:26295583

  12. Single-cell lineage tracking analysis reveals that an established cell line comprises putative cancer stem cells and their heterogeneous progeny

    Science.gov (United States)

    Sato, Sachiko; Rancourt, Ann; Sato, Yukiko; Satoh, Masahiko S.

    2016-01-01

    Mammalian cell culture has been used in many biological studies on the assumption that a cell line comprises putatively homogeneous clonal cells, thereby sharing similar phenotypic features. This fundamental assumption has not yet been fully tested; therefore, we developed a method for the chronological analysis of individual HeLa cells. The analysis was performed by live cell imaging, tracking of every single cell recorded on imaging videos, and determining the fates of individual cells. We found that cell fate varied significantly, indicating that, in contrast to the assumption, the HeLa cell line is composed of highly heterogeneous cells. Furthermore, our results reveal that only a limited number of cells are immortal and renew themselves, giving rise to the remaining cells. These cells have reduced reproductive ability, creating a functionally heterogeneous cell population. Hence, the HeLa cell line is maintained by the limited number of immortal cells, which could be putative cancer stem cells. PMID:27003384

  13. Dynamics of Protein Expression Reveals Primary Targets and Secondary Messengers of Estrogen Receptor Alpha Signaling in MCF-7 Breast Cancer Cells.

    Science.gov (United States)

    Drabovich, Andrei P; Pavlou, Maria P; Schiza, Christina; Diamandis, Eleftherios P

    2016-06-01

    Estrogen receptor alpha (ERα)-mediated proliferation of breast cancer cells is facilitated through expression of multiple primary target genes, products of which induce a secondary response to stimulation. To differentiate between the primary and secondary target proteins of ERα signaling, we measured dynamics of protein expression induced by 17β-estradiol in MCF-7 breast cancer cells. Measurement of the global proteomic effects of estradiol by stable isotope labeling by amino acids in cell culture (SILAC) resulted in identification of 103 estrogen-regulated proteins, with only 40 of the corresponding genes having estrogen response elements. Selected reaction monitoring (SRM) assays were used to validate the differential expression of 19 proteins and measure the dynamics of their expression within 72 h after estradiol stimulation, and in the absence or presence of 4-hydroxytamoxifen, to confirm ERα-mediated signaling. Dynamics of protein expression unambiguously revealed early and delayed response proteins and well correlated with presence or absence of estrogen response elements in the corresponding genes. Finally, we quantified dynamics of protein expression in a rarely studied network of transcription factors with a negative feedback loop (ERα-EGR3-NAB2). Because NAB2 protein is a repressor of EGR3-induced transcription, siRNA-mediated silencing of NAB2 resulted in the enhanced expression of the EGR3-induced protein ITGA2. To conclude, we provided a high-quality proteomic resource to supplement genomic and transcriptomic studies of ERα signaling. PMID:27067054

  14. Quantitative phosphoproteomics reveals genistein as a modulator of cell cycle and DNA damage response pathways in triple-negative breast cancer cells.

    Science.gov (United States)

    Fang, Yi; Zhang, Qian; Wang, Xin; Yang, Xue; Wang, Xiangyu; Huang, Zhen; Jiao, Yuchen; Wang, Jing

    2016-03-01

    Around one sixth of breast cancer cases are classified as triple-negative breast cancer (TNBC), named after the absence of the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2); however, patients with TNBC suffer from poor clinical outcome and shortage of targeted therapy. Genistein, an estrogenic soy isoflavone, shows anticancer effects in TNBC cells such as inducing G2/M cell cycle arrest and apoptosis. However, the underlying mechanism of its anticancer effects is poorly understood and its elucidation can help the development of novel therapeutic strategies for TNBC. In this study, by combining isobaric tag-based TMT labeling with titanium dioxide-based phosphopeptide enrichment, we quantitated 5,445 phosphorylation sites on 2,008 phosphoproteins in the TNBC cell line MDA-MB-231, upon genistein treatment. Our analysis revealed 332 genistein-regulated phosphorylation sites on 226 proteins. Our data show that genistein can regulate several biological processes during the cell cycle, including DNA replication, cohesin complex cleavage, and kinetochore formation. Furthermore, genistein can also activate DNA damage response, including activation of ATR and BRCA1 complex. Overall, our study presents evidence at a phosphoproteomic level that genistein is able to inhibit TNBC cell growth by regulating the cell cycle and DNA damage response in a more complex manner. Our findings help elucidate the mechanisms through which genistein exerts its anticancer effects in TNBC cells. PMID:26783066

  15. NMD and microRNA expression profiling of the HPCX1 locus reveal MAGEC1 as a candidate prostate cancer predisposition gene

    International Nuclear Information System (INIS)

    Several predisposition loci for hereditary prostate cancer (HPC) have been suggested, including HPCX1 at Xq27-q28, but due to the complex structure of the region, the susceptibility gene has not yet been identified. In this study, nonsense-mediated mRNA decay (NMD) inhibition was used for the discovery of truncating mutations. Six prostate cancer (PC) patients and their healthy brothers were selected from a group of HPCX1-linked families. Expression analyses were done using Agilent 44 K oligoarrays, and selected genes were screened for mutations by direct sequencing. In addition, microRNA expression levels in the lymphoblastic cells were analyzed to trace variants that might alter miRNA expression and explain partly an inherited genetic predisposion to PC. Seventeen genes were selected for resequencing based on the NMD array, but no truncating mutations were found. The most interesting variant was MAGEC1 p.Met1?. An association was seen between the variant and unselected PC (OR = 2.35, 95% CI = 1.10-5.02) and HPC (OR = 3.38, 95% CI = 1.10-10.40). miRNA analysis revealed altogether 29 miRNAs with altered expression between the PC cases and controls. miRNA target analysis revealed that 12 of them also had possible target sites in the MAGEC1 gene. These miRNAs were selected for validation process including four miRNAs located in the X chromosome. The expressions of 14 miRNAs were validated in families that contributed to the significant signal differences in Agilent arrays. Further functional studies are needed to fully understand the possible contribution of these miRNAs and MAGEC1 start codon variant to PC

  16. Fragile X mental retardation protein regulates trans-synaptic signaling in Drosophila

    Science.gov (United States)

    Friedman, Samuel H.; Dani, Neil; Rushton, Emma; Broadie, Kendal

    2013-01-01

    SUMMARY Fragile X syndrome (FXS), the most common inherited determinant of intellectual disability and autism spectrum disorders, is caused by loss of the fragile X mental retardation 1 (FMR1) gene product (FMRP), an mRNA-binding translational repressor. A number of conserved FMRP targets have been identified in the well-characterized Drosophila FXS disease model, but FMRP is highly pleiotropic in function and the full spectrum of FMRP targets has yet to be revealed. In this study, screens for upregulated neural proteins in Drosophila fmr1 (dfmr1) null mutants reveal strong elevation of two synaptic heparan sulfate proteoglycans (HSPGs): GPI-anchored glypican Dally-like protein (Dlp) and transmembrane Syndecan (Sdc). Our recent work has shown that Dlp and Sdc act as co-receptors regulating extracellular ligands upstream of intracellular signal transduction in multiple trans-synaptic pathways that drive synaptogenesis. Consistently, dfmr1 null synapses exhibit altered WNT signaling, with changes in both Wingless (Wg) ligand abundance and downstream Frizzled-2 (Fz2) receptor C-terminal nuclear import. Similarly, a parallel anterograde signaling ligand, Jelly belly (Jeb), and downstream ERK phosphorylation (dpERK) are depressed at dfmr1 null synapses. In contrast, the retrograde BMP ligand Glass bottom boat (Gbb) and downstream signaling via phosphorylation of the transcription factor MAD (pMAD) seem not to be affected. To determine whether HSPG upregulation is causative for synaptogenic defects, HSPGs were genetically reduced to control levels in the dfmr1 null background. HSPG correction restored both (1) Wg and Jeb trans-synaptic signaling, and (2) synaptic architecture and transmission strength back to wild-type levels. Taken together, these data suggest that FMRP negatively regulates HSPG co-receptors controlling trans-synaptic signaling during synaptogenesis, and that loss of this regulation causes synaptic structure and function defects characterizing the FXS

  17. Fragile X mental retardation protein regulates trans-synaptic signaling in Drosophila

    Directory of Open Access Journals (Sweden)

    Samuel H. Friedman

    2013-11-01

    Fragile X syndrome (FXS, the most common inherited determinant of intellectual disability and autism spectrum disorders, is caused by loss of the fragile X mental retardation 1 (FMR1 gene product (FMRP, an mRNA-binding translational repressor. A number of conserved FMRP targets have been identified in the well-characterized Drosophila FXS disease model, but FMRP is highly pleiotropic in function and the full spectrum of FMRP targets has yet to be revealed. In this study, screens for upregulated neural proteins in Drosophila fmr1 (dfmr1 null mutants reveal strong elevation of two synaptic heparan sulfate proteoglycans (HSPGs: GPI-anchored glypican Dally-like protein (Dlp and transmembrane Syndecan (Sdc. Our recent work has shown that Dlp and Sdc act as co-receptors regulating extracellular ligands upstream of intracellular signal transduction in multiple trans-synaptic pathways that drive synaptogenesis. Consistently, dfmr1 null synapses exhibit altered WNT signaling, with changes in both Wingless (Wg ligand abundance and downstream Frizzled-2 (Fz2 receptor C-terminal nuclear import. Similarly, a parallel anterograde signaling ligand, Jelly belly (Jeb, and downstream ERK phosphorylation (dpERK are depressed at dfmr1 null synapses. In contrast, the retrograde BMP ligand Glass bottom boat (Gbb and downstream signaling via phosphorylation of the transcription factor MAD (pMAD seem not to be affected. To determine whether HSPG upregulation is causative for synaptogenic defects, HSPGs were genetically reduced to control levels in the dfmr1 null background. HSPG correction restored both (1 Wg and Jeb trans-synaptic signaling, and (2 synaptic architecture and transmission strength back to wild-type levels. Taken together, these data suggest that FMRP negatively regulates HSPG co-receptors controlling trans-synaptic signaling during synaptogenesis, and that loss of this regulation causes synaptic structure and function defects characterizing the FXS disease state.

  18. Triplex DNA-binding proteins are associated with clinical outcomes revealed by proteomic measurements in patients with colorectal cancer

    Directory of Open Access Journals (Sweden)

    Nelson Laura D

    2012-06-01

    with ErbB1, mTOR, PTEN, and Stat5. Western blots confirmed that full-length and truncated beta-catenin expression correlated with U2AF65 expression in tumor extracts. Conclusions Increased triplex DNA-binding activity in vitro correlates with lymph node disease, metastasis, and reduced overall survival in colorectal cancer, and increased U2AF65 expression is associated with total and truncated beta-catenin expression in high-stage colorectal tumors.

  19. [Lung cancer reveal by mandibular metastasis: a case at the Centre of Consultation and Dental Treatment Dental of Casablanca (CCDTC)].

    Science.gov (United States)

    Bouzoubaa, S; Khazana, M; Slimani, F; Chekkoury, E I; Benyahya, I

    2014-03-01

    Metastatic tumors result from hematogenous spread through a tumor located at a distance. All these tumors represent about 1% of malignant tumors of the oral cavity (1). The most common location is the mandible (70%), more rarely maxillary (2). The most frequently encountered tumors are carcinomas or adenocarcinomas of mammary origin, brocho-lung, prostate, kidney or another. This study reports the case of a 46 year-old man, who presented for consultation with a low left laterofacial swelling, paresthesia lip and chin straight associated with pain at the lower edge of the mandible evolving for 2 months. The patient is known to take alcohol and tobacco for 20 years. The panoramic radiograph showed radiolucent image with blurred boundaries at the lower right premolar region. Dentascan revealed an irregular osteolytic lesion with rupture of the table lingual. After surgical exploration, the pathological examination is for a well-differentiated and invasive adenocarcinoma of the mandible. Extension work-up shows the presence of a tumor right lung, a lytic lesion at the 8th costal arch, the fourth dorsal vertebra and another location in fibula. The surgical exploration of pulmonary was performed and confirmed the pulmonary primitive localization of adenocarcinoma. PMID:24979959

  20. Human Lymphoid Translocation Fragile Zones Are Hypomethylated and Have Accessible Chromatin

    OpenAIRE

    Lu, Zhengfei; Lieber, Michael R.; Tsai, Albert G.; Pardo, Carolina E.; Müschen, Markus; Kladde, Michael P.; Hsieh, Chih-Lin

    2015-01-01

    Chromosomal translocations are a hallmark of hematopoietic malignancies. CG motifs within translocation fragile zones (typically 20 to 600 bp in size) are prone to chromosomal translocation in lymphomas. Here we demonstrate that the CG motifs in human translocation fragile zones are hypomethylated relative to the adjacent DNA. Using a methyltransferase footprinting assay on isolated nuclei (in vitro), we find that the chromatin at these fragile zones is accessible. We also examined in vivo ac...

  1. Broad clinical involvement in a family affected by the fragile X premutation

    OpenAIRE

    Chonchaiya, W; Utari, A; Pereira, GM; F. Tassone; Hessl, D.; Hagerman, RJ

    2009-01-01

    The mutations in the FMR1 gene have been described as a family of disorders called fragile X-associated disorders including fragile X syndrome, fragile X-associated tremor/ataxia syndrome, primary ovarian insufficiency, and other problems associated with the premutation, such as hypothyroidism, hypertension, neuropathy, anxiety, depression, attention-deficit hyperactivity disorders, and autism spectrum disorders. The premutation is relatively common in the general population affecting 1 of 13...

  2. Family Environment and Behavior Problems in Children, Adolescents, and Adults with Fragile X Syndrome

    OpenAIRE

    Greenberg, Jan S.; Seltzer, Marsha Mailick; Baker, Jason K.; Smith, Leann E.; Warren, Steven F.; Brady, Nancy; Hong, Jinkuk

    2012-01-01

    We examine how the family environment is associated with aspects of the Fragile X syndrome phenotype during childhood, adolescence, and adulthood. Mothers of children (n = 48), adolescents (n = 85), and adults (n = 34) with Fragile X syndrome participated in a multisite study. For children and adults with Fragile X syndrome, the presence of warmth and positivity and the absence of criticism were associated with fewer behavior problems. Although a higher level of criticism was significantly as...

  3. Extending Minsky's classifications of fragility to government and the open economy

    OpenAIRE

    Wray , L. Randall

    2006-01-01

    Minsky's classification of fragility according to hedge, speculative, and Ponzi positions is well-known. He wrote about fragile positions of individual firms and of the economy as a whole, with the economy transitioning naturally from a robust financial structure (dominated by hedge units) to a fragile structure (dominated by speculative units). In most of Minsky's writing, he introduced government through its impact on the private sector with its spending and balance sheet operations as stab...

  4. DNA demethylation induced by 5-azacytidine does not affect fragile X expression.

    OpenAIRE

    Glover, T W; Coyle-Morris, J; Pearce-Birge, L; Berger, C; Gemmill, R M

    1986-01-01

    Experiments were performed to determine the role of DNA demethylation in fragile X expression. Fragile X positive lymphoblastoid cells were treated with 5-azacytidine and harvested for analysis of fragile X expression both directly following treatment and after a recovery period in the absence of the drug. The effectiveness of 5-azacytidine treatment in inducing DNA demethylation was concurrently monitored by analysis of methylation changes at random autosomal loci in isolated DNA from treate...

  5. Discrimination Learning and Attentional Set Formation in a Mouse Model of Fragile X

    OpenAIRE

    Casten, Kimberly S.; Gray, Annette C; Burwell, Rebecca D.

    2011-01-01

    Fragile X Syndrome is the most prevalent genetic cause of mental retardation. Selective deficits in executive function, including inhibitory control and attention, are core features of the disorder. In humans, Fragile X results from a trinucleotide repeat in the Fmr1 gene that renders it functionally silent and has been modeled in mice by targeted deletion of the Fmr1 gene. Fmr1 knockout (KO) mice recapitulate many features of Fragile X syndrome, but evidence for deficits in executive functio...

  6. Evaluation of Fragility of the Economic System in Poyang Lake Ecological Economic Zone

    OpenAIRE

    Cheng, Qiao-zhen; Chen, Xiao-ling; Zhu, Feng-feng; Zhu, Jing

    2012-01-01

    From two aspects, namely the sensitivity of regional economic system to internal and external interference, and its resilience, we establish the evaluation indicator system of fragility of the economic system in Poyang Lake Ecological Economic Zone, and evaluate the internal differences in fragility of the regional economic system, using set pair analysis method. The results show that there is a great difference in fragility of the economic system between different administrative units; the d...

  7. Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome

    OpenAIRE

    Jung, Kwang-Mook; Sepers, Marja; Henstridge, Christopher M.; Lassalle, Olivier; Neuhofer, Daniela; Martin, Henry; Ginger, Melanie; Frick, Andreas; DiPatrizio, Nicholas V.; Mackie, Ken; Katona, Istvan; Piomelli, Daniele; Manzoni, Olivier J.

    2012-01-01

    Fragile X syndrome, the most commonly known genetic cause of autism, is due to loss of the fragile X mental retardation protein, which regulates signal transduction at metabotropic glutamate receptor-5 in the brain. Fragile X mental retardation protein deletion in mice enhances metabotropic glutamate receptor-5-dependent long-term depression in the hippocampus and cerebellum. Here we show that a distinct type of metabotropic glutamate receptor-5-dependent long-term depression at excitatory sy...

  8. Excess protein synthesis in Drosophila Fragile X mutants impairs long-term memory

    OpenAIRE

    Bolduc, François V.; Bell, Kimberly; Cox, Hilary; Broadie, Kendal; Tully, Tim

    2008-01-01

    We used Drosophila olfactory memory in order to understand in vivo the molecular basis of cognitive defect in Fragile X syndrome. We observed that Fragile X protein (FMRP) was required acutely and interacted with argonaute1 and staufen in long-term memory (LTM). Occlusion of long-term memory formation in Fragile X mutants could be rescued by protein synthesis inhibitors, suggesting that excess baseline protein synthesis could impact negatively on cognition.

  9. FMR1 fully expanded mutation with minimal methylation in a high functioning fragile X male.

    OpenAIRE

    Wang, Z.; Taylor, A K; Bridge, J.A.

    1996-01-01

    Cytogenetic and molecular genetic analysis of a peripheral blood sample from a 31 year old, non-mentally retarded male with a family history of fragile X syndrome showed unexpected results. Nine percent of cells evaluated cytogenetically expressed a fragile X chromosome and molecular examination of the FMR1 gene showed a highly unusual pattern defined as a minimally methylated fully expanded mutation. This case illustrates the need to recognise exceptional variations of fragile X syndrome mut...

  10. Strategy for reliable prenatal detection of normal male carriers of the fragile X syndrome

    OpenAIRE

    Halley, Dicky; Ouweland, Ans; Deelen, Wouter; Verma, Chandra; Oostra, Ben

    1994-01-01

    textabstractPrenatal diagnosis of fragile X syndrome identifying full mutations has been described. Here we report on a case of a prenatal test concerning a normal male carrier of the fragile X syndrome. Southern blot analysis of the fragile X gene resulted in the identification of a premutation in DNA isolated from the chorionic villus sample. Using a polymerase chain reaction (PCR)based assay the CGG repeat length was determined to be 82 CGG repeat units. Confirmation of this premutation in...

  11. RNA-mediated neurodegeneration in fragile X-associated tremor/ataxia syndrome

    OpenAIRE

    Li, Yujing; Jin, Peng

    2012-01-01

    Carriers of fragile X syndrome (FXS) have FMR1 alleles, called premutations, with a number of 5’-untranslated CGG repeats somewhere between patients, who have over 200 repeats, and normal individuals, with fewer than 60 repeats. Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder, has been recognized in older male fragile X premutation carriers, and FXTAS is uncoupled from the neurodevelopmental disorder, FXS. Several lines of evidence have led to the ...

  12. Book review: the Congo, Haiti and Afghanistan: fragile states and the maintenance of violence

    OpenAIRE

    Wadi, Ramona

    2012-01-01

    Fragile States shows how the monopoly of violence is a crucial element in maintaining state fragility. By taking case studies from The Democratic Republic of Congo, Haiti and Afghanistan, the authors intend to define and clarify the meaning behind fragile statehood and to determine why outside intervention is often very limited in its actions to halt or prevent war and conflict in these countries. Ramona Wadi values the book’s analysis which, in addition to imparting a deep insight into the c...

  13. Difficult diagnosis of the fragile X syndrome made possible by direct detection of DNA mutations.

    OpenAIRE

    Tarleton, J; Wong, S.; Heitz, D.; Schwartz, C.

    1992-01-01

    Genetic recombination near the fragile X locus (Xq27.3) has frequently been a problem in linkage studies of families in which the fragile X is segregating. This case report illustrates the resolution of a difficult situation in a fragile X family for whom cytogenetic studies were inconclusive and where recombination had twice confounded attempts at prenatal DNA diagnosis by RFLP analysis. Using a newly developed DNA probe, StB12.3, for direct detection of DNA instability in the fragile X locu...

  14. [Cancer].

    Science.gov (United States)

    de la Peña-López, Roberto; Remolina-Bonilla, Yuly Andrea

    2016-09-01

    Cancer is a group of diseases which represents a significant public health problem in Mexico and worldwide. In Mexico neoplasms are the second leading cause of death. An increased morbidity and mortality are expected in the next decades. Several preventable risk factors for cancer development have been identified, the most relevant including tobacco use, which accounts for 30% of the cancer cases; and obesity, associated to another 30%. These factors, in turn, are related to sedentarism, alcohol abuse and imbalanced diets. Some agents are well knokn to cause cancer such as ionizing radiation, viruses such as the papilloma virus (HPV) and hepatitis virus (B and C), and more recently environmental pollution exposure and red meat consumption have been pointed out as carcinogens by the International Agency for Research in Cancer (IARC). The scientific evidence currently available is insufficient to consider milk either as a risk factor or protective factor against different types of cancer. PMID:27603890

  15. Development of fragility functions to estimate homelessness after an earthquake

    Science.gov (United States)

    Brink, Susan A.; Daniell, James; Khazai, Bijan; Wenzel, Friedemann

    2014-05-01

    Immediately after an earthquake, many stakeholders need to make decisions about their response. These decisions often need to be made in a data poor environment as accurate information on the impact can take months or even years to be collected and publicized. Social fragility functions have been developed and applied to provide an estimate of the impact in terms of building damage, deaths and injuries in near real time. These rough estimates can help governments and response agencies determine what aid may be required which can improve their emergency response and facilitate planning for longer term response. Due to building damage, lifeline outages, fear of aftershocks, or other causes, people may become displaced or homeless after an earthquake. Especially in cold and dangerous locations, the rapid provision of safe emergency shelter can be a lifesaving necessity. However, immediately after an event there is little information available about the number of homeless, their locations and whether they require public shelter to aid the response agencies in decision making. In this research, we analyze homelessness after historic earthquakes using the CATDAT Damaging Earthquakes Database. CATDAT includes information on the hazard as well as the physical and social impact of over 7200 damaging earthquakes from 1900-2013 (Daniell et al. 2011). We explore the relationship of both earthquake characteristics and area characteristics with homelessness after the earthquake. We consider modelled variables such as population density, HDI, year, measures of ground motion intensity developed in Daniell (2014) over the time period from 1900-2013 as well as temperature. Using a base methodology based on that used for PAGER fatality fragility curves developed by Jaiswal and Wald (2010), but using regression through time using the socioeconomic parameters developed in Daniell et al. (2012) for "socioeconomic fragility functions", we develop a set of fragility curves that can be

  16. Seismic Fragility of the LANL Fire Water Distribution System

    Energy Technology Data Exchange (ETDEWEB)

    Greg Mertz

    2007-03-30

    The purpose of this report is to present the results of a site-wide system fragility assessment. This assessment focuses solely on the performance of the water distribution systems that supply Chemical and Metallurgy Research (CMR), Weapons Engineering and Tritium Facility (WETF), Radioactive Liquid Waste Treatment Facility (RLWTF), Waste Characterization, Reduction, Repackaging Facility (WCRRF), and Transuranic Waste Inspectable Storage Project (TWISP). The analysis methodology is based on the American Lifelines Alliance seismic fragility formulations for water systems. System fragilities are convolved with the 1995 LANL seismic hazards to develop failure frequencies. Acceptance is determined by comparing the failure frequencies to the DOE-1020 Performance Goals. This study concludes that: (1) If a significant number of existing isolation valves in the water distribution system are closed to dedicate the entire water system to fighting fires in specific nuclear facilities; (2) Then, the water distribution systems for WETF, RLWTF, WCRRF, and TWISP meet the PC-2 performance goal and the water distribution system for CMR is capable of surviving a 0.06g earthquake. A parametric study of the WETF water distribution system demonstrates that: (1) If a significant number of valves in the water distribution system are NOT closed to dedicate the entire water system to fighting fires in WETF; (2) Then, the water distribution system for WETF has an annual probability of failure on the order of 4 x 10{sup -3} that does not meet the PC-2 performance goal. Similar conclusions are expected for CMR, RLWTF, WCRRF, and TWISP. It is important to note that some of the assumptions made in deriving the results should be verified by personnel in the safety-basis office and may need to be incorporated in technical surveillance requirements in the existing authorization basis documentation if credit for availability of fire protection water is taken at the PC-2 level earthquake levels

  17. Preliminary Seismic Response and Fragility Analysis for DACS Cabinet

    International Nuclear Information System (INIS)

    A DACS cabinet is installed in the main control room. The objective of this paper is to perform seismic analyses and evaluate the preliminary structural integrity and seismic capacity of the DACS cabinet. For this purpose, a 3-D finite element model of the DACS cabinet was developed and its modal analyses are carried out to analyze the dynamic characteristics. The response spectrum analyses and the related safety evaluation are then performed for the DACS cabinet subject to seismic loads. Finally, the seismic margin and seismic fragility of the DACS cabinet are investigated. A seismic analysis and preliminary structural integrity of the DACS cabinet under self weight and SSE load have been evaluated. For this purpose, 3-D finite element models of the DACS cabinet were developed. A modal analysis, response spectrum analysis, and seismic fragility analysis were then performed. From the structural analysis results, the DACS cabinet is below the structural design limit of under SSE 0.3g, and can structurally withstand until less than SSE 3g based on an evaluation of the maximum effective stresses. The HCLPF capacity for the DGRS of the SSE 0.3g is 0.55g. A modal analysis, response spectrum analysis, and seismic fragility analysis were then performed. From the structural analysis results, the DACS cabinet is below the structural design limit of under SSE 0.3g, and can structurally withstand until less than SSE 3g based on an evaluation of the maximum effective stresses. The HCLPF capacity for the DGRS of the SSE 0.3g is 0.55g. Therefore, it is concluded that the DACS cabinet was safely designed in that no damage to the preliminary structural integrity and sufficient seismic margin is expected

  18. Implementing SPRA probabilistic fragility analysis of four typical nuclear structures

    International Nuclear Information System (INIS)

    In this paper the procedures used and the results obtained in the Seismic Probabilistic Risk Assessment (SPRA) fragility analysis are presented for four typical structures that include three year enclosures and buildings, and a turbine building complex of a pressurized water reactor (PWR) nuclear power plant (NPP) located East of the Rocky Mountains. The major procedures include structural modeling, structural dynamic analysis, failure mode and strength capacity evaluation, determination of randomness and uncertainty parameters of variables involved, and the SPRA fragility and the medium High Confidence Low Probability of Failure (HCLPF50) calculation in terms of the peak ground acceleration (PGA). The three-dimensional (3-D) structural models developed have different features from each other including a fixed-base stick model of a reinforced concrete structure physically separated from a housed tank, a stick model of a reinforced concrete structure including the effects of the housed tank response and structure-foundation interaction (SFI), a fixed-base full size steel frame structure, and a stick model with a combination of reinforced concrete and steel frame members and including the SFI effects. The 3-D response spectrum dynamic analyses were performed directly on these structure models using the site specific free field 50th percentile Uniform Hazard Spectrum shape (UHS) based on a 10,000 year return period earthquake factored to a Review Level Earthquake (RLA) Zero Period Ground Acceleration (ZPGA) of 0.4 g. Different failure modes were evaluated using the associated failure criteria for the structure models. Some insights are expected from the typical application of the SPRA probabilistic fragility analysis of nuclear structures

  19. A simplified fragility analysis of fan type cable stayed bridges

    Institute of Scientific and Technical Information of China (English)

    R. A. Khan; T. K. Datta; S. Ahmad

    2005-01-01

    A simplified fragility analysis of fan type cable stayed bridges using Probabilistic Risk Analysis (PRA)procedure is presented for determining their failure probability under random ground motion. Seismic input to the bridge support is considered to be a risk consistent response spectrum which is obtained from a separate analysis. For the response analysis, the bridge deck is modeled as a beam supported on springs at different points. The stiffnesses of the springs are determined by a separate 2D static analysis of cable-tower-deck system. The analysis provides a coupled stiffness matrix for the spring system. A continuum method of analysis using dynamic stiffness is used to determine the dynamic properties of the bridges .The response of the bridge deck is obtained by the response spectrum method of analysis as applied to multidegree of freedom system which duly takes into account the quasi - static component of bridge deck vibration. The fragility analysis includes uncertainties arising due to the variation in ground motion, material property, modeling, method of analysis,ductility factor and damage concentration effect. Probability of failure of the bridge deck is determined by the First Order Second Moment (FOSM) method of reliability. A three span double plane symmetrical fan type cable stayed bridge of total span 689 m, is used as an illustrative example. The fragility curves for the bridge deck failure are obtained under a number of parametric variations. Some of the important conclusions of the study indicate that (i) not only vertical component but also the horizontal component of ground motion has considerable effect on the probability of failure; (ii) ground motion with no time lag between support excitations provides a smaller probability of failure as compared to ground motion with very large time lag between support excitation; and (iii) probability of failure may considerably increase for soft soil condition.

  20. Seismic Fragility of the LANL Fire Water Distribution System

    International Nuclear Information System (INIS)

    The purpose of this report is to present the results of a site-wide system fragility assessment. This assessment focuses solely on the performance of the water distribution systems that supply Chemical and Metallurgy Research (CMR), Weapons Engineering and Tritium Facility (WETF), Radioactive Liquid Waste Treatment Facility (RLWTF), Waste Characterization, Reduction, Repackaging Facility (WCRRF), and Transuranic Waste Inspectable Storage Project (TWISP). The analysis methodology is based on the American Lifelines Alliance seismic fragility formulations for water systems. System fragilities are convolved with the 1995 LANL seismic hazards to develop failure frequencies. Acceptance is determined by comparing the failure frequencies to the DOE-1020 Performance Goals. This study concludes that: (1) If a significant number of existing isolation valves in the water distribution system are closed to dedicate the entire water system to fighting fires in specific nuclear facilities; (2) Then, the water distribution systems for WETF, RLWTF, WCRRF, and TWISP meet the PC-2 performance goal and the water distribution system for CMR is capable of surviving a 0.06g earthquake. A parametric study of the WETF water distribution system demonstrates that: (1) If a significant number of valves in the water distribution system are NOT closed to dedicate the entire water system to fighting fires in WETF; (2) Then, the water distribution system for WETF has an annual probability of failure on the order of 4 x 10-3 that does not meet the PC-2 performance goal. Similar conclusions are expected for CMR, RLWTF, WCRRF, and TWISP. It is important to note that some of the assumptions made in deriving the results should be verified by personnel in the safety-basis office and may need to be incorporated in technical surveillance requirements in the existing authorization basis documentation if credit for availability of fire protection water is taken at the PC-2 level earthquake levels

  1. Detect Image Tamper by Semi-Fragile Digital Watermarking

    Institute of Scientific and Technical Information of China (English)

    LIUFeilong; WANGYangsheng

    2004-01-01

    To authenticate the integrity of image while resisting some valid image processing such as JPEG compression, a semi-fragile image watermarking is described. Image name, one of the image features, has been used as the key of pseudo-random function to generate the special watermarks for the different image. Watermarks are embedded by changing the relationship between the blocks' DCT DC coefficients, and the image tamper are detected with the relationship of these DCT DC coefficients.Experimental results show that the proposed technique can resist JPEG compression, and detect image tamper in the meantime.

  2. Emerging pharmacologic treatment options for fragile X syndrome

    Directory of Open Access Journals (Sweden)

    Schaefer TL

    2015-04-01

    Full Text Available Tori L Schaefer, Matthew H Davenport, Craig A Erickson Division of Child and Adolescent Psychiatry, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA Abstract: Fragile X syndrome (FXS is the most common single gene cause of intellectual disability and autism spectrum disorder. Caused by a silenced fragile X mental retardation 1 gene and the subsequent deficiency in fragile X mental retardation protein, patients with FXS experience a range of physical, behavioral, and intellectual debilitations. The FXS field, as a whole, has recently met with some challenges, as several targeted clinical trials with high expectations of success have failed to elucidate significant improvements in a variety of symptom domains. As new clinical trials in FXS are planned, there has been much discussion about the use of the commonly used clinical outcome measures, as well as study design considerations, patient stratification, and optimal age range for treatment. The evidence that modification of these drug targets and use of these failed compounds would prove to be efficacious in human clinical study were rooted in years of basic and translational research. There are questions arising as to the use of the mouse models for studying FXS treatment development. This issue is twofold: many of the symptom domains and molecular and biochemical changes assessed and indicative of efficacy in mouse model study are not easily amenable to clinical trials in people with FXS because of the intolerability of the testing paradigm or a lack of noninvasive techniques (prepulse inhibition, sensory hypersensitivity, startle reactivity, or electrophysiologic, biochemical, or structural changes in the brain; and capturing subtle yet meaningful changes in symptom domains such as sociability, anxiety, and hyperactivity in human FXS clinical trials is challenging with the currently used measures (typically parent/caregiver rating scales. Clinicians, researchers, and the

  3. State fragility and its regional implications for peace and stability

    DEFF Research Database (Denmark)

    Mandrup, Thomas

    Abstract: The East African region is characterized by heterogeneous units and by being conflict ridden. Historically the region has been plagued by both the overlay of the Cold war actors resulting in rivalry and intrastate wars, e.g. the conflict between Ethiopia and Somalia in the 1970’s. The end...... of the Cold war left a security void, and the fragility, and in some instances collapse, of the state structures resulted in new state formations and new conflicts, both intra- and inter-state in nature. However, conflicts and security challenges in East Africa are due to amongst other things porous...

  4. Seismic fragility and risk of the Beznau nuclear plant

    International Nuclear Information System (INIS)

    A probabilistic risk assessment of the Swiss Beznau Nuclear Power Plant located on the Aare River near Baden was conducted by Pickard, Lowe and Garrick, Inc., for Nordostschweizerische Kraftwerke AG. In that evaluation, system models, event tress, and fault trees were used to determine the frequency of core melt due to random equipment failure, equipment unavailabilities due to maintenance, and failures initiated by natural hazard events. Earthquakes were one of the extreme natural hazards considered. This paper discusses the fragilities of key structures and equipment that govern the seismic risk level of the Beznau plant and indicates the contribution of seismic risk to the total plant risk

  5. Seismic fragility and risk of the Beznau power plant

    International Nuclear Information System (INIS)

    In the probabilistic risk assessment of the Swiss Beznau nuclear power plant system models, event trees, and fault trees were used to determine the frequency of core melt due to random equipment failure, equipment unavailabilities due to maintenance, and failures initiated by natural hazard events. Earthquakes were one of the extreme natural hazards considered. This paper discusses the fragilities of key structures and equipment that govern the seismic risk level of the Beznau plant and indicates the contribution of seismic risk to the total plant risk. (orig./HP)

  6. Fairness in a Fragile World: The Johannesburg Agenda

    OpenAIRE

    Wolfgang Sachs

    2002-01-01

    Wolfgang Sachs, in his capacity as co-ordinator and editor of a group of 15 people that produced ‘The Johannesburg Memo: Fairness in a Fragile World’, reflects on what has to be radically different in Johannesburg if it is to catch up with the ecological disasters we are facing 10 years on (see www.joburgmemo.org for the full text). This article draws largely on part 2 of that document, ‘The Johannesburg Agenda’, which recommends a southern-led, people- and poverty-centred agenda with a move ...

  7. WATERMARKING AUTHENTICATION: USING THE FRAGILE MODE OR THE ROBUST MODE?

    Institute of Scientific and Technical Information of China (English)

    Chen Dan; Wu Qianhong; Wang Yumin

    2006-01-01

    Due to the lack of a unified authentication model certain mistakes occurred in the use of the watermarking authentication methods. To clarify the confusion, authentication models of robust and fragile watermarking are developed respectively in the paper. Concrete algorithms are proposed to prove the models that different Discrete Wavelet Transform (DWT) domains are utilized to embed the watermarks and quantization method is presented with Just Notice Differences (JNDs) threshold as the quantization size. After the key technologies about the two methods are discussed, we detail the comparison of the two modes and recommend their respective application scenarios as applicable results.

  8. A paradigm of fragile Earth in Priestley's bell jar

    OpenAIRE

    Martin, Daniel; Thompson, Andrew; Stewart, Iain; Gilbert,Edward; Hope, Katrina; Kawai, Grace; Griffiths, Alistair

    2012-01-01

    Background Photosynthesis maintains aerobic life on Earth, and Joseph Priestly first demonstrated this in his eighteenth-century bell jar experiments using mice and mint plants. In order to demonstrate the fragility of life on Earth, Priestley's experiment was recreated using a human subject placed within a modern-day bell jar. Methods A single male subject was placed within a sealed, oxygen-depleted enclosure (12.4% oxygen), which contained 274 C3 and C4 plants for a total of 48 h. A combina...

  9. A new semi-fragile watermarking algorithm for image authentication

    Institute of Scientific and Technical Information of China (English)

    HAN De-zhi; HU Yu-ping

    2005-01-01

    This paper presents a new semi-fragile watermarking algorithm for image authentication which extracts image features from the low frequency domain to generate two watermarks: one for classifying of the intentional content modification and the other for indicating the modified location. The algorithm provides an effective mechanism for image authentication. The watermark generation and watermark embedment are disposed in the image itself, and the received image authentication needs no information about the original image or watermark. The algorithm increases watermark security and prevents forged watermark. Experimental results show that the algorithm can identify intentional content modification and incidental tampering, and also indicate the location where a modification takes place.

  10. A novel DXA-based hip failure index captures hip fragility independent of BMD.

    Science.gov (United States)

    Sievänen, H; Weynand, L S; Wacker, W K; Simonelli, C; Burke, P K; Ragi, S; Del Rio, L

    2008-01-01

    Capability of a novel dual-energy X-ray absorptiometry (DXA)-based hip failure index (HiFI) to discriminate between hip fracture cases and controls was evaluated. Given the constraints of planar DXA, the femoral neck was assumed a foam-filled ( approximately trabecular bone), thin-walled ( approximately cortical bone) sandwich structure, while HiFI estimated the critical force sufficient to buckle the wall of such a structure. Proximal femur DXA data from 1379 women aged 65yr and older, 268 with prior hip fracture were used. Comparison between standard areal bone mineral density (BMD), femur strength index (FSI), and HiFI was based on areas under receiver operatoring characteristic curves (AUC). The mean femoral neck BMD (SD) was 0.689 (0.109) g/cm(2) among the cases and 0.768 (0.119) g/cm(2) among the controls; the mean FSI 1.33 (0.36) and 1.54 (0.41), and the mean HiFI -0.28 (0.14) and -0.18 (0.15), respectively; all intergroup differences were highly significant (pHiFI remained significant (pHiFI. In conclusion, HiFI may capture structural traits that account for femoral neck fragility independently of BMD or FSI. Obviously, the use of actual geometric and structural information from three-dimensional imaging of the femoral neck would help diminish the crude assumptions of the present DXA approach and reveal the true potential of the HiFI approach to gauge hip fragility and identify at-risk individuals for hip fractures. PMID:18456529

  11. Event-related potential alterations in fragile X syndrome

    Directory of Open Access Journals (Sweden)

    Inga Sophia eKnoth

    2012-09-01

    Full Text Available Fragile X Syndrome (FXS is the most common form of X-linked intellectual disability, associated with a wide range of cognitive and behavioural impairments. FXS is caused by a trinucleotide repeat expansion in the FMR1 gene located on the X-chromosome. FMR1 is expected to prevent the expression of the fragile X mental retardation protein (FMRP, which results in altered structural and functional development of the synapse, including a loss of synaptic plasticity. This review aims to unveil the contribution of electrophysiological signal studies for the understanding of the information processing impairments in FXS patients. We discuss relevant event-related potential (ERP studies conducted with full mutation FXS patients and clinical populations sharing symptoms with FXS in a developmental perspective. Specific deviances found in FXS ERP profiles are described. Alterations are reported in N1, P2, Mismatch Negativity (MMN, N2 and P3 components in FXS compared to healthy controls. Particularly, deviances in N1 and P2 amplitude seem to be specific to FXS. The presented results suggest a cascade of impaired information processes that are in line with symptoms and anatomical findings in FXS.

  12. Fragile X mental retardation protein interacts with TDG

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Fragile X syndrome is the most common form of inherited mental retardation disease,resulting from absent of expression of its disease gene FMR1.To study the function of the fragile X mental retardation protein (FMRP) through protein/protein interaction,a mouse embryo cDNA library was screened by the yeast two-hybrid system.A clone was found to interact specifically with FMRP.The cDNA of this clone ( Genbank accession number af102875 ) encoded a protein highly homologous to human G/T mismatch-specific DNA thymine glycosylase ( hTDG ).Interactions between various alternatively spliced FMRP isoforms and a series of mTDG deletion proteins were further studied in the yeast two-hybrid system and their interaction amino acid regions were determined.Interaction between FMRP and TDG existed inside exon 13 of FMRP ( amino acid residue 397-425 ) and around amino acid residue 122-346 of TDG.These results will be helpful to the study of the biological role of FMRP.

  13. Drift-free MPEG-4 AVC semi-fragile watermarking

    Science.gov (United States)

    Hasnaoui, M.; Mitrea, M.

    2014-02-01

    While intra frame drifting is a concern for all types of MPEG-4 AVC compressed-domain video processing applications, it has a particular negative impact in watermarking. In order to avoid the drift drawbacks, two classes of solutions are currently considered in the literature. They try either to compensate the drift distortions at the expense of complex decoding/estimation algorithms or to restrict the insertion to the blocks which are not involved in the prediction, thus reducing the data payload. The present study follows a different approach. First, it algebraically models the drift distortion spread problem by considering the analytic expressions of the MPEG-4 AVC encoding operations. Secondly, it solves the underlying algebraic system under drift-free constraints. Finally, the advanced solution is adapted to take into account the watermarking peculiarities. The experiments consider an m-QIM semi-fragile watermarking method and a video surveillance corpus of 80 minutes. For prescribed data payload (100 bit/s), robustness (BER < 0.1 against transcoding at 50% in stream size), fragility (frame modification detection with accuracies of 1/81 from the frame size and 3s) and complexity constraints, the modified insertion results in gains in transparency of 2 dB in PSNR, of 0.4 in AAD, of 0.002 in IF, of 0.03 in SC, of 0.017 NCC and 22 in DVQ.

  14. Tunnelling through weak and fragile rocks of Himalayas

    Institute of Scientific and Technical Information of China (English)

    Goel R.K.

    2014-01-01

    A considerable amount of tunnelling has been going on in India for various projects such as hydroelectric power, irrigation, roads and railways. Most of these projects are located in Himalayas, far away from the urban areas. Tunnelling through weak and jointed rock masses such as the one in the Himalayas is a challenging task for the planners, designers, engineers and geologists because of high overburden, thickly vegetated surface, weak, poor and fragile rocks and highly varying geology with the presence of numerous small and big shear zones, faults, etc. Due to these reasons, various tunnelling problems have been faced in the past and are still being encountered. Failures and the problems may be regarded as challenges and opportunities for generating new knowledge base and thereby increasing self-reliance in tunnelling. The experiences of Himalayan tunnelling through weak and fragile rocks covering varying and mixed geology, understanding on tunnelling in squeezing ground conditions and applicability of TBM in Himalayas are presented. It has also been highlighted that the probe holes planning, drilling and mon-itoring shall be followed seriously to reduce the geological surprises.

  15. Fragility assessment method of Concrete Wall Subjected to Impact Loading

    Energy Technology Data Exchange (ETDEWEB)

    Hahm, Daegi; Shin, Sang Shup; Choi, In-Kil [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2014-10-15

    These studies have been aimed to verify and ensure the safety of the targeted walls and structures especially in the viewpoint of the deterministic approach. However, recently, the regulation and the assessment of the safety of the nuclear power plants (NPPs) against to an aircraft impact are strongly encouraged to adopt a probabilistic approach, i.e., the probabilistic risk assessment of an aircraft impact. In Korea, research to develop aircraft impact risk quantification technology was initiated in 2012 by Korea Atomic Energy Research Institute (KAERI). In this paper, for the one example of the probabilistic safety assessment approach, a method to estimate the failure probability and fragility of concrete wall subjected to impact loading caused by missiles or engine parts of aircrafts will be introduced. This method and the corresponding results will be used for the total technical roadmap and the procedure to assess the aircraft impact risk (Fig.1). A method and corresponding results of the estimation of the failure probability and fragility for a concrete wall subjected to impact loadings caused by missiles or engine parts of aircrafts was introduced. The detailed information of the target concrete wall in NPP, and the example aircraft engine model is considered safeguard information (SGI), and is not contained in this paper.

  16. Thinking through health capacity development for Fragile States.

    Science.gov (United States)

    Mark, Annabelle; Jones, Mike

    2013-01-01

    The purpose of this paper is to consider capacity development for healthcare in Fragile States and its roles, for example, in securing civil and political stability, as well as improved health, within the various contexts prevailing in fragile settings across the world. As a precursor to this, however, it is important to understand how, in rapidly changing environments, the role and contribution of different donors will have an impact in different ways. This paper sets out to interpret these issues, and what becomes apparent is the need to develop an understanding of the value base of donors, which we demonstrate through the development of a value-based framework. This highlights the separate motivations and choices made by donors, but what is apparent is that all remain within the positivist perspective perhaps for reasons of accountability and transparency. However, the emergence of new interpretations drawing on systems thinking, and followed by complexity theory more recently, in understanding contexts, suggests that the favouring of any one of these perspective can be counterproductive, without a consideration of the contexts in which they occur. In seeking an explanation of these environmental contexts, which also address the perspectives in use, we suggest the use of wider multi-ontology sense-making framework such as Cynefin. Through this approach, analytical insights can be given into the interpretation, decision and intervention processes available in these different and often changing environments, thus enabling greater coherence between donor values and recipient contexts. PMID:23047746

  17. Molecular/clinical correlations in females with fragile X

    Energy Technology Data Exchange (ETDEWEB)

    Sobesky, W.E.; Riddle, J.; Hagerman, R.J. [Children`s Hospital, Denver, CO (United States)] [and others

    1996-08-09

    Females who are affected by fragile X syndrome (FXS) can have significant physical, neuropsychological and emotional involvement. This study was designed to explore the relationships between these three domains and to learn how the degree of involvement in each of these phenotypic areas relates to molecular parameters including CGG repeat length and activation ratio (the proportion of normal FMR1 alleles on the active X chromosome). Three groups of females were studied: 35 women who grew up in a fragile X family but do not carry an FMR1 mutation, 92 women with a premutation, and 29 women with a full mutation. Correlations between neurocognitive, physical and emotional traits were calculated for each of the three groups. Within the full mutation group significant correlations were seen between schizotypal traits and full scale IQ. The Lie scale was significantly correlated with the physical findings index. The activation ratio correlated significantly with the measure of executive function (r = .50, P = .01). There was a trend toward correlations of activation ratio with the physical index score, outer ear prominence and IQ. CGG repeat number significantly correlated only with the physical index (r = .44, P = .0 1). Thus, activation ratio may be the more pertinent molecular parameter in full mutation women in determining the degree of cognitive and physical phenotypic involvement. 29 refs., 2 tabs.

  18. Molecular analysis of fragile X syndrome in Antalya Province

    Directory of Open Access Journals (Sweden)

    Bilgen T

    2005-04-01

    Full Text Available Background: Detection of the (CGGn repeats in the FMR1 gene that cause the fragile X syndrome (FXS, has become a milestone for phenotype-genotype correlation in FXS. Aims: To screen the FMR1 gene CGG repeats in index cases with FXS and their family members in the Antalya Province. Setting and design: This study was prospectively conducted between January 200and March 2005 in Department of Medical Biology and Genetics, Faculty of Medicine, Akdeniz University, Antalya. Materials and Methods: A series of 132 cases from three hospitals in Antalya Province were studied. All cases were molecularly screened using non-radioactive Expand Long PCR method that was confirmed by Southern blotting. Results: Seventeen out of 132 cases were found to have a full mutation, including three that were mosaic for premutations/full mutations. Of the 132 cases, eight were found to have the premutation size of the CGG repeats. The remaining 107 cases were identified as normal. Conclusions: Due to premature ovarian failure and Fragile X premutation Tremor/Ataxia Syndrome related with the premutation, the detection of the premutation will provide valuable information both for clinical follow-up and genetic counseling. In conclusion, our data suggest that expansion of CGG repeats in the FMR1 gene can be analyzed by Expand Long PCR, an efficient and non-radioactive method that can be used to monitor the expansion of premutation to full mutation, which would eventually lead to reduce the FXS prevalence.

  19. Fragility assessment method of Concrete Wall Subjected to Impact Loading

    International Nuclear Information System (INIS)

    These studies have been aimed to verify and ensure the safety of the targeted walls and structures especially in the viewpoint of the deterministic approach. However, recently, the regulation and the assessment of the safety of the nuclear power plants (NPPs) against to an aircraft impact are strongly encouraged to adopt a probabilistic approach, i.e., the probabilistic risk assessment of an aircraft impact. In Korea, research to develop aircraft impact risk quantification technology was initiated in 2012 by Korea Atomic Energy Research Institute (KAERI). In this paper, for the one example of the probabilistic safety assessment approach, a method to estimate the failure probability and fragility of concrete wall subjected to impact loading caused by missiles or engine parts of aircrafts will be introduced. This method and the corresponding results will be used for the total technical roadmap and the procedure to assess the aircraft impact risk (Fig.1). A method and corresponding results of the estimation of the failure probability and fragility for a concrete wall subjected to impact loadings caused by missiles or engine parts of aircrafts was introduced. The detailed information of the target concrete wall in NPP, and the example aircraft engine model is considered safeguard information (SGI), and is not contained in this paper

  20. Gene expression relationship between prostate cancer cells of Gleason 3, 4 and normal epithelial cells as revealed by cell type-specific transcriptomes

    International Nuclear Information System (INIS)

    Prostate cancer cells in primary tumors have been typed CD10-/CD13-/CD24hi/CD26+/CD38lo/CD44-/CD104-. This CD phenotype suggests a lineage relationship between cancer cells and luminal cells. The Gleason grade of tumors is a descriptive of tumor glandular differentiation. Higher Gleason scores are associated with treatment failure. CD26+ cancer cells were isolated from Gleason 3+3 (G3) and Gleason 4+4 (G4) tumors by cell sorting, and their gene expression or transcriptome was determined by Affymetrix DNA array analysis. Dataset analysis was used to determine gene expression similarities and differences between G3 and G4 as well as to prostate cancer cell lines and histologically normal prostate luminal cells. The G3 and G4 transcriptomes were compared to those of prostatic cell types of non-cancer, which included luminal, basal, stromal fibromuscular, and endothelial. A principal components analysis of the various transcriptome datasets indicated a closer relationship between luminal and G3 than luminal and G4. Dataset comparison also showed that the cancer transcriptomes differed substantially from those of prostate cancer cell lines. Genes differentially expressed in cancer are potential biomarkers for cancer detection, and those differentially expressed between G3 and G4 are potential biomarkers for disease stratification given that G4 cancer is associated with poor outcomes. Differentially expressed genes likely contribute to the prostate cancer phenotype and constitute the signatures of these particular cancer cell types

  1. Cerebral protein synthesis in a knockin mouse model of the fragile X premutation

    NARCIS (Netherlands)

    M. Qin (Mei); T. Huang (Tianjian); Z. Liu (Zhonghua); M. Kader (Michael); T. Burlin (Thomas); Z. Xia (Zengyan); Z. Zeidler (Zachary); R.K. Hukema (Renate); C.B. Smith (Carolyn B.)

    2014-01-01

    textabstractThe (CGG)n-repeat in the 5’-untransiated region of the fragile X mental retardation gene (FMRi) gene is polymorphic and may become unstable on transmission to the next generation. In fragile X syndrome, CGG repeat lengths exceed 200, resulting in silencing of FMRi and absence of its prot

  2. Ocular Motor Indicators of Executive Dysfunction in Fragile X and Turner Syndromes

    Science.gov (United States)

    Lasker, Adrian G.; Mazzocco, Michele M. M.; Zee, David S.

    2007-01-01

    Fragile X and Turner syndromes are two X-chromosome-related disorders associated with executive function and visual spatial deficits. In the present study, we used ocular motor paradigms to examine evidence that disruption to different neurological pathways underlies these deficits. We tested 17 females with fragile X, 19 females with Turner…

  3. Delineating the Profile of Autism Spectrum Disorder Characteristics in Cornelia de Lange and Fragile X Syndromes

    Science.gov (United States)

    Moss, Joanna; Oliver, Chris; Nelson, Lisa; Richards, Caroline; Hall, Scott

    2013-01-01

    An atypical presentation of autism spectrum disorder is noted in Cornelia de Lange and Fragile X syndromes, but there are few detailed empirical descriptions. Participants in this study were individuals with Cornelia de Lange syndrome (n = 130, M age = 17.19), Fragile X syndrome (n = 182, M age = 16.94), and autism spectrum disorder (n = 142, M…

  4. The correlation between fragility, density, and atomic interaction in glass-forming liquids

    Science.gov (United States)

    Wang, Lijin; Guan, Pengfei; Wang, W. H.

    2016-07-01

    The fragility that controls the temperature-dependent viscous properties of liquids as the glass transition is approached, in various glass-forming liquids with different softness of the repulsive part of atomic interactions at different densities, is investigated by molecular dynamic simulations. We show that the landscape of fragility in purely repulsive systems can be separated into three regions denoted as RI, RII, and RIII, respectively, with qualitatively disparate dynamic behaviors: RI which can be described by "softness makes strong glasses," RII where fragility is independent of softness and can only be tuned by density, and RIII with constant fragility, suggesting that density plays an unexpected role for understanding the repulsive softness dependence of fragility. What is more important is that we unify the long-standing inconsistence with respect to the repulsive softness dependence of fragility by observing that a glass former can be tuned more fragile if nonperturbative attraction is added into it. Moreover, we find that the vastly dissimilar influences of attractive interaction on fragility could be estimated from the structural properties of related zero-temperature glasses.

  5. Effective updating process of seismic fragilities using Bayesian method and information entropy

    International Nuclear Information System (INIS)

    Seismic probabilistic safety assessment (SPSA) is an effective method for evaluating overall performance of seismic safety of a plant. Seismic fragilities are estimated to quantify the seismically induced accident sequences. It is a great concern that the SPSA results involve uncertainties, a part of which comes from the uncertainty in the seismic fragility of equipment and systems. A straightforward approach to reduce the uncertainty is to perform a seismic qualification test and to reflect the results on the seismic fragility estimate. In this paper, we propose a figure-of-merit to find the most cost-effective condition of the seismic qualification tests about the acceleration level and number of components tested. Then a mathematical method to reflect the test results on the fragility update is developed. A Bayesian method is used for the fragility update procedure. Since a lognormal distribution that is used for the fragility model does not have a Bayes conjugate function, a parameterization method is proposed so that the posterior distribution expresses the characteristics of the fragility. The information entropy is used as the figure-of-merit to express importance of obtained evidence. It is found that the information entropy is strongly associated with the uncertainty of the fragility. (author)

  6. Autistic Features, Personality, and Adaptive Behavior in Males with the Fragile X Syndrome and No Autism.

    Science.gov (United States)

    Kerby, Dave S.; Dawson, Brenda L.

    1994-01-01

    Nine adult males with mental retardation resulting from Fragile X syndrome were compared to males with mental retardation of other etiology. Fragile X males showed a distinct psychological profile with more autistic features, more schizoid features, and more schizotypal features. These males were also more shy, more socially withdrawn, less…

  7. Mathematics Learning Disabilities in Girls with Fragile X or Turner Syndrome during Late Elementary School

    Science.gov (United States)

    Murphy, Melissa M.; Mazzocco, Michele M. M.

    2008-01-01

    The present study focuses on math and related skills among 32 girls with fragile X (n = 14) or Turner (n = 18) syndrome during late elementary school. Performance in each syndrome group was assessed relative to Full Scale IQ-matched comparison groups of girls from the general population (n = 32 and n = 89 for fragile X syndrome and Turner…

  8. Behavioral Assessment of Social Anxiety in Females with Turner or Fragile X Syndrome.

    Science.gov (United States)

    Lesniak-Karpiak, Katarzyna; Mazzocco, Michele M. M.; Ross, Judith L.

    2003-01-01

    This study compared 29 females with Turner syndrome and 21 females with fragile X syndrome (ages 6-22) on a videotaped role-play interaction with 34 females in a comparison group. Three of eight behavioral measures of social skills differentiated the participant groups. Fragile-X subjects required more time to initiate interactions and Turner…

  9. Resolution of Spatial and Temporal Visual Attention in Infants with Fragile X Syndrome

    Science.gov (United States)

    Farzin, Faraz; Rivera, Susan M.; Whitney, David

    2011-01-01

    Fragile X syndrome is the most common cause of inherited intellectual impairment and the most common single-gene cause of autism. Individuals with fragile X syndrome present with a neurobehavioural phenotype that includes selective deficits in spatiotemporal visual perception associated with neural processing in frontal-parietal networks of the…

  10. Discourse Skills of Boys with Fragile X Syndrome in Comparison to Boys with Down Syndrome

    Science.gov (United States)

    Roberts, Joanne; Martin, Gary E.; Moskowitz, Lauren; Harris, Adrianne A.; Foreman, Jamila; Nelson, Lauren

    2007-01-01

    Purpose: This study compared the conversational discourse skills of boys who have fragile X syndrome with and without autism spectrum disorder (ASD) with those of boys with Down syndrome and boys who are typically developing. Method: Participants were boys who have fragile X syndrome with (n = 26) and without (n = 28) ASD, boys with Down syndrome…

  11. Early White-Matter Abnormalities of the Ventral Frontostriatal Pathway in Fragile X Syndrome

    Science.gov (United States)

    Haas, Brian W.; Barnea-Goraly, Naama; Lightbody, Amy A.; Patnaik, Swetapadma S.; Hoeft, Fumiko; Hazlett, Heather; Piven, Joseph; Reiss, Allan L.

    2009-01-01

    Aim: Fragile X syndrome is associated with cognitive deficits in inhibitory control and with abnormal neuronal morphology and development. Method: In this study, we used a diffusion tensor imaging (DTI) tractography approach to reconstruct white-matter fibers in the ventral frontostriatal pathway in young males with fragile X syndrome (n = 17;…

  12. Examining the Function of Problem Behavior in Fragile X Syndrome: Preliminary Experimental Analysis

    Science.gov (United States)

    Langthorne, Paul; McGill, Peter; O'Reilly, Mark F.; Lang, Russell; Machalicek, Wendy; Chan, Jeffrey Michael; Rispoli, Mandy

    2011-01-01

    Fragile X syndrome is the most common inherited cause of intellectual and developmental disability. The influence of environmental variables on behaviors associated with the syndrome has received only scant attention. The current study explored the function served by problem behavior in fragile X syndrome by using experimental functional analysis…

  13. Adaptive Skills, Behavior Problems, and Parenting Stress in Mothers of Boys with Fragile X Syndrome

    Science.gov (United States)

    Sarimski, Klaus

    2010-01-01

    The relationship of temperament, atypical behaviors, and adaptive behavior of young boys with Fragile X syndrome on mothers' parenting stress was analyzed. Twenty-six boys with Fragile X syndrome (30-88 months of age) participated. The overall development of the participants was significantly delayed with a specific profile of adaptive behaviors…

  14. Differences in Visual Orienting between Persons with Down or Fragile X Syndrome

    Science.gov (United States)

    Flanagan, Tara; Enns, James T.; Murphy, Melissa M.; Russo, Natalie; Abbeduto, Leonard; Randolph, Beth; Burack, Jacob A.

    2007-01-01

    The voluntary and reflexive orienting abilities of persons with Down syndrome and fragile X syndrome, at average MA levels of approximately 4 and 7 years, were compared with an RT task. Reflexive orienting abilities appeared to develop in accordance with MA for the participants with Down syndrome but not for those with fragile X syndrome. However,…

  15. The Trajectory of Mathematics Skills and Working Memory Thresholds in Girls with Fragile X Syndrome

    Science.gov (United States)

    Murphy, Melissa M.; Mazzocco, Michele M. M.

    2009-01-01

    Fragile X syndrome is a common genetic disorder associated with executive function deficits and poor mathematics achievement. In the present study, we examined changes in math performance during the elementary and middle school years in girls with fragile X syndrome, changes in the working memory loads under which children could complete a…

  16. Positron Emission Tomography (PET Quantification of GABAA Receptors in the Brain of Fragile X Patients.

    Directory of Open Access Journals (Sweden)

    Charlotte D'Hulst

    Full Text Available Over the last several years, evidence has accumulated that the GABAA receptor is compromised in animal models for fragile X syndrome (FXS, a common hereditary form of intellectual disability. In mouse and fly models, agonists of the GABAA receptor were able to rescue specific consequences of the fragile X mutation. Here, we imaged and quantified GABAA receptors in vivo in brain of fragile X patients using Positron Emission Topography (PET and [11C]flumazenil, a known high-affinity and specific ligand for the benzodiazepine site of GABAA receptors. We measured regional GABAA receptor availability in 10 fragile X patients and 10 control subjects. We found a significant reduction of on average 10% in GABAA receptor binding potential throughout the brain in fragile X patients. In the thalamus, the brain region showing the largest difference, the GABAA receptor availability was even reduced with 17%. This is one of the first reports of a PET study of human fragile X brain and directly demonstrates that the GABAA receptor availability is reduced in fragile X patients. The study reinforces previous hypotheses that the GABAA receptor is a potential target for rational pharmacological treatment of fragile X syndrome.

  17. Prepulse Inhibition in Patients with Fragile X-associated Tremor Ataxia Syndrome

    OpenAIRE

    Schneider, Andrea; Ballinger, Elizabeth; Chavez, Alyssa; Tassone, Flora; Randi J Hagerman; Hessl, David

    2010-01-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects carriers of the fragile X premutation, typically after age 50. Common symptoms include intention tremor, ataxia, neuropathy, autonomic dysfunction, cognitive decline, and dementia.

  18. Does Attention Constrain Developmental Trajectories in Fragile X Syndrome? A 3-Year Prospective Longitudinal Study

    Science.gov (United States)

    Cornish, Kim; Cole, Victoria; Longhi, Elena; Karmiloff-Smith, Annette; Scerif, Gaia

    2012-01-01

    Basic attentional processes and their impact on developmental trajectories in fragile X syndrome were assessed in a 3-year prospective study. Although fragile X syndrome is a monogenic X-linked disorder, there is striking variability in outcomes even in young boys with the condition. Attention is a key factor constraining interactions with the…

  19. Behavioral Intervention for Problem Behavior in Children with Fragile X Syndrome

    Science.gov (United States)

    Moskowitz, Lauren J.; Carr, Edward G.; Durand, V. Mark

    2011-01-01

    Parents and professionals typically report problem behavior as a significant concern for children with fragile X syndrome. In the present study, the authors explored whether behaviorally based interventions would result in a reduction in problem behavior and an improvement in quality of life for 3 children with fragile X syndrome and their…

  20. Expressive Language during Conversational Speech in Boys with Fragile X Syndrome

    Science.gov (United States)

    Roberts, Joanne E.; Hennon, Elizabeth A.; Price, Johanna R.; Dear, Elizabeth; Anderson, Kathleen; Vandergrift, Nathan A.

    2007-01-01

    We compared the expressive syntax and vocabulary skills of 35 boys with fragile X syndrome and 27 younger typically developing boys who were at similar nonverbal mental levels. During a conversational speech sample, the boys with fragile X syndrome used shorter, less complex utterances and produced fewer different words than did the typically…

  1. An Investigation of Narrative Ability in Boys with Autism and Fragile X Syndrome

    Science.gov (United States)

    Hogan-Brown, Abigail L.; Losh, Molly; Martin, Gary E.; Mueffelmann, Deborah J.

    2013-01-01

    Whereas pragmatic language difficulties are characteristic of both autism and Fragile X syndrome, it is unclear whether such deficits are qualitatively similar or whether certain skills are differentially affected. This study compared narrative competence in boys with autism, Fragile X syndrome, Down syndrome, and typical development. Results…

  2. Public private cooperation fragile states: Report on field research mission to North Kivu and Ituri

    NARCIS (Netherlands)

    Douma, P.; Bolhuis, E.E.; Klaver, D.C.; Zawadi, Y.

    2009-01-01

    This field study is part of the Schokland project to research among others the possibilities for Public Private Cooperation (PPC) in stimulating Economic Growth in Fragile States. Fragile states are relatively far behind in achieving the Millennium Development Goals (MDGs) and in order to reduce fra

  3. Identifying aid effectiveness challenges in fragile and conflict-affected states

    OpenAIRE

    Ishihara, Yoichiro

    2012-01-01

    Fragile and conflict-affected states face daunting challenges for development. Aid has a greater importance on development in these states than in others, and therefore aid effectiveness management and delivery of aid bears serious consideration. Despite its significance, aid effectiveness is appreciably lower in fragile and conflict-affected states than in others. What are the key aid ...

  4. Between Development and Security: The European Union, Governance and Fragile States

    NARCIS (Netherlands)

    W. Hout (Wil)

    2009-01-01

    textabstractThis paper presents an analysis of recently adopted EU policies on fragile states. While the European Union has incorporated governance issues into its strategies for fragile states, its approach to governance has a highly technocratic character, with a strong emphasis on public sector r

  5. Success in Difficult Environments : A Portfolio Analysis of Fragile and Conflict-Affected States

    OpenAIRE

    Ralston, Laura

    2014-01-01

    The World Bank Group has identified support to fragile and conflict-affected states as a strategic priority. This paper provides a systematic portfolio review of the International Development Association-funded projects in fragile and conflict-affected states during 2001 to 2013 and a detailed empirical analysis of the correlations between project and country-level characteristics with pro...

  6. Promoting democracy in fragile states : insights from a field experiment in Liberia

    OpenAIRE

    Mvukiyehe, Eric; Samii, Cyrus

    2015-01-01

    A field experiment in rural Liberia is used to study democratic participation in fragile states. Fragile states are marked by political fragmentation, local patronage systems, and voter vulnerability. To understand the effects of such conditions on democratic expression through elections, the experiment introduced new forms of interaction between rural citizens and third-party actors: (i) ...

  7. A Multiple Interaction Analysis Reveals ADRB3 as a Potential Candidate for Gallbladder Cancer Predisposition via a Complex Interaction with Other Candidate Gene Variations.

    Science.gov (United States)

    Rai, Rajani; Kim, Jong Joo; Misra, Sanjeev; Kumar, Ashok; Mittal, Balraj

    2015-01-01

    Gallbladder cancer is the most common and a highly aggressive biliary tract malignancy with a dismal outcome. The pathogenesis of the disease is multifactorial, comprising the combined effect of multiple genetic variations of mild consequence along with numerous dietary and environmental risk factors. Previously, we demonstrated the association of several candidate gene variations with GBC risk. In this study, we aimed to identify the combination of gene variants and their possible interactions contributing towards genetic susceptibility of GBC. Here, we performed Multifactor-Dimensionality Reduction (MDR) and Classification and Regression Tree Analysis (CRT) to investigate the gene-gene interactions and the combined effect of 14 SNPs in nine genes (DR4 (rs20576, rs6557634); FAS (rs2234767); FASL (rs763110); DCC (rs2229080, rs4078288, rs7504990, rs714); PSCA (rs2294008, rs2978974); ADRA2A (rs1801253); ADRB1 (rs1800544); ADRB3 (rs4994); CYP17 (rs2486758)) involved in various signaling pathways. Genotyping was accomplished by PCR-RFLP or Taqman allelic discrimination assays. SPSS software version 16.0 and MDR software version 2.0 were used for all the statistical analysis. Single locus investigation demonstrated significant association of DR4 (rs20576, rs6557634), DCC (rs714, rs2229080, rs4078288) and ADRB3 (rs4994) polymorphisms with GBC risk. MDR analysis revealed ADRB3 (rs4994) to be crucial candidate in GBC susceptibility that may act either alone (p ADRB3 rs4994 as candidate influencing GBC susceptibility. PMID:26602921

  8. Handbook of nuclear power plant seismic fragilities, Seismic Safety Margins Research Program

    Energy Technology Data Exchange (ETDEWEB)

    Cover, L.E.; Bohn, M.P.; Campbell, R.D.; Wesley, D.A.

    1983-12-01

    The Seismic Safety Margins Research Program (SSMRP) has a gola to develop a complete fully coupled analysis procedure (including methods and computer codes) for estimating the risk of an earthquake-induced radioactive release from a commercial nuclear power plant. As part of this program, calculations of the seismic risk from a typical commercial nuclear reactor were made. These calculations required a knowledge of the probability of failure (fragility) of safety-related components in the reactor system which actively participate in the hypothesized accident scenarios. This report describes the development of the required fragility relations and the data sources and data reduction techniques upon which they are based. Both building and component fragilities are covered. The building fragilities are for the Zion Unit 1 reactor which was the specific plant used for development of methodology in the program. Some of the component fragilities are site-specific also, but most would be usable for other sites as well.

  9. Handbook of nuclear power plant seismic fragilities, Seismic Safety Margins Research Program

    International Nuclear Information System (INIS)

    The Seismic Safety Margins Research Program (SSMRP) has a gola to develop a complete fully coupled analysis procedure (including methods and computer codes) for estimating the risk of an earthquake-induced radioactive release from a commercial nuclear power plant. As part of this program, calculations of the seismic risk from a typical commercial nuclear reactor were made. These calculations required a knowledge of the probability of failure (fragility) of safety-related components in the reactor system which actively participate in the hypothesized accident scenarios. This report describes the development of the required fragility relations and the data sources and data reduction techniques upon which they are based. Both building and component fragilities are covered. The building fragilities are for the Zion Unit 1 reactor which was the specific plant used for development of methodology in the program. Some of the component fragilities are site-specific also, but most would be usable for other sites as well

  10. Robust and fragile Werner states in the collective dephasing Robust and fragile Werner states in the collective dephasing

    CERN Document Server

    Li, S B; Li, S B; Xu, J B; Li, Shang-Bin; Xu, Jing-Bo; Li, Shang-Bin; Xu, Jing-Bo

    2005-01-01

    We investigate the concurrence and Bell violation of the Werner or Werner-like states in the presence of collective dephasing. It is shown that the Werner and certain kinds of Werner-like states are robust against the collective dephasing, and some kinds of Werner-like states is fragile and becomes completely disentangled in a finite-time. The threshold time of complete disentanglement of the Werner state is given. The influence of external driving field on the finite-time disentanglement of Werner states is discussed. Finally, we present a simple method to control the stationary state entanglement of two qubits. We investigate the concurrence and Bell violation of the Werner or Werner-like states in the presence of collective dephasing. It is shown that the Werner and certain kinds of Werner-like states are robust against the collective dephasing, and some kinds of Werner-like states is fragile and becomes completely disentangled in a finite-time. The threshold time of complete disentanglement of the Werner ...

  11. Modest alterations in patterns of motor neuron dendrite morphology in the Fmr1 knockout mouse model for Fragile X

    OpenAIRE

    Thomas, Christina C.; Combe, Crescent L.; Dyar, Kenneth A.; Inglis, Fiona M.

    2008-01-01

    Fragile X, an inheritable form of mental retardation, is caused by the inactivation of a gene on the X chromosome, FMR1 which codes for an RNA binding protein, Fragile X Mental Retardation Protein. Loss of this protein is associated with reduced complexities of neuronal dendrites and alterations in spine morphology in a number of cortical brain regions, and these deficits may underlie the cognitive impairment observed in fragile X patients. Among the many symptoms of fragile X are altered mot...

  12. Fluorescent in-situ hybridization of cattle and sheep chromosomes with cloned human fragile-X DNA

    DEFF Research Database (Denmark)

    Ali, Ahmd; Thomsen, Preben Dybdahl; Babar, M.E.

    2009-01-01

    An extensive study on spontaneous and 5-Fluorodeoxyuridine induced fragile sites identified Xq31 in cattle (Bos taurus) and (Xq24, Xq26) in sheep (Ovis aries) in addition to several autosomal fragile sites (under publication). A ZOO-FISH study using three cloned human fragile-X probes with CCG...

  13. Scaling Up Family Therapy in Fragile, Conflict-Affected States.

    Science.gov (United States)

    Charlés, Laurie L

    2015-09-01

    This article discusses the design and delivery of two international family therapy-focused mental health and psychosocial support training projects, one in a fragile state and one in a post-conflict state. The training projects took place in Southeast Asia and the Middle East/North Africa. Each was funded, supported, and implemented by local, regional, and international stakeholders, and delivered as part of a broader humanitarian agenda to develop human resource capacity to work with families affected by atrocities. The two examples illustrate how task-shifting/task-sharing and transitional justice approaches were used to inform the scaling-up of professionals involved in each project. They also exemplify how state-citizen phenomena in each location affected the project design and delivery. PMID:25315510

  14. Improved response factor methods for seismic fragility of reactor building

    International Nuclear Information System (INIS)

    A seismic probabilistic risk assessment (PRA) method has been applied to evaluate the safety of nuclear reactor buildings during earthquakes. Improvement was made to two methods (based on linear response and based on non-linear response) of fragility analysis in seismic PRA. The conventional method, which is based on linear response, considers increases of seismic capacity implicitly, using the non-linear behaviour of the structure. We described how to evaluate the capacity increasing factor for the linear response method. Secondly, we proposed a method based on the non-linear response and a stratified two-point estimation method which can efficiently evaluate the variability of non-linear responses. We applied the two method to a PWR-type nuclear reactor building and ascertained that these method are useful and effective. (orig.)

  15. Eastern Seaboard Electric Grid Fragility Maps Supporting Persistent Availability

    Energy Technology Data Exchange (ETDEWEB)

    Walker, Kimberly A [ORNL; Weigand, Gilbert G [ORNL; Fernandez, Steven J [ORNL

    2012-11-01

    Persistently available power transmission can be disrupted by weather causing power outages with economic and social consequences. This research investigated the effects on the national power grid from a specific weather event, Hurricane Irene, that caused approximately 5.7 million customer power outages along the Eastern Seaboard in August of 2011. The objective was to describe the geographic differences in the grid s vulnerability to these events. Individual factors, such as wind speed or precipitation, were correlated with the number of outages to determine the greatest mechanism of power failure in hopes of strengthening the future power grid. The resulting fragility maps not only depicted 18 counties that were less robust than the design-standard robustness model and three counties that were more robust, but also drew new damage contours with correlated wind speeds and county features.

  16. The quest for targeted therapy in fragile X syndrome.

    Science.gov (United States)

    Zeidler, Shimriet; Hukema, Renate K; Willemsen, Rob

    2015-01-01

    Fragile X syndrome (FXS) is the most common, monogenetic cause of intellectual disability and autism-spectrum disorders. Although there is no effective therapy, greater understanding of disturbed neuronal pathways has introduced options for targeted therapy. But whereas many FXS phenotypes were improved in preclinical studies with drugs targeting these pathways in the FXS mouse model, attempts to translate these animal-model success stories into treatment of patients in clinical trials have been extremely disappointing. Complicating factors, particularly in animal studies, include mouse inbred strains, variability in functional studies between laboratories, publication bias and lack of reliable and objective primary outcome measures in both mice and patients. Possibly most important, however, is one factor that has been little explored: the complexity of the molecular imbalance in FXS and the need to simultaneously target several different disturbed pathways and different cellular compartments. New, well-conceived animal studies should generate more productive approaches in the quest for targeted therapy for FXS. PMID:26294013

  17. Fragile X-associated disorders: a clinical overview.

    Science.gov (United States)

    Gallagher, Anne; Hallahan, Brian

    2012-03-01

    Fragile X Syndrome (FraX) is the most common inherited cause of learning disability worldwide. FraX is an X-linked neuro-developmental disorder involving an unstable trinucleotide repeat expansion of cytosine guanine guanine (CGG). Individuals with the full mutation of FraX have >200 GG repeats with premutation carriers having 55-200 GG repeats. A wide spectrum of physical, behavioural, cognitive, psychiatric and medical problems have been associated with both full mutation and premutation carriers of FraX. In this review, we detail the clinical profile and examine the aetiology, epidemiology, neuropathology, neuroimaging findings and possible management strategies for individuals with both the full mutation and premutation of FraX. PMID:21748281

  18. Resilience in the face of fragile X syndrome.

    Science.gov (United States)

    Fourie, Chantel L; Theron, Linda C

    2012-10-01

    In this article, we communicate transformative findings from a case study on the resilience of a young woman with fragile X syndrome (FXS), a genetic condition involving mental impairment and physical, emotional, and behavioral challenges. We explored the resilience of "Lucy," a spirited 16-year-old North American, using informal interviews with her, formal interviews with significant adults in her life, and observations (visual and anecdotal) over 20 months. In reporting the information-rich case of Lucy, well supported by her ecology to rise above full-mutation FXS, we encourage a positive perspective of living with FXS. Although we recognize the limitations of a single case study, our findings offer tentative, process-oriented insights into resilience in contexts of genetic disability, previously unreported in conjunction with FXS. We concluded that the processes informing Lucy's resilience were partly her responsibility and partly her social ecology's, and comprised intrapersonal agency, unconditional positive acceptance and belonging, and support toward mastery. PMID:22745364

  19. Infant Development in Fragile X Syndrome: Cross-Syndrome Comparisons.

    Science.gov (United States)

    Roberts, Jane E; McCary, Lindsay M; Shinkareva, Svetlana V; Bailey, Donald B

    2016-06-01

    This study examined the developmental profile of male infants with fragile X syndrome (FXS) and its divergence from typical development and development of infants at high risk for autism associated with familial recurrence (ASIBs). Participants included 174 boys ranging in age from 5 to 28 months. Cross-sectional profiles on the Mullen Scales of Early Learning indicated infants with FXS could be differentiated from typically developing infants and ASIBs by 6 months of age. Infants with FXS displayed a trend of lower developmental skills with increasing age that was unique from the typically developing and ASIB groups. Findings suggest infants with FXS present with more significant, pervasive and early emerging delays than previously reported with potentially etiologically distinct developmental profiles. PMID:26864160

  20. Importance of liquid fragility for energy applications of ionic liquids

    Science.gov (United States)

    Sippel, P.; Lunkenheimer, P.; Krohns, S.; Thoms, E.; Loidl, A.

    2015-09-01

    Ionic liquids (ILs) are salts that are liquid close to room temperature. Their possible applications are numerous, e.g., as solvents for green chemistry, in various electrochemical devices, and even for such “exotic” purposes as spinning-liquid mirrors for lunar telescopes. Here we concentrate on their use for new advancements in energy-storage and -conversion devices: Batteries, supercapacitors or fuel cells using ILs as electrolytes could be important building blocks for the sustainable energy supply of tomorrow. Interestingly, ILs show glassy freezing and the universal, but until now only poorly understood dynamic properties of glassy matter, dominate many of their physical properties. We show that the conductivity of ILs, an essential figure of merit for any electrochemical application, depends in a systematic way not only on their glass temperature but also on the so-called fragility, characterizing the non-canonical super-Arrhenius temperature dependence of their ionic mobility.