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Sample records for pk tp system

  1. Standard systems for measurement of pK values and ionic mobilities: 2. Univalent weak bases.

    Science.gov (United States)

    Slampová, Andrea; Krivánková, Ludmila; Gebauer, Petr; Bocek, Petr

    2009-04-24

    This paper contributes to the methodology of measuring pK values and ionic mobilities by capillary zone electrophoresis by introducing the principle of constant ionic strength and minimum interaction of analytes with counterionic components and presenting a standard system of cationic buffers for measurements of weak bases. The system is designed so that all buffers comprise the same concentration of Cl(-) present as the only counter anion. This minimizes problems caused by interactions between the counterion and the analytes which may otherwise bring biased values of obtained effective mobilities. Further, the buffer system provides constant and accurately known ionic strength for an entire set of measurements. When additionally all measurements are performed with constant Joule heating, one correction for ionic strength and temperature is then needed for the obtained set of experimental data. This considerably facilitates their evaluation and regression analysis as the corrections for ionic strength and Joule heating need not be implemented in the computation software and may be applied only once to the final regression results. An experimental example of the proposed methodology is presented and the reliability and the advantages of the proposed system are shown, where the known problematic groups of amines and pyridine were measured with high accuracy and without any notice of anomalous behavior.

  2. Real-Time Monitoring of TP Load in a Mississippi Delta Stream Using a Dynamic Data Driven Application System

    Science.gov (United States)

    Ouyang, Y.; Leininger, T.; Hatten, J. A.

    2012-12-01

    Elevated phosphorus (P) in surface waters can cause eutrophication of aquatic ecosystems and can impair water for drinking, industry, agriculture, and recreation. Currently, little effort has been devoted to monitoring real-time variation and load of total P (TP) in surface waters due to the lack of suitable and/or cost-effective wireless sensors. However, when considering human health, drinking water supply, and rapidly developing events such as algal blooms, the availability of timely P information is very critical. In this study, we developed a new approach in the form of a dynamic data driven application system (DDDAS) for monitoring the real-time variation and load of TP in surface water. This DDDAS consisted of the following three major components: (1) a User Control that interacts with Schedule Run to implement the DDDAS with starting and ending times; (2) a Schedule Run that activates the Hydstra model; and (3) a Hydstra model that downloads the real-time data from a US Geological Survey (USGS) website that is updated every 15 minutes with data from USGS monitoring stations, predicts real-time variation and load of TP, graphs the variables in real-time on a computer screen, and sends email alerts when the TP exceeds a certain value. The DDDAS was applied to monitor real-time variation and load of TP for 30 days in Deer Creek, a stream located east of Leland, Mississippi, USA. Results showed that the TP contents in the stream ranged from 0.24 to 0.48 mg L-1 with an average of 0.30 mg L-1 for a 30-day monitoring period, whereas the cumulative load of TP from the stream was about 2.8kg for the same monitoring period. Our study suggests that the DDDAS developed in this study was useful for estimating the real-time variation and load of TP in surface water ecosystems.

  3. Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer

    NARCIS (Netherlands)

    P.M.J.J. Berns (Els); C.J. Cornelisse (Cees); J.A. Foekens (John); R. Vossen; M.P. Look (Maxime); J.G.M. Klijn (Jan); P. Devilee (Peter); S.C. Henzen-Logmans; I.L. van Staveren (Iris); B. Bakker (Bert); W.L.J. van Putten (Wim); M. Inganas; H. Portengen (Henk); M.E. Meijer van Gelder (Marion); C.J. Claassen

    2000-01-01

    textabstractTP53 has been implicated in regulation of the cell cycle, DNA repair, and apoptosis. We studied, in primary breast tumors through direct cDNA sequencing of exons 2-11, whether TP53 gene mutations can predict response in patients with advanced disease to either

  4. Systemic injection of kainic acid: Gliosis in olfactory and limbic brain regions quantified with ( sup 3 H)PK 11195 binding autoradiography

    Energy Technology Data Exchange (ETDEWEB)

    Altar, C.A.; Baudry, M. (Genentech, Inc., South San Francisco, CA (USA))

    1990-09-01

    Neurodegenerative diseases may result from excessive stimulation of excitatory amino acid receptors by endogenous ligands. Because neuronal degeneration is associated with glial proliferation and hypertrophy, the degenerative changes throughout rat brain following the systemic administration of kainic acid (12 mg/kg) were mapped with quantitative autoradiography of (3H)PK 11195. This radioligand binds to a mitochondrial benzodiazepine binding site (MBBS) on microglia and astrocytes. Analysis of eight horizontal and four coronal brain levels revealed up to 16-fold increases in (3H)PK 11195 binding from 1 to 5 weeks but not 1 day after kainate injection. Increases in (3H)PK 11195 binding were predominantly in ventral limbic brain regions and olfactory projections to neocortical areas, with the olfactory cortex greater than subiculum/CA1 greater than anterior olfactory nucleus, medial thalamic nucleus, and piriform cortex greater than cingulate cortex and rostral hippocampus greater than dentate gyrus, septum, and amygdala greater than entorhinal cortex and temporal cortex. Little or no enhancement of (3H)PK 11195 binding was observed in numerous regions including the caudate-putamen, substantia nigra, nucleus accumbens, olfactory tubercle, cerebellum, thalamic nuclei, choroid plexus, medulla, parietal or occipital cortex, or pons. A 2-fold greater extent of neurodegeneration was obtained in ventral portions of the olfactory bulb, entorhinal cortex, temporal cortex, and dentate gyrus compared with the dorsal portions of these structures. The pattern of increase in (3H)PK 11195 binding closely matched the patterns of neuronal degeneration reported following parenteral kainate injection. These findings strengthen the notion that quantitative autoradiography of (3H)PK 11195 is a valuable tool to quantify the extent of neuronal degeneration.

  5. TP53 hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy.

    Science.gov (United States)

    Munch-Petersen, Helga D; Asmar, Fazila; Dimopoulos, Konstantinos; Areškevičiūtė, Aušrinė; Brown, Peter; Girkov, Mia Seremet; Pedersen, Anja; Sjö, Lene D; Heegaard, Steffen; Broholm, Helle; Kristensen, Lasse S; Ralfkiaer, Elisabeth; Grønbæk, Kirsten

    2016-04-22

    Primary central nervous system lymphoma (PCNSL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) confined to the CNS. TP53 mutations (MUT-TP53) were investigated in the context of MIR34A/B/C- and DAPK promoter methylation status, and associated with clinical outcomes in PCNSL patients. In a total of 107 PCNSL patients clinical data were recorded, histopathology reassessed, and genetic and epigenetic aberrations of the p53-miR34-DAPK network studied. TP53 mutational status (exon 5-8), with structural classification of single nucleotide variations according to the IARC-TP53-Database, methylation status of MIR34A/B/C and DAPK, and p53-protein expression were assessed. The 57/107 (53.2 %) patients that were treated with combination chemotherapy +/- rituximab (CCT-treated) had a significantly better median overall survival (OS) (31.3 months) than patients treated with other regimens (high-dose methotrexate/whole brain radiation therapy, 6.0 months, or no therapy, 0.83 months), P TP53 mutations were identified in 32/86 (37.2 %), among which 12 patients had hotspot/direct DNA contact mutations. CCT-treated patients with PCNSL harboring a hotspot/direct DNA contact MUT-TP53 (n = 9) had a significantly worse OS and progression free survival (PFS) compared to patients with non-hotspot/non-direct DNA contact MUT-TP53 or wild-type TP53 (median PFS 4.6 versus 18.2 or 45.7 months), P = 0.041 and P = 0.00076, respectively. Multivariate Cox regression analysis confirmed that hotspot/direct DNA contact MUT-TP53 was predictive of poor outcome in CCT-treated PCNSL patients, P = 0.012 and P = 0.008; HR: 1.86 and 1.95, for OS and PFS, respectively. MIR34A, MIR34B/C, and DAPK promoter methylation were detected in 53/93 (57.0 %), 80/84 (95.2 %), and 70/75 (93.3 %) of the PCNSL patients with no influence on survival. Combined MUT-TP53 and MIR34A methylation was associated with poor PFS (median 6.4 versus 38.0 months), P = 0.0070. This

  6. TP Decoding

    CERN Document Server

    Lu, Yi; Montanari, Andrea

    2007-01-01

    'Tree pruning' (TP) is an algorithm for probabilistic inference on binary Markov random fields. It has been recently derived by Dror Weitz and used to construct the first fully polynomial approximation scheme for counting independent sets up to the `tree uniqueness threshold.' It can be regarded as a clever method for pruning the belief propagation computation tree, in such a way to exactly account for the effect of loops. In this paper we generalize the original algorithm to make it suitable for decoding linear codes, and discuss various schemes for pruning the computation tree. Further, we present the outcomes of numerical simulations on several linear codes, showing that tree pruning allows to interpolate continuously between belief propagation and maximum a posteriori decoding. Finally, we discuss theoretical implications of the new method.

  7. DNA-PK assay

    Science.gov (United States)

    Anderson, Carl W.; Connelly, Margery A.

    2004-10-12

    The present invention provides a method for detecting DNA-activated protein kinase (DNA-PK) activity in a biological sample. The method includes contacting a biological sample with a detectably-labeled phosphate donor and a synthetic peptide substrate defined by the following features to provide specific recognition and phosphorylation by DNA-PK: (1) a phosphate-accepting amino acid pair which may include serine-glutamine (Ser-Gln) (SQ), threonine-glutamine (Thr-Gln) (TQ), glutamine-serine (Gln-Ser) (QS), or glutamine-threonine (Gln-Thr) (QT); (2) enhancer amino acids which may include glutamic acid or glutamine immediately adjacent at the amino- or carboxyl- side of the amino acid pair and forming an amino acid pair-enhancer unit; (3) a first spacer sequence at the amino terminus of the amino acid pair-enhancer unit; (4) a second spacer sequence at the carboxyl terminus of the amino acid pair-enhancer unit, which spacer sequences may include any combination of amino acids that does not provide a phosphorylation site consensus sequence motif; and, (5) a tag moiety, which may be an amino acid sequence or another chemical entity that permits separating the synthetic peptide from the phosphate donor. A compostion and a kit for the detection of DNA-PK activity are also provided. Methods for detecting DNA, protein phosphatases and substances that alter the activity of DNA-PK are also provided. The present invention also provides a method of monitoring protein kinase and DNA-PK activity in living cells. -A composition and a kit for monitoring protein kinase activity in vitro and a composition and a kit for monitoring DNA-PK activities in living cells are also provided. A method for identifying agents that alter protein kinase activity in vitro and a method for identifying agents that alter DNA-PK activity in living cells are also provided.

  8. Transcellular transport of 4-iodo-L-meta-tyrosine via system L across monolayers of kidney epithelial cell line LLC-PK{sub 1}

    Energy Technology Data Exchange (ETDEWEB)

    Shikano, Naoto E-mail: sikano@ipu.ac.jp; Kawai, Keiichi; Nakajima, Syuichi; Kubodera, Akiko; Kubota, Nobuo; Ishikawa, Nobuyoshi; Saji, Hideo

    2004-05-01

    The substance 4-[{sup 125}I]iodo-L-meta-tyrosin (4-[{sup 125}I]mTyr) is a radioiodinated amino acid that exhibits high in vivo stability and rapid renal elimination in vivo. We investigated transport of 4-[{sup 125}I]mTyr in LLC-PK{sub 1} (porcine kidney epithelial cell line) monolayers grown on collagen-coated, micro-porous membrane filters. We found that 4-[{sup 125}I]mTyr transport in LLC-PK{sub 1} cells was carrier-mediated and sodium-independent, and that 4-[{sup 125}I]mTyr transport was similar to that of L-Tyr and 3-iodo-{alpha}-methyl-L-tyrosine. The results of the inhibition experiments suggest that 4-[{sup 125}I]mTyr transport is predominantly mediated by a L-type amino acid transporter 1-like porcine homologue (a component of system L) in both basolateral and apical membrane.

  9. Omega 3 (peripheral type benzodiazepine binding) site distribution in the rat immune system: an autoradiographic study with the photoaffinity ligand (/sup 3/H)PK 14105

    Energy Technology Data Exchange (ETDEWEB)

    Benavides, J.; Dubois, A.; Dennis, T.; Hamel, E.; Scatton, B.

    1989-04-01

    The anatomical distribution of omega 3 (peripheral type benzodiazepine binding) sites in the immune system organs of the rat has been studied autoradiographically at both macroscopic and microscopic levels of resolution using either reversible or irreversible (UV irradiation) labeling with (/sup 3/H)PK 14105. In thymus sections, (/sup 3/H)PK 14105 labeled with high affinity (Kd, derived from saturation experiments = 10.8 nM) a single population of sites which possessed the pharmacological characteristics of omega 3 sites. In the thymus gland, higher omega 3 site densities were detected in the cortex than in the medulla; in these subregions, silver grains were associated to small (10-18 microns diameter) cells. In the spleen, omega 3 sites were more abundant in the white than in the red pulp. In the white pulp, silver grains were denser in the marginal zone than in the vicinity of the central artery and labeling was, as in the thymus, associated to small cytoplasm-poor cells. In the red pulp, omega 3 site associated silver grains were observed mainly in the Bilroth cords. In the lymph nodes, the medullary region showed a higher labeling than the surrounding follicles and paracortex. A significant accumulation of silver grains was observed in the lymph node medullary cords. In the intestine, Peyer patches were particularly enriched in omega 3 sites (especially in the periphery of the follicles). The distribution of omega 3 sites in the immune system organs suggests a preferential labeling of cells of T and monocytic lineages. This is consistent with the proposed immunoregulatory properties of some omega 3 site ligands.

  10. Real-time estimation of TP load in a Mississippi Delta Stream using a dynamic data driven application system

    Science.gov (United States)

    Ying Ouyang; Theodor D. Leininger; Jeff Hatten

    2013-01-01

    Elevated phosphorus (P) in surface waters can cause eutrophication of aquatic ecosystems and can impair water for drinking, industry, agriculture, and recreation. Currently, no effort has been devoted to estimating real-time variation and load of total P (TP) in surface waters due to the lack of suitable and/or cost-effective wireless sensors. However, when considering...

  11. Association study between the TP53 Rs1042522G/C polymorphism and susceptibility to systemic lupus erythematosus in a Chinese Han population.

    Science.gov (United States)

    Yang, Jie; Zhu, Ji-Min; Wu, Song; Li, Jing; Wang, Ming-Rui; Wang, Ting-Ting; Lu, Yu-Wei

    2017-04-01

    Tumour suppressor protein 53 (p53) plays a central role in apoptosis, cell proliferation and death. Previously studies found contribution of functional p53 Arg72Pro polymorphism (TP53 rs1042522G/C polymorphism) in the development of systemic lupus erythematosus (SLE) remains controversial. In this study, for the first time, we evaluated its association with SLE in a Chinese Han population. This case-control study enrolled 1470 SLE patients and 2283 healthy controls. The genotyping of TP53 rs1042522 polymorphism was determined by Sequenom Mass ARRAY technology. Statistical analysis was conducted by Chi-square test (χ (2) test). Odds ratio (OR) with 95% confidence interval (CI) was calculated using unconditional logistic regression with adjusting age and sex. Allele and genotype frequencies of TP53 rs1042522G/C polymorphism showed statistically significant difference between the SLE patients and the normal controls (C vs. G: OR = 0.89, 95% CI 0.89-0.97, p = 0.01; (GC + CC) vs. GG using recessive model: OR = 0.84, 95% CI 0.73-0.96, p = 0.01; GC vs. GG using co-dominant model: OR = 0.86, 95% CI 0.74-0.99, p = 0.04; CC vs. GG using co-dominant model: OR = 0.80, 95% CI 0.66-0.96, p = 0.02; GC vs. GG using co-dominant model: OR = 0.86, 95% CI 0.74-0.99, p = 0.02). In addition, there was weak association between discoid rash and distribution of TP53 rs1042522G/C polymorphism in SLE patients (C vs. G: OR = 1.25, 95% CI 1.00-1.55, p = 0.04; CC vs. GG using co-dominant model: OR = 1.54, 95% CI 1.10-2.36, p = 0.04). Our finding suggests a significant relationship between the TP53 rs1042522G/C polymorphism and SLE. TP53 rs1042522G/C polymorphism would be promising as an indicator of SLE as well as the therapeutic target if its functions and mechanisms could be further investigated.

  12. Human Growth Hormone Delivery with a Microneedle Transdermal System: Preclinical Formulation, Stability, Delivery and PK of Therapeutically Relevant Doses

    Directory of Open Access Journals (Sweden)

    Mahmoud Ameri

    2014-05-01

    Full Text Available This study evaluated the feasibility of coating formulated recombinant human growth hormone (rhGH on a titanium microneedle transdermal delivery system, Zosano Pharma (ZP-hGH, and assessed preclinical patch delivery performance. Formulation rheology and surface activity were assessed by viscometry and contact angle measurement. rhGH liquid formulation was coated onto titanium microneedles by dip-coating and drying. The stability of coated rhGH was determined by size exclusion chromatography-high performance liquid chromatography (SEC-HPLC. Preclinical delivery and pharmacokinetic studies were conducted in female hairless guinea pigs (HGP using rhGH coated microneedle patches at 0.5 and 1 mg doses and compared to Norditropin® a commercially approved rhGH subcutaneous injection. Studies demonstrated successful rhGH formulation development and coating on microneedle arrays. The ZP-hGH patches remained stable at 40 °C for six months with no significant change in % aggregates. Pharmacokinetic studies showed that the rhGH-coated microneedle patches, delivered with high efficiency and the doses delivered indicated linearity with average Tmax of 30 min. The absolute bioavailability of the microneedle rhGH patches was similar to subcutaneous Norditropin® injections. These results suggest that ZP-transdermal microneedle patch delivery of rhGH is feasible and may offer an effective and patient-friendly alternative to currently marketed rhGH injectables.

  13. TP Organics - maheuuringute tehnoloogiaplatvorm

    Index Scriptorium Estoniae

    2015-01-01

    TP Organics on 2008. a loodud Euroopa mahepõllumajanduse ja mahetoidu ning vähese sisendiga põllumajanduse tehnoloogiaplatvorm. Platvormi eesmärk on selgitada välja teadustöö ja uuenduste vajadused ning edastada see info poliitikutele

  14. TP Organics - maheuuringute tehnoloogiaplatvorm

    Index Scriptorium Estoniae

    2015-01-01

    TP Organics on 2008. a loodud Euroopa mahepõllumajanduse ja mahetoidu ning vähese sisendiga põllumajanduse tehnoloogiaplatvorm. Platvormi eesmärk on selgitada välja teadustöö ja uuenduste vajadused ning edastada see info poliitikutele

  15. TP53 hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy

    DEFF Research Database (Denmark)

    Munch-Petersen, Helga D; Asmar, Fazila; Dimopoulos, Konstantinos;

    2016-01-01

    that hotspot/direct DNA contact MUT-TP53 was predictive of poor outcome in CCT-treated PCNSL patients, P = 0.012 and P = 0.008; HR: 1.86 and 1.95, for OS and PFS, respectively. MIR34A, MIR34B/C, and DAPK promoter methylation were detected in 53/93 (57.0 %), 80/84 (95.2 %), and 70/75 (93.3 %) of the PCNSL...

  16. What is TP Organics?

    OpenAIRE

    2014-01-01

    TP Organics is one of the 38 reconised European Technology Platforms, the only one for organic, agro-ecological and low-input food and farming research. European Technology Platforms (ETPs) are industry-led stakeholder fora that develop short to long-term research and innovation agendas and roadmaps for action at EU and national level to be supported by both private and public funding.

  17. Red blood cell PK deficiency: An update of PK-LR gene mutation database.

    Science.gov (United States)

    Canu, Giulia; De Bonis, Maria; Minucci, Angelo; Capoluongo, Ettore

    2016-03-01

    Pyruvate kinase (PK) deficiency is known as being the most common cause of chronic nonspherocytic hemolytic anemia (CNSHA). Clinical PK deficiency is transmitted as an autosomal recessive trait, that can segregate neither in homozygous or in a compound heterozygous modality, respectively. Two PK genes are present in mammals: the pyruvate kinase liver and red blood cells (PK-LR) and the pyruvate kinase muscle (PK-M), of which only the first encodes for the isoenzymes normally expressed in the red blood cells (R-type) and in the liver (L-type). Several reports have been published describing a large variety of genetic defects in PK-LR gene associated to CNSHA. Herein, we present a review of about 250 published mutations and six polymorphisms in PK-LR gene with the corresponding clinical and molecular data. We consulted the PubMed website for searching mutations and papers, along with two main databases: the Leiden Open Variation Database (LOVD, https://grenada.lumc.nl/LOVD2/mendelian_genes/home.php?select_db=PKLR) and Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/gene.php?gene=PKLR) for selecting, reviewing and listing the annotated PK-LR gene mutations present in literature. This paper is aimed to provide useful information to clinicians and laboratory professionals regarding overall reported PK-LR gene mutations, also giving the opportunity to harmonize data regarding PK-deficient individuals.

  18. First observation of γγ-> p$\\bar{p}$K+K- and search for exotic baryons in pK systems

    Energy Technology Data Exchange (ETDEWEB)

    Shen, C. P.; Yuan, C. Z.; Adachi, I.; Aihara, H.; Asner, David M.; Aulchenko, V.; Aushev, T.; Ayad, R.; Babu, V.; Badhrees, I.; Bakich, A. M.; Barberio, E.; Behera, P.; Bhardwaj, V.; Bhuyan, B.; Biswal, J.; Bobrov, A.; Bonvicini, Giovanni; Bozek, A.; Bracko, Marko; Browder, Thomas E.; Cervenkov, D.; Chang, P.; Chekelian, V.; Chen, A.; Cheon, B. G.; Chilikin, K.; Chistov, R.; Cho, K.; Chobanova, V.; Choi, S-K.; Choi, Y.; Cinabro, David A.; Dalseno, J.; Danilov, M.; Dash, N.; Dolezal, Z.; Drasal, Z.; Dutta, D.; Eidelman, S.; Fang, Wenzheng; Fast, James E.; Ferber, T.; Fulsom, Bryan G.; Gaur, Vipin; Gabyshev, N.; Garmash, A.; Gillard, R.; Glattauer, R.; Goldenzweig, P.; Grzymkowska, O.; Haba, J.; Hayasaka, K.; Hayashii, H.; Hou, W. S.; Iijima, T.; Inami, K.; Inguglia, G.; Ishikawa, A.; Itoh, R.; Iwasaki, Y.; Jaegle, Igal; Jeon, H. B.; Joo, K. K.; Julius, T.; Kang, K. H.; Kato, E.; Kiesling, C.; Kim, D. Y.; Kim, J. B.; Kim, K. T.; Kim, S. H.; Kim, Y. J.; Kodys, P.; Korpar, S.; Kotchetkov, Dmitri V.; Krizan, P.; Krokovny, Pavel; Kuzmin, A.; Kwon, Y. J.; Lange, J. S.; Li, C. H.; Li, H.; Li, Y.; Li Gioi, L.; Libby, J.; Liventsev, D.; Lubej, M.; Luo, T.; Masuda, M.; Matsuda, T.; Matvienko, D.; Miyabayashi, K.; Miyata, H.; Mizuk, R.; Mohanty, G. B.; Mohanty, Subhashree; Moll, A.; Moon, H K.; Mussa, R.; Nakano, E.; Nakao, M.; Nanut, T.; Nath, K.; Natkaniec, Z.; Nishida, S.; Ogawa, S.; Olsen, Stephen L.; Ostrowicz, W.; Pakhlov, P.; Pakhlova, G.; Pal, Bilas K.; Park, C. S.; Park, H.; Pesantez, L.; Pestotnik, R.; Petric, M.; Piilonen, Leo E.; Pulvermacher, C.; Rauch, J.; Ritter, M.; Sakai, Y.; Sandilya, Saurabh; Santelj, L.; Sanuki, T.; Savinov, Vladimir; Schluter, T.; Schneider, O.; Schnell, G.; Schwanda, C.; Seino, Y.; Semmler, D.; Senyo, K.; Seong, Ilsoo; Sevior, ME; Shibata, T. A.; Shiu, Jing-Ge; Shwartz, B.; Simon, F.; Sokolov, A.; Solovieva, E.; Stanic, S.; Staric, M.; Strube, Jan F.; Stypula, J.; Sumihama, M.; Sumiyoshi, T.; Takizawa, M.; Tamponi, Umberto; Tanida, K.; Tenchini, F.; Trabelsi, K.; Uchida, M.; Uehara, S.; Uglov, T.; Unno, Y.; Uno, S.; Urquijo, P.; Usov, Y.; Van Hulse, C.; Varner, G.; Wang, C. H.; Wang, M. Z.; Wang, P.; Watanabe, M.; Watanabe, Y.; Williams, K. M.; Won, E.; Yamaoka, Jared AK; Yelton, John; Yook, Youngmin; Yusa, Y.; Zhang, C. C.; Zhang, Z. P.; Zhilich, V.; Zhukova, V.; Zhulanov, V.; Zupanc, A.

    2016-06-30

    The process γγ→p$\\bar{p}$K+K- and its intermediate processes are measured for the first time using a 980 fb-1 data sample collected with the Belle detector at the KEKB asymmetric-energy e+e- collider. The production of p$\\bar{p}$K+K- and a Λ(1520)0 ($\\bar{Λ}$(1520)0) signal in the pK- ($\\bar{p}$K+) invariant mass spectrum are clearly observed. However, no evidence for an exotic baryon near 1540 MeV/c2, denoted as Θ(1540)0 ($\\bar{Θ}$(1540)0) or Θ(1540)++ (Θ(1540)--), is seen in the pK- ($\\bar{p}$K+) or pK+ ($\\bar{p}$K-) invariant mass spectra. Cross sections for γγ→p$\\bar{p}$K+K-, Λ(1520)0$\\bar{p}$K++c.c. and the products σ(γγ→Θ(1540)0$\\bar{p}$K++c.c.)B(Θ(1540)0→pK-) and σ(γγ→Θ(1540)++$\\bar{p}$K-+c.c.)B(Θ(1540)++→pK+) are measured. We also determine upper limits on the products of the χc0 and χc2 two-photon decay widths and their branching fractions to p$\\bar{p}$K+K- at the 90% credibility level.

  19. HVM-TP: A Time Predictable, Portable Java Virtual Machine for Hard Real-Time Embedded Systems

    DEFF Research Database (Denmark)

    Luckow, Kasper Søe; Thomsen, Bent; Korsholm, Stephan Erbs

    2014-01-01

    We present HVMTIME; a portable and time predictable JVM implementation with applications in resource-constrained hard real-time embedded systems. In addition, it implements the Safety Critical Java (SCJ) Level 1 specification. Time predictability is achieved by a combination of time predictable...

  20. Screening of genes for proteins interacting with the PS1TP5 protein of hepatitis B virus: probing a human leukocyte cDNA library using the yeast two-hybrid system

    Institute of Scientific and Technical Information of China (English)

    ZHANG Jian-kang; ZHAO Long-feng; CHENG Jun; GUO Jiang; LUN Yong-zhi; HONG Yuan

    2006-01-01

    Background The hepatitis B virus (HBV) genome includes S, C, P and X regions. The S region is divided into four subregions of pre-pre-S, pre-S1, pre-S2 and S. PS1TP5 (human gene 5 transactivated by pre-S1 protein of HBV) is a novel target gene transactivated by the pre-S1 protein that has been screened with a suppression subtractive hybridization technique in our laboratory (GenBank accession: AY427953). In order to investigate the biological function of the PS1TP5 protein, we performed a yeast two-hybrid system 3 to screen proteins from a human leukocyte cDNA library interacting with the PS 1TP5 protein.Methods The reverse transcription polymerase chain reaction (RT-PCR) was performed to amplify the gene of PS1TP5 from the mRNA of HepG2 cells and the gene was then cloned into the pGEM-T vector. After being sequenced and analyzed with Vector NTI 9.1 and NCBI BLAST software, the target gene of PS1TP5 was cut from the pGEM-T vector and cloned into a yeast expression plasmid pGBKT7, then "bait" plasmid pGBKT7-PS 1TP5 was transformed into the yeast strain AH109. The yeast protein was isolated and analyzed with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting hybridization.After expression of the pGBKT7-PS1TP5 fusion protein in the AH109 yeast strain was accomplished, a yeast two-hybrid screening was performed by mating AH 109 with Y 187 containing a leukocyte cDNA library plasmid.The mated yeast was plated on quadruple dropout medium and assayed for α-gal activity. The interaction between the PS1TP5 protein and the proteins obtained from positive colonies was further confirmed by repeating the yeast two-hybrid screen. After extracting and sequencing of plasmids from blue colonies we carried out a bioinformatic analysis.Results Forty true positive colonies were selected and sequenced, full length sequences were obtained and we searched for homologous DNA sequences from GenBank. Among the 40 positive colonies, 23 coding genes

  1. Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents.

    Science.gov (United States)

    Takahashi, Koichi; Patel, Keyur; Bueso-Ramos, Carlos; Zhang, Jianhua; Gumbs, Curtis; Jabbour, Elias; Kadia, Tapan; Andreff, Michael; Konopleva, Marina; DiNardo, Courtney; Daver, Naval; Cortes, Jorge; Estrov, Zeev; Futreal, Andrew; Kantarjian, Hagop; Garcia-Manero, Guillermo

    2016-03-22

    We screened TP53 mutations in 168 MDS patients who were treated with HMA and evaluated predictive and prognostic value of TP53 mutations. Overall response to HMA was not different based on TP53 mutation status (45% vs. 32% in TP53-mutated and wild type [WT], respectively, P = 0.13). However, response duration was significantly shorter in TP53-mutated patients compared to WT patients (5.7 months vs. 28.5 months, P = 0.003). Longitudinal analysis of TP53 mutations after HMA showed that TP53 mutations almost always persisted at times of disease progression. TP53-mutated patients showed significantly worse overall survival (OS) compared to WT patients (9.4 months vs. 20.7 months, P TP53 mutations distinguished prognosis in the subgroup of patients with complex karyotype and Revised International Prognostic Scoring System (IPSS-R) defined very high-risk disease. Multivariate analysis showed that TP53 mutation status is significantly prognostic for OS after adjusting prognostic effect from other factors. The current study provides evidence that TP53 mutations are independently prognostic in MDS patients treated with HMA. While TP53-mutated MDS patients initially respond well to HMA, their duration of response is significantly shorter than WT patients. Novel strategies to improve duration of response in TP53-mutated MDS are urgently needed.

  2. Digitaalisen markkinoinnin tehostaminen PK-sektorilla

    OpenAIRE

    Viisteensaari, Keijo

    2015-01-01

    Opinnäytetyössä käsiteltiin digitaalista markkinointia. Työssä annetaan tietoa, miten PK-sektorin yrityksessä voidaan toteuttaa tuloksellista digitaalista markkinointia. Opinnäytetyö sisältää oppaan, jonka avulla PK-sektorin yrityksessä voidaan toteuttaa digitaalinen markkinointi. Työ ei paneudu teknisiin yksityiskohtiin vaan markkinoinnin näkökulmaan digitaalisen markkinoinnin toteuttamisessa. Aiheena digitaalinen markkinointi on ajankohtainen ja tärkeä, koska markkinointi on yhä enemmän sii...

  3. Number & operations drill sheets : grades PK-2

    CERN Document Server

    Reed, Nat

    2010-01-01

    For grades PK-2, our Common Core State Standards-based resource meets the number & operations concepts addressed by the NCTM standards and encourages the students to review the concepts in unique ways. Each drill sheet contains warm-up and timed drill activities for the student to practice number & operations concepts.

  4. Algebra task sheets : grades pk-2

    CERN Document Server

    Reed, Nat

    2009-01-01

    For grades PK-2, our Common Core State Standards-based resource meets the algebraic concepts addressed by the NCTM standards and encourages the students to learn and review the concepts in unique ways. Each task sheet is organized around a central problem taken from real-life experiences of the students.

  5. Geometry task sheets : grades pk-2

    CERN Document Server

    Rosenberg, Mary

    2009-01-01

    For grades PK-2, our Common Core State Standards-based resource meets the geometry concepts addressed by the NCTM standards and encourages the students to learn and review the concepts in unique ways. Each task sheet is organized around a central problem taken from real-life experiences of the students.

  6. Antioxidants Condition Pleiotropic Vascular Responses to Exogenous H2O2: Role of Modulation of Vascular TP Receptors and the Heme Oxygenase System

    Science.gov (United States)

    Zhang, Fan; Monu, Sumit R.; Sodhi, Komal; Bellner, Lars; Lamon, Brian D.; Zhang, Yilun; Abraham, Nader G.; Nasjletti, Alberto

    2013-01-01

    Abstract Aims: Hydrogen peroxide (H2O2), a nonradical oxidant, is employed to ascertain the role of redox mechanisms in regulation of vascular tone. Where both dilation and constriction have been reported, we examined the hypothesis that the ability of H2O2 to effect vasoconstriction or dilation is conditioned by redox mechanisms and may be modulated by antioxidants. Results: Exogenous H2O2 (0.1–10.0 μM), dose-dependently reduced the internal diameter of rat renal interlobular and 3rd-order mesenteric arteries (pantioxidants, including tempol, pegylated superoxide dismutase (PEG-SOD), butylated hydroxytoluene (BHT), and biliverdin (BV). However, as opposed to tempol or PEG-SOD, BHT & BV, antioxidants targeting radicals downstream of H2O2, also uncovered vasodilation. Innovations: Redox-dependent vasoconstriction to H2O2 was blocked by inhibitors of cyclooxygenase (COX) (indomethacin-10 μM), thromboxane (TP) synthase (CGS13080-10 μM), and TP receptor antagonist (SQ29548-1 μM). However, H2O2 did not increase vascular thromboxane B2 release; instead, it sensitized the vasculature to a TP agonist, U46619, an effect reversed by PEG-SOD. Antioxidant-conditioned dilatory response to H2O2 was accompanied by enhanced vascular heme oxygenase (HO)-dependent carbon monoxide generation and was abolished by HO inhibitors or by HO-1 & 2 antisense oligodeoxynucleotides treatment of SD rats. Conclusion: These results demonstrate that H2O2 has antioxidant-modifiable pleiotropic vascular effects, where constriction and dilation are brought about in the same vascular segment. H2O2-induced oxidative stress increases vascular TP sensitivity and predisposes these arterial segments to constrictor prostanoids. Conversely, vasodilation is reliant upon HO-derived products whose synthesis is stimulated only in the presence of antioxidants targeting radicals downstream of H2O2. Antioxid. Redox Signal. 18, 471–480. PMID:22867102

  7. Adaptation of the migrant worker’s body to the occupational risk factors from the position of functional system of P.K. Anokhin

    Directory of Open Access Journals (Sweden)

    М. Khodzhiev

    2016-12-01

    Full Text Available The adverse factors of labor process of migrants were studied as the factors of risk of formation of unsatisfactory adaptation and damage to health. The results of the study of adaptation of migrants to the labor process from the standpoint of the theory of functional systems were presented. The first subsystem of physical activities and neuro-emotional tension of labor determines the formation of certain stages of the adaptation process in terms of heart rate variability (the second sub-system. The result of migrant workers’ sympathetic chain of regulation’s activity level shows that the adaptive stress syndrome on the physiological indicators is expressed in a change of heart rate variability: different levels of stress index of SI associated with high physical (muscle, neuro-emotional stresses; marked increase in the power of spectrum of very low-frequency component (VLF, while the increase in heart rate. The features of the functional state of the body and the degree of adaptation in terms of activity of regulatory systems – PARS (optimal 1.19 ± 0.28; allowable stress 40.5 ± 0.62; overvoltage 6.21 ± 0.82 points were determined. On the basis of the production studies of migrant workers, the approaches to quantitative evaluation to the degree of adaptation of workers to the labor process associated with the combined effects of physical, neural and emotional labor intensity on the human body were science-based and developed. The degree of stress adaptation process corresponds to the stage of self-control (optimum stress activation (allowable stress, the mobilization of the 1st, 2nd, 3-th degree (degrees of over-stress of 1,2,3 degrees. Unfavorable stage of mobilization of 2–3 degrees of migrant workers was determined (an increase in the stress index S1, PARS indicator, the relative power of VLF range, a reduction in the SDNN. Events of medical and social support represent the third sub-system in the general system theory.

  8. Immunohistochemical correlates of TP53 somatic mutations in cancer.

    Science.gov (United States)

    Murnyák, Balázs; Hortobágyi, Tibor

    2016-10-04

    Despite controversy on the correlation between p53 accumulation and TP53 mutational status, immunohistochemical (IHC) detection of overexpressed protein has long been used as a surrogate method for mutation analysis. The aim of our study was to characterise the IHC expression features of TP53 somatic mutations and define their occurrence in human cancers. A large-scale database analysis was conducted in the IARC TP53 Database (R17); 7878 mutations with IHC features were retrieved representing 60 distinct tumour sites. The majority of the alterations were immunopositive (p TP53 mutations were divided into three IHC groups according to mutation frequency and IHC positivity. Each group had female dominance. Among the IHC groups, significant correlations were observed with age at diagnosis in breast, bladder, liver, haematopoietic system and head & neck cancers. An increased likelihood of false negative IHC associated with rare nonsense mutations was observed in certain tumour sites. Our study demonstrates that p53 immunopositivity largely correlates with TP53 mutational status but expression is absent in certain mutation types.Besides, describing the complex IHC expression of TP53 somatic mutations, our results reveal some caveats for the diagnostic practice.

  9. Microsoft Office 365 Pk-yritysten tuottavuusratkaisuna

    OpenAIRE

    Nyström, Taina

    2015-01-01

    Tuottavuus on tämän päivän trendi, sitä vaaditaan lähes joka taholta kiristyneessä kilpailutilanteessa ja digitalisoituneessa maailmassa. Opinnäytetyön tavoitteena oli selvittää Office 365 -pilvipalvelun soveltuvuutta Pk-yritysten tuottavuusratkaisuksi. Työn lähtökohtana oli ammatillinen mielenkiinto Office 365 -palveluita kohtaan. Tutkimuksessa selvitettiin Office 365 -palveluun siirtyneiden yritysten kokemia hyötyjä ja etuja. Tutkimustuloksilla selvitettiin, miten Office 365 -palvelu kulmin...

  10. Liikelahjat mikro- ja pk-yrityksissä

    OpenAIRE

    Danhammer, Joni

    2014-01-01

    Liikelahjat ovat osa yrityksen menekinedistämistä ja kuuluvat tiiviisti yrityksen markkinointiviestintään. Kuitenkin yleinen talouden kiristynyt tilanne ja vuoden 2014 alussa voimaan astunut verouudistus liikelahjojen verovähennyksissä ovat asioita, jotka vaikuttavat liikelahjojen menekkiin ja niiden antamistapojen muuttumiseen mikro- ja pk-yrityksissä. Näin ollen yrityksillä tulisi tässä tilanteessa olla selkeä käsitys siitä, millaisia liikelahjoja yritys haluaa nykyisin henkilökunnalleen ja...

  11. Tp-e interval and Tp-e/QT ratio in patients with Human Immunodeficiency Virus.

    Science.gov (United States)

    Ünal, Sefa; Yayla, Çağrı; Açar, Burak; Ertem, Ahmet G; Akboğa, Mehmet K; Gökaslan, Serkan; Erdöl, Mehmet A; Sönmezer, Meliha Ç; Kaya Kiliç, Esra; Ataman Hatipoğlu, Çiğdem; Aydoğdu, Sinan; Temizhan, Ahmet

    2017-03-09

    Human Immunodeficiency Virus (HIV) infection and AIDS are known to cause cardiovascular diseases such as premature coronary artery disease, cardiomyopathy, and arrhythmias. Recently, Tp-e interval and Tp-e/QT ratio has been shown as a novel marker of ventricular repolarization. We aimed to evaluate the ventricular repolarization using Tp-e interval and Tp-e/QT ratio in patients with Human Immunodeficiency Virus (HIV) infection. Totally 48 patients with HIV and 60 control subjects were enrolled to the study. Tp-e interval, Tp-e/QT and Tp-e/QTc ratio were measured from the 12-lead electrocardiogram. Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio were significantly higher in patients with HIV than control subjects (all pe interval and disease duration (r=0.298, p=0.048). and inverse correlation between Tp-e interval and CD4 count(r=-0.303, p=0.036). Our study showed that Tp-e interval, Tp-e/QT and Tp-e/QTc ratios were increased in patients with HIV than control subjects.

  12. Photoregulated expression of the PsPK3 and PsPK5 genes in pea seedlings.

    Science.gov (United States)

    Khanna, R; Lin, X; Watson, J C

    1999-01-01

    The PsPK3 and PsPK5 genes of the garden pea encode protein-serine/threonine kinases whose catalytic domains are closely related to known signal transducing kinases from animals and fungi. The PsPK3 polypeptide is predicted to be located in the nucleus, whereas PsPK5 is a homologue of NPH1, the probable blue light receptor for phototropism from Arabidopsis. We found previously that when etiolated pea seedlings are illuminated with continuous white light, PsPK3 and PsPK5 transcript levels within apical buds decline substantially, reaching their minimum levels within one day of exposure to light. The role of light in regulating the expression of the PsPK3 and PsPK5 genes was investigated further. To gain insight into the rapidity with which expression changes, 6-day old, dark-grown pea seedlings were transferred to continuous white light, and PsPK3 and PsPK5 RNA levels monitored over the ensuing 24 h. While transcripts from the RbcS gene family increase, the PsPK3 and PsPK5 mRNAs decline rapidly to their minimum levels. PsPK5 mRNA declines 10-fold in ca. 2 h, whereas PsPK3 mRNA declines 4-fold in ca. 8 h. We used single pulses of light to elucidate which photoreceptor triggers the negative regulation of PsPK3 and PsPK5 gene expression. To assess phytochrome involvement, etiolated seedlings were treated with single pulses of red light, red followed by far-red light, or far-red light alone. RbcS induction by a red light pulse is reversible with a subsequent far-red light pulse, clearly showing that phytochrome mediates its induction. Likewise, RbcS expression is induced with a single pulse of blue light or a dichromatic pulse of red+blue light. However, none of these pulses trigger the PsPK3 and PsPK5 mRNA levels to decline. Given the lack of effectiveness of light pulses, etiolated seedlings were transferred to continuous light of three different qualities to determine the spectral sensitivity of PsPK3 and PsPK5 gene expression. Exposure to continuous red, continuous

  13. Monitoring VoIP Traffic Using OnePK Technology

    OpenAIRE

    Spišiak, Matej

    2014-01-01

    Tato bakalářská práce se zabývá novou proprietární technologií od Cisco Systems zvanou OnePK (One Platform Kit). Soustřeďuje se na možnosti použití v oblasti zberu statistických dat o VoIP provozu. Používá DataPath service set, ktorý zabezpečuje sběr paketů ze síťových zařízení firmy Cisco. DataPath service set posílá pakety na vstup aplikace, která tvoří VoIP statistiku z příchozích SIP paketů. Tato aplikace a provedené testy na technologii OnePK jsou výsledky této práce. This bachelor's ...

  14. [Numerical simulation of TP transport after overflow of rainwater into urban lake].

    Science.gov (United States)

    Gong, Chun-Sheng; Mao, Xian-Zhong; Zhang, Xi-Hui

    2009-04-15

    Based on the three-dimensional advection-diffusion-reflection equation, a two-dimensional TP transport equation was deduced to simulate TP distribution and transport after overflow rainwater into urban lake from storm sewer system during rainstorm. The model has a good agreement with a group of monitor data at Lake Lichee in Shenzhen, China. The model was applied to compute the scenario in Lake Lichee under the design rainstorm, and analyse the fate of TP. It shows that TP flux into lake is 15.385 kg under city storm intensity of 28 mm/h, in which 62.3% of flux goes into water in lake and 28.1% TP flux settles surface sediment. It would take 3.0 days for the integrated treatment project operation to recover TP to the level before the rain.

  15. The decay of $\\Lambda_b\\rightarrow p~K^-$ in QCD factorization approach

    CERN Document Server

    Zhu, Jie; Wei, Zheng-Tao

    2016-01-01

    With only the tree level operator, the decay of $\\Lambda_b\\rightarrow pK$ is predicted to be one order smaller than the experimental data. The QCD penguin effects should be taken into account. In this paper, we explore the one-loop QCD corrections to the decay of $\\Lambda_b\\to pK$ within the framework of QCD factorization approach. For the baryon system, the diquark approximation is adopted. The transition hadronic matrix elements between $\\Lambda_b$ and $p$ are calculated in the light front quark model. The branching ratio of $\\Lambda_b\\rightarrow pK$ is predicted to be about $4.85\\times 10^{-6}$ which is consistent with experimental data $(4.9\\pm 0.9)\\times 10^{-6}$. The CP violation is about 5\\% in theory.

  16. [PK/PD modeling of aminoglycoside nephrotoxicity].

    Science.gov (United States)

    Rougier, F; Corvaisier, S; Ducher, M; Claude, D; Jelliffe, R W; Maire, P

    2003-06-01

    Aminoglycosides are bactericidial antibiotics with a serum concentration-dependent activity. They are mainly eliminated by the kidneys and the main difficulty arising in clinical use is their uptake by the renal cortex which leads to nephrotoxicity. An ototoxicity is also reported. We propose a PK/PD modelling of aminoglycoside nephrotoxicity which unifies more fourty years of physiological knowledge. This deterministic model successively describes the pharmacokinetics of aminoglycosides, their storage into renal cortex, their effect on renal cells, their consequences on the renal function through tubuloglomerular feedback and the changes in the serum concentrations of creatinine that is considered as a toxicity marker. The simulation of the model displays the leading effect of the shape and daily-time of administration schedule on the search for minimizing toxicity.

  17. Seroreactivity and immunogenicity of Tp0965, a hypothetical membrane protein of Treponema pallidum

    Institute of Scientific and Technical Information of China (English)

    LONG Fu-quan; ZHANG Jin-ping; SHANG Guang-dong; SHANG Shu-xian; GONG Kuang-long; WANG Qian-qiu

    2012-01-01

    Background Treponema pallidum (T.pallidum) subsp.pallidum is the causative agent of syphilis.Analysis of recombinant antigens of T.pallidum led to the identification of potential candidate antigens for vaccine development and syphilis serodiagnosis.Tp0965 was predicted to be a membrane fusion protein and was found to be reactive with infected human sera in previous studies,but the results were controversial.In this research,the antigenicity and immunoreactivity of recombinant protein Tp0965 were assessed.Methods T.pallidum subsp.pallidum (Nichols strain) was propagated and isolated and the genomic DNA was extracted.The Tp0965 gene was amplified by polymerase chain reaction (PCR).Then the recombinant protein Tp0965 was expressed in Escherichia coli and purified by nickel-nitrilotriacetic acid (Ni-NTA) purification system.The reactivities of protein Tp0965 were examined by immunoblot analysis and indirect enzyme-linked immunosorbent assay.The antisera against protein Tp0965 were obtained by immune rabbits and the immunogenicity of antisera were detected by indirect enzyme-linked immunosorbent assay.Results Recombinant protein Tp0965 was expressed successfully in vitro.Immunoblot assay showed that the recombinant protein Tp0965 could be recognized by human syphilitic sera of all stages.Indirect enzyme-linked immunosorbent assay showed there were only 4 of 74 human syphilitic sera that failed to show reactivity to recombinant antigen Tp0965,and lack of reactivity of Tp0965 to all 28 uninfected sera.A low titer of antiserum against Tp0965 in immune rabbits could be detected after the third time of immunization.Conclusions The recombinant antigen Tp0965 shows excellent sensitivity for the reactivity with sera from syphilitic individuals at all stages.The results also demonstrate a potential application for the serodiagnosis of syphilis.

  18. [TP53 mutations and molecular epidemiology].

    Science.gov (United States)

    Otsuka, Kazunori; Ishioka, Chikashi

    2007-05-01

    Tumor suppressor p53 protein is activated by a variety of cellular stresses through several pathways and transactivates its downstream genes, including regulators of cell cycle, apoptosis and DNA repair. The loss of p53 function by TP53 gene mutations therefore fails to activate these genes and is thought to be a critical cause of carcinogenesis and/or tumor progression. TP53 is one of the most frequently mutated genes in human cancer. TP53 mutations are found in about 50% of human cancers, although the frequency of TP53 mutations differs among tumor types. However, the degree of functional disorder of mutant p53 varies according to the type of TP53 mutation. And the effects of p53 on cancer formation and/or progression are influenced by the degree of p53 dysfunction. So it is important to analyze the effects of TP53 mutations carefully according to the oncogenicity of each mutation from the molecular epidemiological point of view. Here, together with some cautions needed for analyzing and interpreting the significance of TP53 gene mutations, we present some examples of the identified specific mutation spectrum and the correlation between the prognosis and TP53 mutation in some cancers.

  19. Expression signature based on TP53 target genes doesn't predict response to TP53-MDM2 inhibitor in wild type TP53 tumors.

    Science.gov (United States)

    Sonkin, Dmitriy

    2015-10-22

    A number of TP53-MDM2 inhibitors are currently under investigation as therapeutic agents in a variety of clinical trials in patients with TP53 wild type tumors. Not all wild type TP53 tumors are sensitive to such inhibitors. In an attempt to improve selection of patients with TP53 wild type tumors, an mRNA expression signature based on 13 TP53 transcriptional target genes was recently developed (Jeay et al. 2015). Careful reanalysis of TP53 status in the study validation data set of cancer cell lines considered to be TP53 wild type detected TP53 inactivating alterations in 23% of cell lines. The subsequent reanalysis of the remaining TP53 wild type cell lines clearly demonstrated that unfortunately the 13-gene signature cannot predict response to TP53-MDM2 inhibitor in TP53 wild type tumors.

  20. PK-sensitive PrPSc is infectious and shares basic structural features with PK-resistant PrPSc

    Science.gov (United States)

    One of the main characteristics of the transmissible isoform of the prion protein (PrPSc) is its partial resistance to proteinase K (PK) digestion. Diagnosis of prion disease typically relies upon immunodetection of PK-digested PrPSc following Western blot or ELISA. More recently, researchers determ...

  1. TP53 dysfunction in diffuse large B-cell lymphoma.

    Science.gov (United States)

    Lu, Ting-Xun; Young, Ken H; Xu, Wei; Li, Jian-Yong

    2016-01-01

    The aberrations of TP53 gene and dysregulation of the TP53 pathway are important in the pathogenesis of many human cancers, including malignant lymphomas, especially for diffuse large B cell lymphoma (DLBCL). By regulating many downstream target genes or molecules, TP53 governs major defenses against tumor growth and promotes cellular DNA repair, apoptosis, autophagy, cell cycle arrest, signaling, transcription, immune or inflammatory responses and metabolism. Dysfunction of TP53, including microRNA regulations, copy number alterations of TP53 pathway and TP53 itself, dysregulation of TP53 regulators, and somatic mutations by abnormal TP53 function modes, play an important role in lymphoma generation, progression and invasion. The role of TP53 in DLBCL has been widely explored recently. In this review, we summarized recent advances on different mechanisms of TP53 in DLBCL and new therapeutic approaches to overcome TP53 inactivation.

  2. Main: FBA1 [TP Atlas

    Lifescience Database Archive (English)

    Full Text Available t systems Bacterial protein export systems Katsumi Imada Department of Macromolecular Science, Graduate Scho...ents - The energy source of the protein export in the type III secretion system has been elucidated - Five ma

  3. SCPS-TP: A Satellite-Enhanced TCP

    Science.gov (United States)

    Scott, Keith; Torgerson, Leigh

    2004-01-01

    This viewgraph presentation reviews the Space Communications Protocol Standard Transport Protocol (SCPS-TP) which is a satellite enhanced Transport Control Protocol (TCP). The contents include: 1) Purpose; 2) Background; 3) Stressed Communication Environments; 4) SCPS-TP Features; 5) SCPS-TP Performance; 6) Performance Enhancing Proxies (PEPs); and 7) Ongoing and Future SCPS-TP Work.

  4. Protein - TP Atlas | LSDB Archive [Life Science Database Archive metadata

    Lifescience Database Archive (English)

    Full Text Available otein information on other websites. Data file File name: tp_atlas_protein.zip Fi...le URL: ftp://ftp.biosciencedbc.jp/archive/tp_atlas/LATEST/tp_atlas_protein.zip File size: 49.8 KB Simple se...arch URL http://togodb.biosciencedbc.jp/togodb/view/tp_atlas_protein#en Data acquisition method - Data analy

  5. Gene expression as a function of TP53 status; Genexpression in Abhaengigkeit vom TP53 Status

    Energy Technology Data Exchange (ETDEWEB)

    Wrona, A.; Zschenker, O.; Dikomey, E.; Borgmann, K. [Institut fuer Biophysik und Strahlenbiologie, Universitaetsklinikum Eppendorf Hamburg (Germany)

    2004-07-01

    The goal of the present study was to determine the influence of TP53 on gene expression following radiation exposure and whether this has an effect on the occurrence of chromosome aberrations. [German] Ziel dieser Untersuchung war es, festzustellen, welchen Einfluss TP53 auf die Expression von Genen nach Bestrahlung hat und ob sich dies auf die Bildung von Chromosomenaberrationen auswirkt. (orig.)

  6. Tp-e interval and Tp-e/QT ratio in patients with celiac disease.

    Science.gov (United States)

    Demirtaş, K; Yayla, Ç; Yüksel, M; Açar, B; Ünal, S; Ertem, A G; Kaplan, M; Akpinar, M Y; Kiliç, Z M Y; Kayaçetin, E

    2017-10-07

    Celiac disease is a chronic immune-mediated disease of the small intestine. It has been known that dilated cardiomyopathy and ischemic coronary artery disease have become more frequent in patients with celiac disease. The aim of the study was to assess Tp-e interval and Tp-e/QT ratio in patients with celiac disease. This study was conducted at a single center in collaboration with gastroenterology and cardiology clinics. Between January 2014 and June 2015, a total of 76 consecutive patients were enrolled (38 patients with celiac disease and 38 control subjects). Tp-e interval, Tp-e/QT and Tp-e/QTc ratio were measured from the 12-lead electrocardiogram. Tp-e interval (64.2±11.0 vs. 44.5±6.0; pceliac disease than control subjects. There was a significant positive correlation between Tp-e/QTc ratio and disease duration in patients with celiac disease (r=0.480, p=0.003) and also there was a significant positive correlation between Tp-e/QTc ratio and erythrocyte sedimentation rate (r=0.434, pceliac disease. Whether these changes increase the risk of ventricular arrhythmia deserve further studies. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.

  7. Bifunctional role of the Treponema pallidum extracellular matrix binding adhesin Tp0751.

    Science.gov (United States)

    Houston, Simon; Hof, Rebecca; Francescutti, Teresa; Hawkes, Aaron; Boulanger, Martin J; Cameron, Caroline E

    2011-03-01

    Treponema pallidum, the causative agent of syphilis, is a highly invasive pathogenic spirochete capable of attaching to host cells, invading the tissue barrier, and undergoing rapid widespread dissemination via the circulatory system. The T. pallidum adhesin Tp0751 was previously shown to bind laminin, the most abundant component of the basement membrane, suggesting a role for this adhesin in host tissue colonization and bacterial dissemination. We hypothesized that similar to that of other invasive pathogens, the interaction of T. pallidum with host coagulation proteins, such as fibrinogen, may also be crucial for dissemination via the circulatory system. To test this prediction, we used enzyme-linked immunosorbent assay (ELISA) methodology to demonstrate specific binding of soluble recombinant Tp0751 to human fibrinogen. Click-chemistry-based palmitoylation profiling of heterologously expressed Tp0751 confirmed the presence of a lipid attachment site within this adhesin. Analysis of the Tp0751 primary sequence revealed the presence of a C-terminal putative HEXXH metalloprotease motif, and in vitro degradation assays confirmed that recombinant Tp0751 purified from both insect and Escherichia coli expression systems degrades human fibrinogen and laminin. The proteolytic activity of Tp0751 was abolished by the presence of the metalloprotease inhibitor 1,10-phenanthroline. Further, inductively coupled plasma-mass spectrometry showed that Tp0751 binds zinc and calcium. Collectively, these results indicate that Tp0751 is a zinc-dependent, membrane-associated protease that exhibits metalloprotease-like characteristics. However, site-directed mutagenesis of the HEXXH motif to HQXXH did not abolish the proteolytic activity of Tp0751, indicating that further mutagenesis studies are required to elucidate the critical active site residues associated with this protein. This study represents the first published description of a T. pallidum protease capable of degrading host

  8. Human biodistribution and radiation dosimetry of {sup 11}C-(R)-PK11195, the prototypic PET ligand to image inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Hirvonen, Jussi; Roivainen, Anne; Virta, Jere; Helin, Semi; Naagren, Kjell; Rinne, Juha O. [University of Turku and Turku University Hospital, Turku PET Centre, P.O. Box 52, Turku (Finland)

    2010-03-15

    The positron emission tomography (PET) radiotracer {sup 11}C-(R)-PK11195 allows the in vivo imaging in humans of the translocator protein 18 kDa (TSPO), previously called peripheral benzodiazepine receptor (PBR), a marker of inflammation. Despite its widespread use, the radiation burden associated with {sup 11}C-(R)-PK11195 in humans is not known. To examine this, we performed dynamic whole-body imaging with PET and {sup 11}C-(R)-PK11195 in healthy humans. Five healthy male volunteers were scanned with PET and {sup 11}C-(R)-PK11195, using a dynamic whole-body imaging protocol. An organ-specific method was used to measure accumulated radioactivity in source organs, and residence times were calculated as areas under the curve of time-activity curves expressed as percentage of injected radioactivity. Residence times were used as input for OLINDA/EXM 1.0 software to model the equivalent organ doses and the effective dose for the 70-kg man. After intravenous injection of {sup 11}C-(R)-PK11195, radioactivity accumulated in organs rich in TSPO as well as routes of excretion: the hepatobiliary system and the urine. The mean effective dose was 4.8 {mu}Sv/MBq according to International Commission on Radiological Protection (ICRP) Publication 60 and 5.1 {mu}Sv/MBq according to ICRP Publication 103, and the highest equivalent organ doses were observed in the kidneys (14.0 {mu}Sv/MBq), spleen (12.5 {mu}Sv/MBq) and small intestine (12.2 {mu}Sv/MBq). Imaging of TSPO with PET using {sup 11}C-(R)-PK11195 is associated with modest radiation exposure, similar in magnitude to most other {sup 11}C-labelled PET tracers, suggesting feasibility of {sup 11}C-(R)-PK11195 imaging in clinical human studies involving multiple scans in the same subjects per year. (orig.)

  9. Use of the integration elements encoded by the temperate lactococcal bacteriophage TP901-1

    DEFF Research Database (Denmark)

    Brøndsted, Lone; Hammer, Karin

    1999-01-01

    Previously we showed that only one phage-expressed protein (Orf1), a 425-bp region upstream of the orf1 gene (presumably encoding a promoter), and the attP region are necessary and also sufficient for integration of the bacteriophage TP901-1 genome into the chromosome of Lactococcus lactis subsp......P region seem to be necessary for site-specific integration of the temperate bacteriophage TP901-1. By use of the integrative elements (attP and orf1) expressed by the temperate lactococcal bacteriophage TP901-1, a system for obtaining stable chromosomal single-copy transcriptional fusions in L. lactis...

  10. Overexpressed TP73 induces apoptosis in medulloblastoma

    Directory of Open Access Journals (Sweden)

    Perlaky Laszlo

    2007-07-01

    Full Text Available Abstract Background Medulloblastoma is the most common malignant brain tumor of childhood. Children who relapse usually die of their disease, which reflects resistance to radiation and/or chemotherapy. Improvements in outcome require a better understanding of the molecular basis of medulloblastoma growth and treatment response. TP73 is a member of the TP53 tumor suppressor gene family that has been found to be overexpressed in a variety of tumors and mediates apoptotic responses to genotoxic stress. In this study, we assessed expression of TP73 RNA species in patient tumor specimens and in medulloblastoma cell lines, and manipulated expression of full-length TAp73 and amino-terminal truncated ΔNp73 to assess their effects on growth. Methods We analyzed medulloblastoma samples from thirty-four pediatric patients and the established medulloblastoma cell lines, Daoy and D283MED, for expression of TP73 RNA including the full-length transcript and the 5'-terminal variants that encode the ΔNp73 isoform, as well as TP53 RNA using quantitative real time-RTPCR. Protein expression of TAp73 and ΔNp73 was quantitated with immunoblotting methods. Clinical outcome was analyzed based on TP73 RNA and p53 protein expression. To determine effects of overexpression or knock-down of TAp73 and ΔNp73 on cell cycle and apoptosis, we analyzed transiently transfected medulloblastoma cell lines with flow cytometric and TUNEL methods. Results Patient medulloblastoma samples and cell lines expressed full-length and 5'-terminal variant TP73 RNA species in 100-fold excess compared to non-neoplastic brain controls. Western immunoblot analysis confirmed their elevated levels of TAp73 and amino-terminal truncated ΔNp73 proteins. Kaplan-Meier analysis revealed trends toward favorable overall and progression-free survival of patients whose tumors display TAp73 RNA overexpression. Overexpression of TAp73 or ΔNp73 induced apoptosis under basal growth conditions in vitro and

  11. Complex Biological Systems Analysis of Cell Cycling Models in Carcinogenesis: I. The essential roles of modifications in the c-Myc, TP53/p53, p27 and hTERT modules in Cancer Initiation and Progression

    CERN Document Server

    Prisecaru, V I

    2004-01-01

    A new approach to the integration of results from a modular, complex biological systems analysis of nonlinear dynamics in cell cycling network transformations that are leading to carcinogenesis is proposed. Carcinogenesis is a complex process that involves dynamically inter-connected biomolecules in the intercellular, membrane, cytosolic, nuclear and nucleolar compartments that form numerous inter-related pathways referred to as networks. One such network module contains the cell cyclins whose functions are essential to cell cycling and division. Cyclins are proteins that also link to several critical pro-apoptotic and other cell cycling/division components, such as: c-Myc, p27, the tumor suppressor gene TP53 and its product-- the p53 protein with key roles in controlling DNA repair, inducing apoptosis and activating p21 (which can depress cell cyclins if activated), mdm2(with its biosynthesis activated by p53 and also, in its turn, inhibiting p53), p21, the Thomsen-Friedenreich antigen(T- antigen),Rb,Bax, Ba...

  12. Main: FBA2 [TP Atlas

    Lifescience Database Archive (English)

    Full Text Available plicated proteolytic machinery Proteolytic system: proteasome Keiji Tanaka The Tokyo Metropolitan Institute of Medical... Science, Tokyo Metropolitan Organization for Medical Research - Cells possess the protein degradi

  13. Main: FBB1 [TP Atlas

    Lifescience Database Archive (English)

    Full Text Available 1 regulatory system could lead to therapeutics developments for cancers and metabolic diseases - Keap1 was f...ve in normal cells, we have shown that constitutive Nrf2 activation affords cancer cells with protection from chemotherapeutic

  14. Main: FEB2 [TP Atlas

    Lifescience Database Archive (English)

    Full Text Available t of new taste substances and taste evaluation systems Taste receptors Atsuko Yamashita Structural Physiolog... taste - Structural and functional analyses of taste receptors are vital for the rational evaluation

  15. Main: FEB4 [TP Atlas

    Lifescience Database Archive (English)

    Full Text Available fixation system and their functional improvement Carbon dioxide fixation enzymes Kunio Miki Graduate School ...have determined the structures and functions of the two novel enzymes - Design of Tk-Rubisco with improve

  16. Modelling and Optimising TinyTP over IrDA Stacks

    Directory of Open Access Journals (Sweden)

    Boucouvalas A. C.

    2005-01-01

    Full Text Available TinyTP is the IrDA transport layer protocol for indoor infrared communications. For the first time, this paper presents a mathematical model for TinyTP over the IrDA protocol stacks taking into account the presence of bit errors. Based on this model, we carry out a comprehensive optimisation study to improve system performance at the transport layer. Four major parameters are optimised for maximum throughput including TinyTP receiver window, IrLAP window and frame size, as well as IrLAP turnaround time. Equations are derived for the optimum IrLAP window and frame sizes. Numerical results show that the system throughput is significantly improved by implementing the optimised parameters. The major contribution of this work is the modelling of TinyTP including the low-layer protocols and optimisation of the overall throughput by appropriate parameter selection.

  17. TP53 mutations, expression and interaction networks in human cancers.

    Science.gov (United States)

    Wang, Xiaosheng; Sun, Qingrong

    2017-01-03

    Although the associations of p53 dysfunction, p53 interaction networks and oncogenesis have been widely explored, a systematic analysis of TP53 mutations and its related interaction networks in various types of human cancers is lacking. Our study explored the associations of TP53 mutations, gene expression, clinical outcomes, and TP53 interaction networks across 33 cancer types using data from The Cancer Genome Atlas (TCGA). We show that TP53 is the most frequently mutated gene in a number of cancers, and its mutations appear to be early events in cancer initiation. We identified genes potentially repressed by p53, and genes whose expression correlates significantly with TP53 expression. These gene products may be especially important nodes in p53 interaction networks in human cancers. This study shows that while TP53-truncating mutations often result in decreased TP53 expression, other non-truncating TP53 mutations result in increased TP53 expression in some cancers. Survival analyses in a number of cancers show that patients with TP53 mutations are more likely to have worse prognoses than TP53-wildtype patients, and that elevated TP53 expression often leads to poor clinical outcomes. We identified a set of candidate synthetic lethal (SL) genes for TP53, and validated some of these SL interactions using data from the Cancer Cell Line Project. These predicted SL genes are promising candidates for experimental validation and the development of personalized therapeutics for patients with TP53-mutated cancers.

  18. A remembrance of Professor TP FENG

    Institute of Scientific and Technical Information of China (English)

    Richard W. Tsien

    2007-01-01

    @@ It is both an honor and pleasure to be given this opportunity to remember Professor TP FENG and his many contributions.He made many important scientific discoveries,labored mightily to establish firmly Physiology and Neuroscience in China,and was a major force in setting a high standard for scientific inquiry.

  19. Main: FEB1 [TP Atlas

    Lifescience Database Archive (English)

    Full Text Available y in urban areas - Male peptide pheromone ESP1 regulates female reproductive behavior...male tear fluids Various social behaviors in mice are regulated by chemical signals called pheromones that a... and neural mechanisms that are involved in the decoding of ESP family signals in the vomeronasal system, which leads to behavior

  20. Nutlin‐3a selects for cells harbouring TP 53 mutations

    OpenAIRE

    Kucab, Jill E.; Hollstein, Monica; Volker M. Arlt; Phillips, David H.

    2016-01-01

    TP53 mutations occur in half of all human tumours. Mutagen‐induced or spontaneous TP53 mutagenesis can be studied in vitro using the human TP53 knock‐in (Hupki) mouse embryo fibroblast (HUF) immortalisation assay (HIMA). TP53 mutations arise in up to 30% of mutagen‐treated, immortalised HUFs; however, mutants are not identified until TP53 sequence analysis following immortalisation (2–5 months) and much effort is expended maintaining TP53‐WT cultures. In order to improve the selectivity of th...

  1. The Application of L2TP VPN%L2TP VPN的应用

    Institute of Scientific and Technical Information of China (English)

    宁云亭

    2009-01-01

    介绍了虚拟专用网络的产生背景、实现方式、性能特点.重点介绍了L2TP VPN与IPsec VPN虚拟专用网络,比较了构成特点和适用对象,给出了构建L2TP VPN网络实例.

  2. Nutlin-3a selects for cells harbouring TP53 mutations.

    Science.gov (United States)

    Kucab, Jill E; Hollstein, Monica; Arlt, Volker M; Phillips, David H

    2017-02-15

    TP53 mutations occur in half of all human tumours. Mutagen-induced or spontaneous TP53 mutagenesis can be studied in vitro using the human TP53 knock-in (Hupki) mouse embryo fibroblast (HUF) immortalisation assay (HIMA). TP53 mutations arise in up to 30% of mutagen-treated, immortalised HUFs; however, mutants are not identified until TP53 sequence analysis following immortalisation (2-5 months) and much effort is expended maintaining TP53-WT cultures. In order to improve the selectivity of the HIMA for HUFs harbouring TP53 mutations, we explored the use of Nutlin-3a, an MDM2 inhibitor that leads to stabilisation and activation of wild-type (WT) p53. First, we treated previously established immortal HUF lines carrying WT or mutated TP53 with Nutlin-3a to examine the effect on cell growth and p53 activation. Nutlin-3a induced the p53 pathway in TP53-WT HUFs and inhibited cell growth, whereas most TP53-mutated HUFs were resistant to Nutlin-3a. We then assessed whether Nutlin-3a treatment could discriminate between TP53-WT and TP53-mutated cells during the HIMA (n = 72 cultures). As immortal clones emerged from senescent cultures, each was treated with 10 µM Nutlin-3a for 5 days and observed for sensitivity or resistance. TP53 was subsequently sequenced from all immortalised clones. We found that all Nutlin-3a-resistant clones harboured TP53 mutations, which were diverse in position and functional impact, while all but one of the Nutlin-3a-sensitive clones were TP53-WT. These data suggest that including a Nutlin-3a counter-screen significantly improves the specificity and efficiency of the HIMA, whereby TP53-mutated clones are selected prior to sequencing and TP53-WT clones can be discarded.

  3. Main - TP Atlas | LSDB Archive [Life Science Database Archive metadata

    Lifescience Database Archive (English)

    Full Text Available switchLanguage; BLAST Search Image Search Home About Archive Update History Data List Contact us TP Atlas...d License Update History of This Database Site Policy | Contact Us Main - TP Atlas | LSDB Archive ...

  4. Bioinformatics and phylogenetic analysis of human Tp73 gene

    African Journals Online (AJOL)

    Imtiaz

    2013-06-26

    Jun 26, 2013 ... Key words: Tp73, Bioinformatics, phylogenetics analysis, cancer, Tp53. INTRODUCTION ... splicing at C-terminal end of that protein and give rise to six different p73 terminal variants ..... 33 in human lung cancers. Cancer Res.

  5. PK20, a new opioid-neurotensin hybrid peptide that exhibits central and peripheral antinociceptive effects

    Directory of Open Access Journals (Sweden)

    Tsuda Yuko

    2010-12-01

    Full Text Available Abstract Background The clinical treatment of various types of pain relies upon the use of opioid analgesics. However most of them produce, in addition to the analgesic effect, several side effects such as the development of dependence and addiction as well as sedation, dysphoria, and constipation. One solution to these problems are chimeric compounds in which the opioid pharmacophore is hybridized with another type of compound to incease antinociceptive effects. Neurotensin-induced antinociception is not mediated through the opioid system. Therefore, hybridizing neurotensin with opioid elements may result in a potent synergistic antinociceptor. Results Using the known structure-activity relationships of neurotensin we have synthesized a new chimeric opioid-neurotensin compound PK20 which is characterized by a very strong antinociceptive potency. The observation that the opioid antagonist naltrexone did not completely reverse the antinociceptive effect, indicates the partial involvement of the nonopioid component in PK20 in the produced analgesia. Conclusions The opioid-neurotensin hybrid analogue PK20, in which opioid and neurotensin pharmacophores overlap partially, expresses high antinociceptive tail-flick effects after central as well as peripheral applications.

  6. Download - TP Atlas | LSDB Archive [Life Science Database Archive metadata

    Lifescience Database Archive (English)

    Full Text Available Simple search and download 1 README README_e.html - 2 Main tp_atlas_en.zip (20.1 KB) Simple search and download 3 Protein tp_atlas..._protein.zip (49.8 KB) Simple search and download 4 Network File tp_atlas_csml.zip (2....02 MB) - 5 Image File tp_atlas_png.zip (6.93 MB) - Downlaod via FTP Joomla SEF UR

  7. Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of the hypothalamic-pituitary-gonadal axis following treatment with GnRH analogues

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Senderovitz, Thomas

    2007-01-01

    for the population PK/PD data analysis. A systematic population PK/PD model-building framework using stochastic differential equations was applied to the data to identify nonlinear dynamic dependencies and to deconvolve the functional feedback interactions of the HPG axis. Results In our final PK/PD model of the HPG......Aims To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of the hypothalamic-pituitary-gonadal (HPG) axis describing the changes in luteinizing hormone (LH) and testosterone concentrations following treatment with the gonadotropin-releasing hormone (GnRH) agonist triptorelin...... for the different dynamic responses observed after administration of both GnRH agonists and GnRH receptor blockers, suggesting that the model adequately characterizes the underlying physiology of the endocrine system....

  8. TP53 Promoter Methylation in Primary Glioblastoma: Relationship with TP53 mRNA and Protein Expression and Mutation Status

    OpenAIRE

    JESIONEK-KUPNICKA, DOROTA; Szybka, Malgorzata; Malachowska, Beata; Fendler, Wojciech; Potemski, Piotr; Piaskowski, Sylwester; Jaskolski, Dariusz; Papierz, Wielislaw; Skowronski, Wieslaw; Och, Waldemar; Kordek, Radzislaw; ZAWLIK, IZABELA

    2014-01-01

    Reduced expression of TP53 by promoter methylation has been reported in several neoplasms. It remains unclear whether TP53 promoter methylation is associated with reduced transcriptional and protein expression in glioblastoma (GB). The aim of our work was to study the impact of TP53 methylation and mutations on TP53 mRNA level and protein expression in 42 molecularly characterized primary GB tumors. We also evaluate the impact of all molecular alterations on the overall patient survival. The ...

  9. A comparison of the structure of the PK-sensitive and PK-resistant forms of PrPSc(Abstract)

    Science.gov (United States)

    Background/Introduction. One of the distinctive phenotypes of the infectious isoform of PrP(PrPSc)is its resistance to proteinase K (PK) digestion. The diagnosis of prion diseases is based on this phenotypic observation. More recently, researchers determined that there is a sizeable fraction of PrPS...

  10. TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data.

    Science.gov (United States)

    Bouaoun, Liacine; Sonkin, Dmitriy; Ardin, Maude; Hollstein, Monica; Byrnes, Graham; Zavadil, Jiri; Olivier, Magali

    2016-09-01

    TP53 gene mutations are one of the most frequent somatic events in cancer. The IARC TP53 Database (http://p53.iarc.fr) is a popular resource that compiles occurrence and phenotype data on TP53 germline and somatic variations linked to human cancer. The deluge of data coming from cancer genomic studies generates new data on TP53 variations and attracts a growing number of database users for the interpretation of TP53 variants. Here, we present the current contents and functionalities of the IARC TP53 Database and perform a systematic analysis of TP53 somatic mutation data extracted from this database and from genomic data repositories. This analysis showed that IARC has more TP53 somatic mutation data than genomic repositories (29,000 vs. 4,000). However, the more complete screening achieved by genomic studies highlighted some overlooked facts about TP53 mutations, such as the presence of a significant number of mutations occurring outside the DNA-binding domain in specific cancer types. We also provide an update on TP53 inherited variants including the ones that should be considered as neutral frequent variations. We thus provide an update of current knowledge on TP53 variations in human cancer as well as inform users on the efficient use of the IARC TP53 Database.

  11. Analysis list: TP63 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available TP63 Epidermis + hg19 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/TP63.1....tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/TP63.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/TP63....10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/TP63.Epidermis.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/Epidermis.gml ...

  12. TP53 dysfunction in CLL: Implications for prognosis and treatment.

    Science.gov (United States)

    Te Raa, Gera D; Kater, Arnon P

    2016-03-01

    Despite the availability of novel targeted agents, TP53 defects remain the most important adverse prognostic factor in chronic lymphocytic leukemia (CLL). Detection of deletion of TP53 locus (17p deletion) by fluorescent in situ hybridization (FISH) has become standard and performed prior to every line of treatment as the incidence dramatically increases as relapses occur. As monoallelic mutations of TP53 equally affect outcome, novel methods are being developed to improve detection of TP53 defects and include next-generation sequencing (NGS) and functional assays. TP53 defects highly affect outcome of immunochemotherapy but also alter response durations of tyrosine kinase inhibitors. Although BCR-targeting agents and Bcl-2-inhibitos have achieved durable responses in some patients with TP53 defects, long-term follow-up is currently lacking. In this review biological and clinical consequences of TP53 dysfunction as well as applicability of currently available methods to detect TP53 defects are described. In addition, proposed novel therapeutic strategies specifically for patients with TP53 dysfunction are discussed. In summary, the only curative treatment option for TP53-defective CLL is still allogeneic hematopoietic stem cell transplantation. Other treatment strategies such as rationale combinations of agents with different (TP53 independent) targets, including kinase inhibitors and inhibitors of anti-apoptotic molecules but also immunomodulatory agents need to be further explored.

  13. TP53 gene status affects survival in advanced mycosis fungoides

    Directory of Open Access Journals (Sweden)

    Gitte Wooler

    2016-11-01

    Full Text Available TP53 is frequently mutated in different types of neoplasms including leukemia and lymphomas. Mutations of TP53 have also been reported in mycosis fungoides (MF, the most common type of cutaneous lymphoma. However, little is known about the frequency, spectrum of mutations and their prognostic significance in MF. In this study we have optimized the protocol for Sanger sequencing of TP53 using DNA extracted from archival paraffin-embedded biopsies. Of 19 samples from patients with stage IIB MF or higher, 31% harboured mutations in TP53. Overall survival of the patients with mutated TP53 was significantly shorter than median survival in the age- and stage-matched patients treated in our Institution. Distribution of mutations was heterogenous in TP53 exons, however C>T transitions were common suggesting the causal role of ultraviolet radiation. We propose that TP53 mutation status would be useful for risk stratification of patients with advanced MF.

  14. Analysis list: TP53 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available encedbc.jp/kyushu-u/hg19/target/TP53.1.tsv http://dbarchive.biosciencedbc.jp/kyushu...-u/hg19/target/TP53.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/TP53.10.tsv http://dbarchive.bioscience...dbc.jp/kyushu-u/hg19/colo/TP53.Blood.tsv,http://dbarchive.bioscienced...bc.jp/kyushu-u/hg19/colo/TP53.Bone.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/TP53.Breast.tsv,http://dbarchive.bioscien...cedbc.jp/kyushu-u/hg19/colo/TP53.Digestive_tract.tsv,http://dbarchive.biosciencedbc

  15. Prolonged Tp-e Interval and Tp-e/QT Ratio in Children with Mitral Valve Prolapse.

    Science.gov (United States)

    Demirol, Mustafa; Karadeniz, Cem; Ozdemir, Rahmi; Çoban, Şenay; Katipoğlu, Nagehan; Yozgat, Yılmaz; Meşe, Timur; Unal, Nurettin

    2016-08-01

    Although it is considered to be a benign condition, previous studies have shown that a subset of patients with mitral valve prolapse (MVP) may be at risk of ventricular arrhythmia and sudden cardiac death (SCD). Previous studies have suggested that the interval between the peak and the end of the T wave (Tp-e) can be used as a marker for the transmural dispersion of repolarization. Increased Tp-e interval and Tp-e/QT ratio are associated with ventricular arrhythmias and SCD. The aim of this study was to assess alterations in ventricular repolarization by using the Tp-e interval and Tp-e/QT ratio in children with MVP and to investigate their relationships with the degree of valvular regurgitation. This study prospectively investigated 110 children with MVP and 107 age- and sex-matched healthy control subjects. Tp-e interval, Tp-e/QT ratio, and QT and QTc dispersions were measured from a 12-lead electrocardiogram and compared between groups. QT and QTc dispersions, Tp-e interval, and Tp-e/QTc ratio were found to be significantly higher in patients with MVP. A positive correlation was found between Tp-e/QTc ratio and increase in the degree of mitral regurgitation (MR) (p e intervals; QT, QTc, or Tp-e dispersions; or Tp-e/QT ratio (all p values >0.05). Individuals with MVP may be more prone to ventricular arrhythmias due to prolonged QTd, QTcd, and Tp-e interval and increased Tp-e/QT and Tp-e/QTc ratios. Therefore, due to their longer life expectancy, children with MVP should be followed up on regarding life-threatening arrhythmias.

  16. Improved sensitivity in the diagnosis of gastro-intestinal tumors by fuzzy logic-based tumor marker profiles including the tumor M2-PK.

    Science.gov (United States)

    Schneider, Joachim; Bitterlich, Norman; Schulze, Guntram

    2005-01-01

    The aim of this study was to improve diagnostic efficiency in the detection of gastro-intestinal cancers by using fuzzy logic modeling in combination with a tumor marker panel (CEA, CA72-4, CA19-9) including Tumor M2-PK. In this prospective study histologically confirmed colorectal (n=247), esophageal (n=86) and gastric cancer (n=122) patients were investigated and compared to control (n=53) persons without any malignant diseases. Tumor M2-PK was measured in plasma with an ELISA (ScheBoBiotech, Germany); all other markers were measured in sera (Roche, Germany). At 95% specificity, tumor detection was possible by the best single marker in colorectal cancer patients in 48% (Tumor M2-PK), in gastric cancers in 61% (CA72-4) and in esophageal cancers in 56% (Tumor M2-PK). A fuzzy logic rule-based system employing a tumor marker panel increased sensitivity significantly in colorectal cancers (pTumor M2-PK and CEA), in gastric cancers (pTumor M2-PK and CA 72-4) and in esophageal cancers (pTumor M2-PK and CA72-4). Adding a third marker further improved the sensitivity only marginally. Fuzzy logic analysis has proven to be more powerful than measurement of single markers alone or combinations using multiple logistic regression analysis of the markers. Therefore, with the fuzzy logic method and a tumor marker panel (including Tumor M2-PK), a new diagnostic tool for the detection of gastro-intestinal cancers is available.

  17. n×k×m格图Pn×Pk×Pm的控制数%DOMINATION NUMBERS OF GRID GRAPHS Pn × Pk × Pm

    Institute of Scientific and Technical Information of China (English)

    姜伟; 杨德林; 刘焕平

    2002-01-01

    n×k× m格图Pn×Pk×Pm是长为n的路与长为k的路与长为m的路的积,本文给出了Pn×Pk×Pm的控制数的一些结论.①当| n|≤3,|k|≤3,| m|≤3时的Pn×Pk×Pm格图的控制数.②当n∈N,k∈N,m∈N时,Pn×Pk×Pm的控制数的一个上界.③利用"隔空配凑"方法,生成Pn×Pk×Pm格图,并用其将Pn×Pk×Pm的控制数的上界加以优化.

  18. De novo sequencing, assembly and analysis of the genome of the laboratory strain Saccharomyces cerevisiae CEN.PK113-7D, a model for modern industrial biotechnology.

    Science.gov (United States)

    Nijkamp, Jurgen F; van den Broek, Marcel; Datema, Erwin; de Kok, Stefan; Bosman, Lizanne; Luttik, Marijke A; Daran-Lapujade, Pascale; Vongsangnak, Wanwipa; Nielsen, Jens; Heijne, Wilbert H M; Klaassen, Paul; Paddon, Chris J; Platt, Darren; Kötter, Peter; van Ham, Roeland C; Reinders, Marcel J T; Pronk, Jack T; de Ridder, Dick; Daran, Jean-Marc

    2012-03-26

    Saccharomyces cerevisiae CEN.PK 113-7D is widely used for metabolic engineering and systems biology research in industry and academia. We sequenced, assembled, annotated and analyzed its genome. Single-nucleotide variations (SNV), insertions/deletions (indels) and differences in genome organization compared to the reference strain S. cerevisiae S288C were analyzed. In addition to a few large deletions and duplications, nearly 3000 indels were identified in the CEN.PK113-7D genome relative to S288C. These differences were overrepresented in genes whose functions are related to transcriptional regulation and chromatin remodelling. Some of these variations were caused by unstable tandem repeats, suggesting an innate evolvability of the corresponding genes. Besides a previously characterized mutation in adenylate cyclase, the CEN.PK113-7D genome sequence revealed a significant enrichment of non-synonymous mutations in genes encoding for components of the cAMP signalling pathway. Some phenotypic characteristics of the CEN.PK113-7D strains were explained by the presence of additional specific metabolic genes relative to S288C. In particular, the presence of the BIO1 and BIO6 genes correlated with a biotin prototrophy of CEN.PK113-7D. Furthermore, the copy number, chromosomal location and sequences of the MAL loci were resolved. The assembled sequence reveals that CEN.PK113-7D has a mosaic genome that combines characteristics of laboratory strains and wild-industrial strains.

  19. TP53 and lacZ mutagenesis induced by 3-nitrobenzanthrone in Xpa-deficient human TP53 knock-in mouse embryo fibroblasts.

    Science.gov (United States)

    Kucab, Jill E; Zwart, Edwin P; van Steeg, Harry; Luijten, Mirjam; Schmeiser, Heinz H; Phillips, David H; Arlt, Volker M

    2016-03-01

    3-Nitrobenzanthrone (3-NBA) is a highly mutagenic compound and possible human carcinogen found in diesel exhaust. 3-NBA forms bulky DNA adducts following metabolic activation and induces predominantly G:CT:A transversions in a variety of experimental systems. Here we investigated the influence of nucleotide excision repair (NER) on 3-NBA-induced mutagenesis of the human tumour suppressor gene TP53 and the reporter gene lacZ. To this end we utilised Xpa -knockout (Xpa-Null) human TP53 knock-in (Hupki) embryo fibroblasts (HUFs). As Xpa is essential for NER of bulky DNA adducts, we hypothesized that DNA adducts induced by 3-NBA would persist in the genomes of Xpa-Null cells and lead to an increased frequency of mutation. The HUF immortalisation assay was used to select for cells harbouring TP53 mutations following mutagen exposure. We found that Xpa-Null Hupki mice and HUFs were more sensitive to 3-NBA treatment than their wild-type (Xpa-WT) counterparts. However, following 3-NBA treatment and immortalisation, a similar frequency of TP53-mutant clones arose from Xpa-WT and Xpa-Null HUF cultures. In cells from both Xpa genotypes G:CT:A transversion was the predominant TP53 mutation type and mutations exhibited bias towards the non-transcribed strand. Thirty-two percent of 3-NBA-induced TP53 mutations occurred at CpG sites, all of which are hotspots for mutation in smokers' lung cancer (codons 157, 158, 175, 245, 248, 273, 282). We also examined 3-NBA-induced mutagenesis of an integrated lacZ reporter gene in HUFs, where we again observed a similar mutant frequency in Xpa-WT and Xpa-Null cells. Our findings suggest that 3-NBA-DNA adducts may evade removal by global genomic NER; the persistence of 3-NBA adducts in DNA may be an important factor in its mutagenicity.

  20. Tumor Growth Model with PK Input for Neuroblastoma Drug Development

    Science.gov (United States)

    2015-09-01

    9/2012 - 4/30/2017 2.40 calendar NCI Anticancer Drug Pharmacology in Very Young Children The proposed studies will use pharmacokinetic... anticancer drugs . DOD W81XWH-14-1-0103 CA130396 (Stewart) 9/1/2014 - 8/31/2016 .60 calendar DOD-DEPARTMENT OF THE ARMY Tumor Growth Model with PK... anticancer drugs . .60 calendar V Foundation Translational (Stewart) 11/1/2012-10/31/2015 THE V FDN FOR CA RES Identification & preclinical testing

  1. Five strands of math tasks big book : grades pk-2

    CERN Document Server

    Reed, Nat; Forest, Chris

    2009-01-01

    For grades PK-2, our Common Core State Standards-based resource meets the five strands of math concepts addressed by the NCTM standards and encourages the students to learn and review the concepts in unique ways. Included are challenging problem-solving tasks which will push the boundaries of critical thought and demonstrate to students the importance of mathematical problems in Number & Operations, Geometry, Measurement, Data Analysis & Probability and Algebra using real world situations.

  2. Five strands of math drills big book : grades PK-2

    CERN Document Server

    Reed, Nat; Forest, Chris

    2011-01-01

    For grades PK-2, our Common Core State Standards-based resource meets the five strands of math concepts addressed by the NCTM standards and encourages the students to review the concepts in unique ways. Included are warm-up and timed drill activities which will push the boundaries of critical thought and demonstrate to students the importance of mathematical problems in Number & Operations, Geometry, Measurement, Data Analysis & Probability and Algebra using real world situations.

  3. On the categorical nature of Korean /pk/ place assimilation

    Science.gov (United States)

    Son, Minjung; Kochetov, Alexei

    2001-05-01

    Korean exhibits regressive place assimilation in /pk/ clusters, which has been described as gradient and rate dependent. However, this assumption has empirically only been tested on the basis of air pressure data [Jun, 1996] which does not provide a direct record of articulator movement. The present study examines articulator movement using EMMA. For three Seoul-dialect speakers, stimuli containing /pk/ clusters were elicited word-medially (for words and nonwords) and in a phrase-boundary condition; two rates were employed. Results show that the labial can indeed reduce word medially, rendering [kk]. However, contrary to previous claims, the data demonstrate that reduction in /pk/ is always categorical, although it is optional or stochastic in its occurrence. Substantial interspeaker variation is observed, with the frequency of reduction being higher at fast rate and ranging overall from 6 at both rates and is never gradient. The lack of reduction in nonsense words and in the phrase boundary condition shows that the process is sensitive to lexical properties. The observed tendency for more gestural overlap word medially compared to the phrase-boundary condition supports the hypothesis that gestural overlap plays a role in the origins of place assimilation. [Work supported by NIH.

  4. A Comparison of Decision Methods for C pk When Data are Autocorrelated

    DEFF Research Database (Denmark)

    Lundkvist, Peder; Vannman, Kerstin; Kulahci, Murat

    2012-01-01

    In many industrial applications, autocorrelated data are becoming increasingly common due to, for example, on-line data collection systems with high-frequency sampling. Therefore, the basic assumption of independent observations for process capability analysis is not valid. The purpose...... of this article is to compare decision methods using the process capability index C-pk when data are autocorrelated. This is done through a case study followed by a simulation study. In the simulation study the actual significance level and power of the decision methods are investigated. The outcome...

  5. Influence of filled d pi-manifold and L/L' ligands on the structure, basicity, and bond rotations of the octahedral and d(6) amido complexes TpRu(L)(L')(NHPh) (Tp = hydridotris(pyrazolyl)borate; L = L' = PMe(3) or P(OMe)(3), or L = CO and L' = PPh(3)): solid-state structures of [TpRu(PMe(3))(2)(NH(2)Ph)][OTf], [TpRu[P(OMe)(3)](2)(NH(2)Ph)][OTf], and TpRu[P(OMe)(3)](2)(NHPh).

    Science.gov (United States)

    Conner, David; Jayaprakash, K N; Gunnoe, T Brent; Boyle, Paul D

    2002-06-03

    It has been suggested that the reactivity of pi-donating ligands bound to late-transition-metal complexes is heightened due to high d-electron counts. Herein, the synthesis and characterization of the Ru(II) amine and Ru(II) amido complexes [TpRuL(2)(NH(2)Ph)][OTf] (OTf = trifluoromethanesulfonate) and TpRuL(2)(NHPh) (L = PMe(3) or P(OMe)(3)) are presented, including solid-state X-ray diffraction studies of [TpRu(PMe(3))(2)(NH(2)Ph)][OTf], [TpRu[P(OMe)(3)](2)(NH(2)Ph)][OTf], and TpRu[P(OMe)(3)](2)(NHPh). The pK(a)'s of the Ru(II) amine complexes and the previously reported [TpRu(CO)(PPh(3))(NH(2)Ph)](+) have been estimated to be comparable to that of malononitrile in methylene chloride. In addition, the impact of the filled dpi-manifold (i.e., Ru(II) and d(6) octahedral systems) on barriers to rotation of the Ru-NHPh moieties has been studied. For TpRu(PMe(3))(2)(NHPh) and TpRu[P(OMe)(3)](2)(NHPh), evidence for hindered rotation about the amido nitrogen and phenyl ipso carbon has been observed, and the relative N-C and Ru-N bond rotational barriers for the series of three amido complexes are discussed in terms of the pi-conflict.

  6. TP53 Mutational Spectrum in Endometrioid and Serous Endometrial Cancers.

    Science.gov (United States)

    Schultheis, Anne M; Martelotto, Luciano G; De Filippo, Maria R; Piscuglio, Salvatore; Ng, Charlotte K Y; Hussein, Yaser R; Reis-Filho, Jorge S; Soslow, Robert A; Weigelt, Britta

    2016-07-01

    Endometrial carcinomas (ECs) are heterogeneous at the genetic level. Although TP53 mutations are highly recurrent in serous endometrial carcinomas (SECs), these are also present in a subset of endometrioid endometrial carcinomas (EECs). Here, we sought to define the frequency, pattern, distribution, and type of TP53 somatic mutations in ECs by performing a reanalysis of the publicly available data from The Cancer Genome Atlas (TCGA). A total of 228 EECs (n=186) and SECs (n=42) from the TCGA data set, for which an integrated genomic characterization was performed, were interrogated for the presence and type of TP53 mutations, and for mutations in genes frequently mutated in ECs. TP53 mutations were found in 15% of EECs and 88% of SECs, and in 91% of copy-number-high and 35% of polymerase (DNA directed), epsilon, catalytic subunit (POLE) integrative genomic subtypes. In addition to differences in prevalence, variations in the type and pattern of TP53 mutations were observed between histologic types and between integrative genomic subtypes. TP53 hotspot mutations were significantly more frequently found in SECs (46%) than in EECs (15%). TP53-mutant EECs significantly more frequently harbored a co-occurring PTEN mutation than TP53-mutant SECs. Finally, a subset of TP53-mutant ECs (22%) was found to harbor frameshift or nonsense mutations. Given that nonsense and frameshift TP53 mutations result in distinct p53 immunohistochemical results that require careful interpretation, and that EECs and SECs display different patterns, types, and distributions of TP53 mutations, the use of the TP53/p53 status alone for the differential diagnosis of EECs and SECs may not be sufficient.

  7. Telomere status in chronic lymphocytic leukemia with TP53 disruption.

    Science.gov (United States)

    Guièze, Romain; Pages, Mélanie; Véronèse, Lauren; Combes, Patricia; Lemal, Richard; Gay-Bellile, Mathilde; Chauvet, Martine; Callanan, Mary; Kwiatkowski, Fabrice; Pereira, Bruno; Vago, Philippe; Bay, Jacques-Olivier; Tournilhac, Olivier; Tchirkov, Andreï

    2016-08-30

    In chronic lymphocytic leukemia (CLL), telomere dysfunction is associated with poor outcomes. TP53 is involved in cellular responses to dysfunctional telomeres, and its inactivation is the strongest adverse prognostic factor for CLL. Given the biological relationship between TP53 and telomeres, and their prognostic value, it is important to improve our understanding of the impact of TP53 alterations on telomeres. We performed a comprehensive study of the deletions and mutations of the TP53 gene and telomere parameters, including hTERT and the shelterin complex, in 115 CLL patients. We found that any type of TP53 alteration was associated with very short telomeres and high hTERT expression, independently of other biological CLL features. Patients with disrupted TP53 showed telomere deletions and chromosomal end-to-end fusions in cells with complex karyotypes. TP53 disruption was characterized by downregulation of shelterin genes. Interestingly, low expression of POT1, TPP1 and TIN2 was also found in some patients with wild-type TP53 and had an adverse impact on progression-free survival after standard genotoxic therapy. In conclusion, we have demonstrated that patients with disrupted TP53 have severe telomere dysfunction and high genomic instability. Thus, the telomeric profile could be tested as a biomarker in CLL patients treated with new therapeutic agents.

  8. The Levels and Distribution of TN, TP and TOC in the South China Sea

    Science.gov (United States)

    Wang, H.; Han, D.

    2012-04-01

    The marine biogeochemistries of carbon, nitrogen and phosphorous have come under increased scrutiny because of their close involvement in climate change and coastal eutrophication. The South China Sea is unique in that located in a subtropical zone, and therefore represents an important regime for biogeochemical studies. However, to our knowledge, few data are available for total nitrogen (TN), total phosphorous (TP) and total organic carbon (TOC) in South Sea, China. The present study aims to contribute to the knowledge of their status through investigating the level and distribution of TN, TP and TOC in South China Sea. A total of 108 seawater samples of 11 sites in south sea, china were collected during August 29- September 4, 2006. An automated and simultaneous method for determination of TN and TOC was applied to all seawater samples. The combined system allowed simultaneous determination for TOC and TN in the same sample using a single injection and provided low detection limits and excellent linear ranges for both TOC and TN. The risk of contamination has been remarkably reduced due to the minimal sample manipulation and automated analyses. And quantitative analyses of TP in seawater were accomplished by a typical chemical method. Concentration ranges of TN and TP were 0.06-0.67, and 0.003-0.071 mg/L, respectively, as well as that of TOC were 0.23-2.51mg/L. The values of TN and TP showed that the status of nutrition is relatively better in south china sea than other marine areas. Moreover, the upright change trend of TN concentration level as well as TP and TOC according to the experimental results at the total 11 sites are simultaneity studied. The concentration of TN initial increases with the increasing of the depth, later the value becomes almost constant. In contrast, the concentration of TOC reduces with the increasing of the depth, later the value becomes almost unchangeable. Compared with the trend of TN and TOC, that of TP appears relatively stable

  9. Disruptive TP53 mutation is associated with aggressive disease characteristics in an orthotopic murine model of oral tongue cancer.

    Science.gov (United States)

    Sano, Daisuke; Xie, Tong-Xin; Ow, Thomas J; Zhao, Mei; Pickering, Curtis R; Zhou, Ge; Sandulache, Vlad C; Wheeler, David A; Gibbs, Richard A; Caulin, Carlos; Myers, Jeffrey N

    2011-11-01

    To characterize tumor growth and metastatic potential in head and neck squamous cell carcinoma (HNSCC) cell lines in an orthotopic murine model of oral tongue cancer and to correlate TP53 mutation status with these findings. Cells from each of 48 HNSCC cell lines were orthotopically injected into the oral tongues of nude mice. Tumor volume, cervical lymph node metastasis, and mouse survival were recorded. Direct sequencing of the TP53 gene and Western blot analysis for the p53 protein after induction with 5-fluorouracil was conducted. Cell lines were categorized as either mutant TP53 or wild-type TP53, and lines with TP53 mutation were further categorized on the basis of type of mutation (disruptive or nondisruptive) and level of p53 protein expression. The behavior of tumors in these different groups was compared. These 48 HNSCC cell lines showed a wide range of behavior from highly aggressive and metastatic to no tumor formation. Mice injected with cells harboring disruptive TP53 mutations had faster tumor growth, greater incidence of cervical lymph node metastasis, and shorter survival than mice injected with cells lacking these mutations. HNSCC cell lines display a wide spectrum of behavior in an orthotopic model of oral cancer. Cell lines with disruptive TP53 mutations are more aggressive in this system, corroborating clinical reports that have linked these mutations to poor patient outcome. ©2011 AACR

  10. A Business Plan for PK Handbags Manufacturing Company

    OpenAIRE

    Somchatvong, Laddaporn

    2009-01-01

    PK Co. Limited is a small family-business-owned company located in Thailand. Since established in 1998, the company’s business is manufacturing women’s fashion handbags for wholesale apparel trading company in Thailand. The company also produces and merchandises premium gifts for Kasikorn Bank, one of the largest banks in Thailand. Over the past ten years, the company has generated more than 200 million Baht in revenue or £ 3.6 million . The founders, Likit and Duangporn Somchatvong, have ...

  11. Fischer-344 Tp53-knockout rats exhibit a high rate of bone and brain neoplasia with frequent metastasis.

    Science.gov (United States)

    Hansen, Sarah A; Hart, Marcia L; Busi, Susheel; Parker, Taybor; Goerndt, Angela; Jones, Kevin; Amos-Landgraf, James M; Bryda, Elizabeth C

    2016-10-01

    Somatic mutations in the Tp53 tumor suppressor gene are the most commonly seen genetic alterations in cancer, and germline mutations in Tp53 predispose individuals to a variety of early-onset cancers. Development of appropriate translational animal models that carry mutations in Tp53 and recapitulate human disease are important for drug discovery, biomarker development and disease modeling. Current Tp53 mouse and rat models have significant phenotypic and genetic limitations, and often do not recapitulate certain aspects of human disease. We used a marker-assisted speed congenic approach to transfer a well-characterized Tp53-mutant allele from an outbred rat to the genetically inbred Fischer-344 (F344) rat to create the F344-Tp53(tm1(EGFP-Pac)Qly)/Rrrc (F344-Tp53) strain. On the F344 genetic background, the tumor spectrum shifted, with the primary tumor types being osteosarcomas and meningeal sarcomas, compared to the hepatic hemangiosarcoma and lymphoma identified in the original outbred stock model. The Fischer model is more consistent with the early onset of bone and central nervous system sarcomas found in humans with germline Tp53 mutations. The frequency of osteosarcomas in F344-Tp53 homozygous and heterozygous animals was 57% and 36%, respectively. Tumors were highly representative of human disease radiographically and histologically, with tumors found primarily on long bones with frequent pulmonary metastases. Importantly, the rapid onset of osteosarcomas in this promising new model fills a current void in animal models that recapitulate human pediatric osteosarcomas and could facilitate studies to identify therapeutic targets.

  12. Fischer-344 Tp53-knockout rats exhibit a high rate of bone and brain neoplasia with frequent metastasis

    Directory of Open Access Journals (Sweden)

    Sarah A. Hansen

    2016-10-01

    Full Text Available Somatic mutations in the Tp53 tumor suppressor gene are the most commonly seen genetic alterations in cancer, and germline mutations in Tp53 predispose individuals to a variety of early-onset cancers. Development of appropriate translational animal models that carry mutations in Tp53 and recapitulate human disease are important for drug discovery, biomarker development and disease modeling. Current Tp53 mouse and rat models have significant phenotypic and genetic limitations, and often do not recapitulate certain aspects of human disease. We used a marker-assisted speed congenic approach to transfer a well-characterized Tp53-mutant allele from an outbred rat to the genetically inbred Fischer-344 (F344 rat to create the F344-Tp53tm1(EGFP-PacQly/Rrrc (F344-Tp53 strain. On the F344 genetic background, the tumor spectrum shifted, with the primary tumor types being osteosarcomas and meningeal sarcomas, compared to the hepatic hemangiosarcoma and lymphoma identified in the original outbred stock model. The Fischer model is more consistent with the early onset of bone and central nervous system sarcomas found in humans with germline Tp53 mutations. The frequency of osteosarcomas in F344-Tp53 homozygous and heterozygous animals was 57% and 36%, respectively. Tumors were highly representative of human disease radiographically and histologically, with tumors found primarily on long bones with frequent pulmonary metastases. Importantly, the rapid onset of osteosarcomas in this promising new model fills a current void in animal models that recapitulate human pediatric osteosarcomas and could facilitate studies to identify therapeutic targets.

  13. Tank Pressure Control Experiment/thermal Phenomena (TPCE/TP)

    Science.gov (United States)

    Hasan, M. M.; Knoll, R. H.

    1992-01-01

    The 'Tank Pressure Control Experiment/Thermal Phenomena (TPCE/TP)' is a reflight of the tank pressure control experiment (TPCE), flown on STS-43 in a standard Get-Away Special (GAS) container in August 1991. The TPCE obtained extensive video and digital data of the jet induced mixing process in a partially filled tank in low gravity environments. It also provided limited data on the thermal processes involved. The primary objective of the reflight of TPCE is to investigate experimentally the phenomena of liquid superheating and pool nucleate boiling at very low heat fluxes in a long duration low gravity environment. The findings of this experiment will be of direct relevance to space based subcritical cryogenic fluid system design and operation. Experiment hardware and results from the first TPCE are described in outline and graphic form.

  14. TP53 Gene Status Affects Survival in Advanced Mycosis Fungoides

    DEFF Research Database (Denmark)

    Wooler, Gitte; Melchior, Linea; Ralfkiaer, Elisabeth

    2016-01-01

    TP53 is frequently mutated in different types of neoplasms including leukemia and lymphomas. Mutations of TP53 have also been reported in mycosis fungoides (MF), the most common type of cutaneous lymphoma. However, little is known about the frequency, spectrum of mutations, and their prognostic s...... for risk stratification of patients with advanced MF....

  15. Missense mutations in the TP53 DNA-binding domain predict outcomes in patients with advanced oral cavity squamous cell carcinoma.

    Science.gov (United States)

    Lapke, Nina; Lu, Yen-Jung; Liao, Chun-Ta; Lee, Li-Yu; Lin, Chien-Yu; Wang, Hung-Ming; Ng, Shu-Hang; Chen, Shu-Jen; Yen, Tzu-Chen

    2016-07-12

    TP53 mutations have been linked to reduced survival in patients with oral cavity squamous cell carcinoma (OSCC). However, the impact of different types of TP53 mutations remains unclear. Here, we demonstrate that the carriage of missense mutations in the TP53 DNA binding domain (DBD missense mutations) is associated with decreased disease-specific survival (DSS) compared with wild-type TP53 (P=0.002) in a cohort of 345 OSCC patients. In contrast, DSS of patients bearing all of the remaining TP53 mutations did not differ from that observed in wild-type TP53 patients (P=0.955). Our classification method for TP53 mutations was superior to previously reported approaches (disruptive, truncating, Evolutionary Action score, mutations in L2/L3/LSH) for distinguishing between low- and high-risk patients. When analyzed in combination with traditional clinicopathological factors, TP53 DBD missense mutations were an independent prognostic factor for shorter DSS (P=0.014) alongside with advanced AJCC T- and N-classifications and the presence of extracapsular spread. A scoring system that included the four independent prognostic factors allowed a reliable patient stratification into distinct risk groups (high-risk patients, 16.2%). Our results demonstrate the usefulness of TP53 DBD missense mutations combined with clinicopathological factors for improving the prognostic stratification of OSCC patients.

  16. BRCA2 and TP53 collaborate in tumorigenesis in zebrafish.

    Directory of Open Access Journals (Sweden)

    Heather R Shive

    Full Text Available Germline mutations in the tumor suppressor genes BRCA2 and TP53 significantly influence human cancer risk, and cancers from humans who inherit one mutant allele for BRCA2 or TP53 often display loss of the wildtype allele. In addition, BRCA2-associated cancers often exhibit mutations in TP53. To determine the relationship between germline heterozygous mutation (haploinsufficiency and somatic loss of heterozygosity (LOH for BRCA2 and TP53 in carcinogenesis, we analyzed zebrafish with heritable mutations in these two genes. Tumor-bearing zebrafish were examined by histology, and normal and neoplastic tissues were collected by laser-capture microdissection for LOH analyses. Zebrafish on a heterozygous tp53(M214K background had a high incidence of malignant tumors. The brca2(Q658X mutation status determined both the incidence of LOH and the malignant tumor phenotype. LOH for tp53 occurred in the majority of malignant tumors from brca2 wildtype and heterozygous mutant zebrafish, and most of these were malignant peripheral nerve sheath tumors. Malignant tumors in zebrafish with heterozygous mutations in both brca2 and tp53 frequently displayed LOH for both genes. In contrast, LOH for tp53 was uncommon in malignant tumors from brca2 homozygotes, and these tumors were primarily undifferentiated sarcomas. Thus, carcinogenesis in zebrafish with combined mutations in tp53 and brca2 typically requires biallelic mutation or loss of at least one of these genes, and the specific combination of inherited mutations influences the development of LOH and the tumor phenotype. These results provide insight into cancer development associated with heritable BRCA2 and TP53 mutations.

  17. TP53 — EDRN Public Portal

    Science.gov (United States)

    TP53, also widely known as p53, acts as a tumor suppressor in many tumor types, responding to diverse cellular stresses to regulate target genes that induce cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. It is involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. p53 protein is expressed at low level in normal cells and at a high level in a variety of transformed cell lines, where it's believed to contribute to transformation and malignancy. p53 is a DNA-binding protein containing transcription activation, DNA-binding, and oligomerization domains. It is postulated to bind to a p53-binding site and activate expression of downstream genes that inhibit growth and/or invasion, and thus function as a tumor suppressor. Mutants of p53 that frequently occur in a number of different human cancers fail to bind the consensus DNA binding site, and hence cause the loss of tumor suppressor activity. Multiple p53 variants due to alternative promoters and multiple alternative splicing have been found. These variants encode distinct isoforms, which can regulate p53 transcriptional activity.

  18. Drug design tools--in silico, in vitro and in vivo ADME/PK prediction and interpretation: is PK in monkey an essential part of a good human PK prediction?

    Science.gov (United States)

    Hosea, Natilie A

    2011-01-01

    Quantitative human pharmacokinetic (PK) predictions play a critical role in assessing the quality of potential drug candidates and in selecting a human starting dose for clinical evaluation, where the parameters of clearance, volume of distribution, and bioavailability as well as the plasma concentration time profiles are the desired endpoints. While there are numerous reports validating the use of different methods for predictions, it still remains an open question as to what animal species to include when extrapolating the animal PK to human. Given toxicological assessment is generally conducted in two species, a rodent and a non-rodent species, prior to evaluation in human subjects, rat, dog and/or monkey are typically the species ADME scientists employ to evaluate PK. However, the question is, can we achieve an adequate prediction without the use of larger species such as monkey? In the end, the data and tools utilized for human PK predictions will depend on a number of factors such as information from observed human PK for structurally related compounds; the primary mechanism of clearance, and the availability of in silico and in vitro tools applicable to the respective clearance mechanism. Despite these dependencies, for most situations, adequate predictions can be achieved without the use of monkey PK for predicting human.

  19. PK/DB: database for pharmacokinetic properties and predictive in silico ADME models.

    Science.gov (United States)

    Moda, Tiago L; Torres, Leonardo G; Carrara, Alexandre E; Andricopulo, Adriano D

    2008-10-01

    The study of pharmacokinetic properties (PK) is of great importance in drug discovery and development. In the present work, PK/DB (a new freely available database for PK) was designed with the aim of creating robust databases for pharmacokinetic studies and in silico absorption, distribution, metabolism and excretion (ADME) prediction. Comprehensive, web-based and easy to access, PK/DB manages 1203 compounds which represent 2973 pharmacokinetic measurements, including five models for in silico ADME prediction (human intestinal absorption, human oral bioavailability, plasma protein binding, blood-brain barrier and water solubility). http://www.pkdb.ifsc.usp.br

  20. A pumpless multi-organ-on-a-chip (MOC) combined with a pharmacokinetic-pharmacodynamic (PK-PD) model.

    Science.gov (United States)

    Lee, Hyuna; Kim, Dae Shik; Ha, Sang Keun; Choi, Inwook; Lee, Jong Min; Sung, Jong Hwan

    2017-02-01

    A multi-organ-on-a-chip (MOC), also known as a human-on-a-chip, aims to simulate whole body response to drugs by connecting microscale cell cultures of multiple tissue types via fluidic channels and reproducing the interaction between them. While several studies have demonstrated the usefulness of MOC at a proof-of-concept level, improvements are needed to enable wider acceptance of such systems; ease of use for general biological researchers, and a mathematical framework to design and interpret the MOC systems. Here, we introduce a pumpless, user-friendly MOC which can be easily assembled and operated, and demonstrate the use of a PK-PD model for interpreting drug's action inside the MOC. The metabolism-dependent anticancer activity of a flavonoid, luteolin, was evaluated in a two-compartment MOC containing the liver (HepG2) and the tumor (HeLa) cells, and the observed anticancer activity was significantly weaker than that anticipated from a well plate study. Simulation of a PK-PD model revealed that simultaneous metabolism and tumor-killing actions likely resulted in a decreased anti-cancer effect. Our work demonstrates that the combined platform of mathematical PK-PD model and an experimental MOC can be a useful tool for gaining an insight into the mechanism of action of drugs with interactions between multiple organs. Biotechnol. Bioeng. 2017;114: 432-443. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  1. TP53 mutations in older adults with acute myeloid leukemia.

    Science.gov (United States)

    Yanada, Masamitsu; Yamamoto, Yukiya; Iba, Sachiko; Okamoto, Akinao; Inaguma, Yoko; Tokuda, Masutaka; Morishima, Satoko; Kanie, Tadaharu; Mizuta, Shuichi; Akatsuka, Yoshiki; Okamoto, Masataka; Emi, Nobuhiko

    2016-04-01

    The net benefits of induction therapy for older adults with acute myeloid leukemia (AML) remain controversial. Because AML in older adults is a heterogeneous disease, it is important to identify those who are unlikely to benefit from induction therapy based on information available at the initial assessment. We used next-generation sequencing to analyze TP53 mutation status in AML patients aged 60 years or older, and evaluated its effects on outcomes. TP53 mutations were detected in 12 of 77 patients (16 %), and there was a significant association between TP53 mutations and monosomal karyotype. Patients with TP53 mutations had significantly worse survival than those without (P = 0.009), and multivariate analysis identified TP53 mutation status as the most significant prognostic factor for survival. Neverthelsess, TP53-mutated patients had a 42 % chance of complete remission and a median survival of 8.0 months, which compares favorably with those who did not undergo induction therapy, even in the short term. These results suggest that screening for TP53 mutations at diagnosis is useful for identifying older adults with AML who are least likely to respond to chemotherapy, although the presence of this mutation alone does not seem to justify rejecting induction therapy.

  2. Image File - TP Atlas | LSDB Archive [Life Science Database Archive metadata

    Lifescience Database Archive (English)

    Full Text Available ormat) for each project. One project has one pathway file originally drawn by Cell Illustrator. Data file File name: tp_atlas..._png.zip File URL: ftp://ftp.biosciencedbc.jp/archive/tp_atlas/LATEST/tp_atlas

  3. Biodistribution and dosimetry of [{sup 123}I]iodo-Pk 11195: a potential agent for SPET imaging of the peripheral benzodiazepine receptor

    Energy Technology Data Exchange (ETDEWEB)

    Versijpt, J. [Groningen Univ. Hospital (Netherlands). Dept. of Biological Psychiatry; Div. of Nuclear Medicine, Ghent Univ. Hospital (Belgium); Dumont, F.; Vos, F. de; Slegers, G. [Dept. of Radiopharmacy, Ghent Univ. (Belgium); Thierens, H. [Dept. of Biomedical Physics and Radiation Protection, Ghent Univ. (Belgium); Jansen, H.; Dierckx, R.A. [Div. of Nuclear Medicine, Ghent Univ. Hospital (Belgium); Santens, P. [Dept. of Neurology, Ghent Univ. Hospital (Belgium); Korf, J. [Groningen Univ. Hospital (Netherlands). Dept. of Biological Psychiatry

    2000-09-01

    The highest concentrations of the peripheral benzodiazepine receptor (PBR) are found in the kidneys and heart. In addition, the PBR has been reported to reflect neuro-inflammatory damage by co-localisation with activated microglia. PK 11195 is a high-affinity ligand for the PBR. The aim of this study was to investigate in humans the biodistribution and dosimetry of [{sup 123}I]iodo-PK 11195, a potential single-photon emission tomography tracer for the PBR. Five healthy volunteers were injected with 112 MBq of [{sup 123}I]iodo-PK 11195. Sequential whole-body scans were performed up to 72 h post injection. Multiple blood samples were taken, and urine was collected to measure the fraction voided by the renal system. Decay-corrected regions of interest of the whole-body images were analysed, and geometric mean count rates were used to determine organ activity. Organ absorbed doses and effective dose were calculated using the MIRD method. [{sup 123}I]iodo-PK 11195 was rapidly cleared from the blood, mainly by the hepatobiliary system. Approximately 22% was voided in urine after 48 h. Average organ residence times were 0.74, 0.44 and 0.29 h for the liver, upper large intestine and lower large intestine, respectively. The testes received the highest dose, 109.4 {mu}Gy/MBq. All other organs investigated received doses of less than 50 {mu}Gy/MBq. The effective dose was 40.3 {mu}Sv/MBq. In conclusion, [{sup 123}I]iodo-PK 11195 is a suitable agent for the visualisation of the PBR and indirectly for the imaging of neuro-inflammatory lesions. Taking into account the radiation burden of 7.46 mSv following an administration of 185 MBq, a [{sup 123}I]iodo-PK 11195 investigation has to be considered an ICRP risk category IIb investigation. (orig.)

  4. 抑癌基因TP53及新家族成员TP63和TP73的研究新进展

    Institute of Scientific and Technical Information of China (English)

    陈中; 张嘉玲; 杨歆萍; 吕海; CARTER Van Waes

    2013-01-01

    抑癌基因TP53在调控细胞周期、细胞凋亡和维持基因组稳定的过程中发挥着重要作用。TP63和TP73是TP53家族中包含的另外两个成员,均具有多种亚型,这些亚型通过自身家族或与其它转录因子家族之间的相互作用,从而对广泛的基因群发挥调控作用。本文将综述TP53及其家族成员TP63、TP73的功能学研究上的最新进展,并将重点介绍我们NIH/NIDCD头颈外科实验室的近期的研究工作所取得的新发现。我们近期的研究结果揭示了在肿瘤炎症的微环境中,存在着一种新的可逆转的动态机制为促炎症细胞因子TNF-α诱导NF—κBc—REL/△Np63ct相互作用,协同促进细胞增殖、生存、炎症和迁移相关基因群的调控。并在有突变的TP53肿瘤中,这些相互作用同时使肿瘤抑制基因TAp73的功能失活,促进肿瘤对TNF—α的抗药性和细胞生存。我们的研究阐述了炎症与肿瘤发生、发展的新机制,其中NF—κB和TP53两大转录因子家族基因的相互作用起到了关键性作用。这一新发现或许可为肿瘤的诊断、治疗和预防提供新的策略。

  5. Development and translational imaging of a TP53 porcine tumorigenesis model.

    Science.gov (United States)

    Sieren, Jessica C; Meyerholz, David K; Wang, Xiao-Jun; Davis, Bryan T; Newell, John D; Hammond, Emily; Rohret, Judy A; Rohret, Frank A; Struzynski, Jason T; Goeken, J Adam; Naumann, Paul W; Leidinger, Mariah R; Taghiyev, Agshin; Van Rheeden, Richard; Hagen, Jussara; Darbro, Benjamin W; Quelle, Dawn E; Rogers, Christopher S

    2014-09-01

    Cancer is the second deadliest disease in the United States, necessitating improvements in tumor diagnosis and treatment. Current model systems of cancer are informative, but translating promising imaging approaches and therapies to clinical practice has been challenging. In particular, the lack of a large-animal model that accurately mimics human cancer has been a major barrier to the development of effective diagnostic tools along with surgical and therapeutic interventions. Here, we developed a genetically modified porcine model of cancer in which animals express a mutation in TP53 (which encodes p53) that is orthologous to one commonly found in humans (R175H in people, R167H in pigs). TP53(R167H/R167H) mutant pigs primarily developed lymphomas and osteogenic tumors, recapitulating the tumor types observed in mice and humans expressing orthologous TP53 mutant alleles. CT and MRI imaging data effectively detected developing tumors, which were validated by histopathological evaluation after necropsy. Molecular genetic analyses confirmed that these animals expressed the R167H mutant p53, and evaluation of tumors revealed characteristic chromosomal instability. Together, these results demonstrated that TP53(R167H/R167H) pigs represent a large-animal tumor model that replicates the human condition. Our data further suggest that this model will be uniquely suited for developing clinically relevant, noninvasive imaging approaches to facilitate earlier detection, diagnosis, and treatment of human cancers.

  6. Native American Women Perceptions in Pk-12 Administrative Positions in North Dakota Public Schools

    Science.gov (United States)

    DeCoteau, Lanelia Irene

    2012-01-01

    Historically Native American women have experienced barriers in their rise to Pk-12 educational leadership positions. There is limited research available on Native American women in educational leadership. Therefore, the purpose for this survey study was to discover what inspired current Pk-12 Native American women educational leaders to choose…

  7. Equidistribution speed towards the Green current for endomorphisms of P-k

    NARCIS (Netherlands)

    Taflin, Johan

    2011-01-01

    Let f be a non-invertible holomorphic endomorphism of P-k. For a hypersurface H of P-k, generic in the Zariski sense, we give an explicit speed of convergence of f(-n)(H) towards the dynamical Green (1, 1)-current of f. (C) 2011 Academie des sciences. Publie par Elsevier Masson SAS. Tous droits rese

  8. A physiologically based pharmacokinetic (PB-PK) model for ethylene dibromide; relevance of extrahepatic metabolism

    NARCIS (Netherlands)

    Hissink, A.M.; Wormhoudt, L.W.; Sherratt, P.J.; Hayes, J.D.; Commandeur, J.N.M.; Vermeulen, N.P.E.; Bladeren, van P.J.

    2000-01-01

    A physiologically-based pharmacokinetic (PB-PK) model was developed for ethylene dibromide (1,2-dibromoethane, EDB) for rats and humans, partly based on previously published in vitro data (Ploemen et al., 1997). In the present study, this PB-PK model has been validated for the rat. In addition, new

  9. De novo sequencing, assembly and analysis of the genome of the laboratory strain Saccharomyces cerevisiae CEN.PK113-7D, a model for modern industrial biotechnology

    Directory of Open Access Journals (Sweden)

    Nijkamp Jurgen F

    2012-03-01

    Full Text Available Abstract Saccharomyces cerevisiae CEN.PK 113-7D is widely used for metabolic engineering and systems biology research in industry and academia. We sequenced, assembled, annotated and analyzed its genome. Single-nucleotide variations (SNV, insertions/deletions (indels and differences in genome organization compared to the reference strain S. cerevisiae S288C were analyzed. In addition to a few large deletions and duplications, nearly 3000 indels were identified in the CEN.PK113-7D genome relative to S288C. These differences were overrepresented in genes whose functions are related to transcriptional regulation and chromatin remodelling. Some of these variations were caused by unstable tandem repeats, suggesting an innate evolvability of the corresponding genes. Besides a previously characterized mutation in adenylate cyclase, the CEN.PK113-7D genome sequence revealed a significant enrichment of non-synonymous mutations in genes encoding for components of the cAMP signalling pathway. Some phenotypic characteristics of the CEN.PK113-7D strains were explained by the presence of additional specific metabolic genes relative to S288C. In particular, the presence of the BIO1 and BIO6 genes correlated with a biotin prototrophy of CEN.PK113-7D. Furthermore, the copy number, chromosomal location and sequences of the MAL loci were resolved. The assembled sequence reveals that CEN.PK113-7D has a mosaic genome that combines characteristics of laboratory strains and wild-industrial strains.

  10. TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution.

    Science.gov (United States)

    Hou, H-A; Chou, W-C; Kuo, Y-Y; Liu, C-Y; Lin, L-I; Tseng, M-H; Chiang, Y-C; Liu, M-C; Liu, C-W; Tang, J-L; Yao, M; Li, C-C; Huang, S-Y; Ko, B-S; Hsu, S-C; Chen, C-Y; Lin, C-T; Wu, S-J; Tsay, W; Chen, Y-C; Tien, H-F

    2015-07-31

    The TP53 mutation is frequently detected in acute myeloid leukemia (AML) patients with complex karyotype (CK), but the stability of this mutation during the clinical course remains unclear. In this study, TP53 mutations were identified in 7% of 500 patients with de novo AML and 58.8% of patients with CK. TP53 mutations were closely associated with older age, lower white blood cell (WBC) and platelet counts, FAB M6 subtype, unfavorable-risk cytogenetics and CK, but negatively associated with NPM1 mutation, FLT3/ITD and DNMT3A mutation. Multivariate analysis demonstrated that TP53 mutation was an independent poor prognostic factor for overall survival and disease-free survival among the total cohort and the subgroup of patients with CK. A scoring system incorporating TP53 mutation and nine other prognostic factors, including age, WBC counts, cytogenetics and gene mutations, into survival analysis proved to be very useful to stratify AML patients. Sequential study of 420 samples showed that TP53 mutations were stable during AML evolution, whereas the mutation was acquired only in 1 of the 126 TP53 wild-type patients when therapy-related AML originated from different clone emerged. In conclusion, TP53 mutations are associated with distinct clinic-biological features and poor prognosis in de novo AML patients and are rather stable during disease progression.

  11. De novo sequencing, assembly and analysis of the genome of the laboratory strain Saccharomyces cerevisiae CEN.PK113-7D, a model for modern industrial biotechnology

    NARCIS (Netherlands)

    Nijkamp, J.F.; Van den Broek, M.A.; Datema, E.; De Kok, S.; Bosman, L.; Luttik, M.A.H.; Daran-Lapujade, P.A.S.; Vongsangnak, W.; Nielsen, J.; Heijne. W.H.M.; Klaassen, P.; Paddon, C.J.; Platt, D.; Kötter, P.; Van Ham, R.C.; Reinders, M.J.T.; Pronk, J.T.; De Ridder, D.; Daran, J.M.

    2012-01-01

    Saccharomyces cerevisiae CEN.PK 113-7D is widely used for metabolic engineering and systems biology research in industry and academia. We sequenced, assembled, annotated and analyzed its genome. Single-nucleotide variations (SNV), insertions/deletions (indels) and differences in genome organization

  12. TP53 Mutations in Nonsmall Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Akira Mogi

    2011-01-01

    Full Text Available The tumor suppressor gene TP53 is frequently mutated in human cancers. Abnormality of the TP53 gene is one of the most significant events in lung cancers and plays an important role in the tumorigenesis of lung epithelial cells. Human lung cancers are classified into two major types, small cell lung cancer (SCLC and nonsmall cell lung cancer (NSCLC. The latter accounts for approximately 80% of all primary lung cancers, and the incidence of NSCLC is increasing yearly. Most clinical studies suggest that NSCLC with TP53 alterations carries a worse prognosis and may be relatively more resistant to chemotherapy and radiation. A deep understanding of the role of TP53 in lung carcinogenesis may lead to a more reasonably targeted clinical approach, which should be exploited to enhance the survival rates of patients with lung cancer. This paper will focus on the role of TP53 in the molecular pathogenesis, epidemiology, and therapeutic strategies of TP53 mutation in NSCLC.

  13. Uptake of inflammatory cell marker [{sup 11}C]PK11195 into mouse atherosclerotic plaques

    Energy Technology Data Exchange (ETDEWEB)

    Laitinen, Iina; Marjamaeki, Paeivi; Naagren, Kjell; Roivainen, Anne; Knuuti, Juhani [University of Turku, Turku PET Centre, Turku (Finland); Laine, V.J.O. [Turku University Hospital, Department of Pathology, Turku (Finland); Wilson, Ian [GE Healthcare Biosciences, Medical Diagnostics, London (United Kingdom); Leppaenen, Pia; Ylae-Herttuala, Seppo [University of Kuopio, A.I. Virtanen Institute, Kuopio (Finland)

    2009-01-15

    The ligand [{sup 11}C]PK11195 binds with high affinity and selectivity to peripheral benzodiazepine receptor, expressed in high amounts in macrophages. In humans, [{sup 11}C]PK11195 has been used successfully for the in vivo imaging of inflammatory processes of brain tissue. The purpose of this study was to explore the feasibility of [{sup 11}C]PK11195 in imaging inflammation in the atherosclerotic plaques. The presence of PK11195 binding sites in the atherosclerotic plaques was verified by examining the in vitro binding of [{sup 3}H]PK11195 onto mouse aortic sections. Uptake of intravenously administered [{sup 11}C]PK11195 was studied ex vivo in excised tissue samples and aortic sections of a LDLR/ApoB48 atherosclerotic mice. Accumulation of the tracer was compared between the atherosclerotic plaques and non-atherosclerotic arterial sites by autoradiography and histological analyses. The [{sup 3}H]PK11195 was found to bind to both the atherosclerotic plaques and the healthy wall. The autoradiography analysis revealed that the uptake of [{sup 11}C]PK11195 to inflamed regions in plaques was more prominent (p = 0.011) than to non-inflamed plaque regions, but overall it was not higher than the uptake to the healthy vessel wall. Also, the accumulation of {sup 11}C radioactivity into the aorta of the atherosclerotic mice was not increased compared to the healthy control mice. Our results indicate that the uptake of [{sup 11}C]PK11195 is higher in inflamed atherosclerotic plaques containing a large number of inflammatory cells than in the non-inflamed plaques. However, the tracer uptake to other structures of the artery wall was also prominent and may limit the use of [{sup 11}C]PK11195 in clinical imaging of atherosclerotic plaques. (orig.)

  14. Analysis of Tp53 Codon 72 Polymorphisms, Tp53 Mutations, and HPV Infection in Cutaneous Squamous Cell Carcinomas

    OpenAIRE

    Loeb, Keith R.; Asgari, Maryam M; Hawes, Stephen E.; Qinghua Feng; Stern, Joshua E.; Mingjun Jiang; Argenyi, Zsolt B.; Ethel-Michele de Villiers; Kiviat, Nancy B.

    2012-01-01

    BACKGROUND: Non-melanoma skin cancers are one of the most common human malignancies accounting for 2-3% of tumors in the US and represent a significant health burden. Epidemiology studies have implicated Tp53 mutations triggered by UV exposure, and human papilloma virus (HPV) infection to be significant causes of non-melanoma skin cancer. However, the relationship between Tp53 and cutaneous HPV infection is not well understood in skin cancers. In this study we assessed the association of HPV ...

  15. A case of gastric cancer with heterogeneous components of EB virus (+)/TP53 (+) and EB virus (-)/TP53 (-).

    Science.gov (United States)

    Matsuda, Ikuo; Kan, Kazuomi; Doi, Sadayuki; Motoki, Yoshiyuki; Onodera, Masayuki; Hirota, Seiichi

    2015-01-01

    Epstein-Barr virus (EBV)-associated gastric adenocarcinoma is a histological subtype of gastric adenocarcinoma, in which all of the carcinoma cells are basically positive for EBV-encoded small RNA (EBER) by in situ hybridization. Although its typical histology has some overlap with gastric carcinoma with lymphoid stroma, absence of massive lymphoid infiltrate is sometimes observed either in whole or in part. EBV-associated adenocarcinoma is one of the four representative molecular pathological subtypes recently identified by comprehensive genomic analysis of gastric adenocarcinomas. According to the analysis, typical EBV-associated gastric adenocarcinoma constitutes an independent molecular pathological subgroup, which is mutually exclusive to TP53-mutated adenocarcinoma with chromosomal instability, another molecular pathological subtype in gastric adenocarcinomas. Here, we report a rare case of gastric cancer heterogeneously composed of EBER (+)/TP53 (+) and EBER (-)/TP53 (-) portions. The EBER (+)/TP53 (+) component with massive lymphoid infiltrate surrounded the EBER (-)/TP53 (-) component showing well to moderately differentiated tubular adenocarcinoma. Although collision of two independent gastric cancers could be the simplest and most possible explanation for this situation, we discussed another possibility. In the case of gastric collision tumors, concurrent development of EBER (+) gastric adenocarcinomas and EBER (-) gastric adenocarcinomas in a single stomach is a rare incident. Since presence of the EBER (+)/TP53 (+) tumor component is atypical in itself, we also discussed the mechanism of development of the clone.

  16. Treponema pallidum subsp. pallidum TP0136 protein is heterogeneous among isolates and binds cellular and plasma fibronectin via its NH2-terminal end.

    Science.gov (United States)

    Ke, Wujian; Molini, Barbara J; Lukehart, Sheila A; Giacani, Lorenzo

    2015-03-01

    Adherence-mediated colonization plays an important role in pathogenesis of microbial infections, particularly those caused by extracellular pathogens responsible for systemic diseases, such as Treponema pallidum subsp. pallidum (T. pallidum), the agent of syphilis. Among T. pallidum adhesins, TP0136 is known to bind fibronectin (Fn), an important constituent of the host extracellular matrix. To deepen our understanding of the TP0136-Fn interaction dynamics, we used two naturally-occurring sequence variants of the TP0136 protein to investigate which region of the protein is responsible for Fn binding, and whether TP0136 would adhere to human cellular Fn in addition to plasma Fn and super Fn as previously reported. Fn binding assays were performed with recombinant proteins representing the two full-length TP0136 variants and their discrete regions. As a complementary approach, we tested inhibition of T. pallidum binding to Fn by recombinant full-length TP0136 proteins and fragments, as well as by anti-TP0136 immune sera. Our results show that TP0136 adheres more efficiently to cellular Fn than to plasma Fn, that the TP0136 NH2-terminal conserved region of the protein is primarily responsible for binding to plasma Fn but that binding sites for cellular Fn are also present in the protein's central and COOH-terminal regions. Additionally, message quantification studies show that tp0136 is highly transcribed during experimental infection, and that its message level increases in parallel to the host immune pressure on the pathogen, which suggests a possible role for this protein in T. pallidum persistence. In a time where syphilis incidence is high, our data will help in the quest to identify suitable targets for development of a much needed vaccine against this important disease.

  17. Coincident In Vitro Analysis of DNA-PK-Dependent and -Independent Nonhomologous End Joining

    Directory of Open Access Journals (Sweden)

    Cynthia L. Hendrickson

    2010-01-01

    Full Text Available In mammalian cells, DNA double-strand breaks (DSBs are primarily repaired by nonhomologous end joining (NHEJ. The current model suggests that the Ku 70/80 heterodimer binds to DSB ends and recruits DNA-PKcs to form the active DNA-dependent protein kinase, DNA-PK. Subsequently, XRCC4, DNA ligase IV, XLF and most likely, other unidentified components participate in the final DSB ligation step. Therefore, DNA-PK plays a key role in NHEJ due to its structural and regulatory functions that mediate DSB end joining. However, recent studies show that additional DNA-PK-independent NHEJ pathways also exist. Unfortunately, the presence of DNA-PKcs appears to inhibit DNA-PK-independent NHEJ, and in vitro analysis of DNA-PK-independent NHEJ in the presence of the DNA-PKcs protein remains problematic. We have developed an in vitro assay that is preferentially active for DNA-PK-independent DSB repair based solely on its reaction conditions, facilitating coincident differential biochemical analysis of the two pathways. The results indicate the biochemically distinct nature of the end-joining mechanisms represented by the DNA-PK-dependent and -independent NHEJ assays as well as functional differences between the two pathways.

  18. Expression pattern of the CsPK3 auxin-responsive protein kinase gene.

    Science.gov (United States)

    Chono, M; Suzuki, Y; Nemoto, K; Yamane, H; Murofushi, N; Yamaguchi, I

    2001-03-01

    We have previously cloned a cDNA of a putative serine/threonine protein kinase gene named CsPK3 from cucumber, the mRNA level of which was up-regulated by auxin and down-regulated by light irradiation. To examine the CsPK3 gene expression in detail, we cloned a genomic DNA of CsPK3 gene and made transgenic tobacco (Nicotiana tabacum L. cv. Petit Havana SR1) plants containing the fused CsPK3 promoter-beta-glucuronidase gene. The beta-glucuronidase expression was detected in the shoot apex, vascular tissues, and the outermost layer of cortex. The histological distribution of CsPK3 mRNA in cucumber seedlings was supported by in situ hybridization, where the positive signals were observed in similar tissues as those observed by beta-glucuronidase staining. The responsiveness of the CsPK3 gene to auxin and light was also confirmed for beta-glucuronidase activity. The pattern of beta-glucuronidase staining changed during the development of the tobacco seedlings. The results of our experiment showed that CsPK3 was expressed in a wide variety of tissues and cells in which the developmental and growth controls by auxin are suggested.

  19. Coincident In Vitro Analysis of DNA-PK-Dependent and -Independent Nonhomologous End Joining

    Science.gov (United States)

    Hendrickson, Cynthia L.; Purkayastha, Shubhadeep; Pastwa, Elzbieta; Neumann, Ronald D.; Winters, Thomas A.

    2010-01-01

    In mammalian cells, DNA double-strand breaks (DSBs) are primarily repaired by nonhomologous end joining (NHEJ). The current model suggests that the Ku 70/80 heterodimer binds to DSB ends and recruits DNA-PKcs to form the active DNA-dependent protein kinase, DNA-PK. Subsequently, XRCC4, DNA ligase IV, XLF and most likely, other unidentified components participate in the final DSB ligation step. Therefore, DNA-PK plays a key role in NHEJ due to its structural and regulatory functions that mediate DSB end joining. However, recent studies show that additional DNA-PK-independent NHEJ pathways also exist. Unfortunately, the presence of DNA-PKcs appears to inhibit DNA-PK-independent NHEJ, and in vitro analysis of DNA-PK-independent NHEJ in the presence of the DNA-PKcs protein remains problematic. We have developed an in vitro assay that is preferentially active for DNA-PK-independent DSB repair based solely on its reaction conditions, facilitating coincident differential biochemical analysis of the two pathways. The results indicate the biochemically distinct nature of the end-joining mechanisms represented by the DNA-PK-dependent and -independent NHEJ assays as well as functional differences between the two pathways. PMID:20706599

  20. Update History of This Database - TP Atlas | LSDB Archive [Life Science Database Archive metadata

    Lifescience Database Archive (English)

    Full Text Available [ Credits ] BLAST Search Image Search Home About Archive Update History Contact us TP Atlas...formation is corrected. 2013/11/19 TP Atlas English archive site is opened. 2008/4/1 TP Atlas ( http://www.t...abase Description Download License Update History of This Database Site Policy | Contact Us Update History of This Database - TP Atlas | LSDB Archive ...

  1. TP53 and Beta-catenin mutations in liver tumours

    Directory of Open Access Journals (Sweden)

    Pierre Hainaut

    2007-02-01

    Full Text Available

    HBV and HCV play key roles in the etiopathogenesis of Hepatocellular carcinoma (HCC . Studies mostly based on cases from Western countries suggest distinct genetic pathways of carcinogenesis involving either TP53 or CTTNB1 mutations. Inappropriate reactivation of Wnt pathway due to mutations in CTNNB1 (Beta-Catenin gene itself is also frequently reported. Mutant Beta-catenin escapes to ubiquitination and down regulation by GSK3-B, it accumulates and trans-activates variety of oncogenes involved in neoplasmic transformation mimicking Wnt pathway activation. Taking into consideration viral infection, chromosome instability and TP53 /Beta-catenin alterations, Laurent-Puig et al. described two distinct HCC profiles in a serie of 137 HCC cases , the first one associates HBV infection with frequent chromosomal alteration and distributes with TP53 mutations, the second would be observed in HBV negative large sized tumors and distributes with Beta-catenin mutations. We have investigated the status of HBV and HCV infections and of genetic alterations in TP53 and CTTNB1 in 26 patients with HCC from Thailand. In tumours, HBV DNA was found in 19 cases (73% and HCV RNA in 4 cases (15.4% cases, 3 of whom were co-infected. Among the 19 HBV positive cases, sequencing of S gene showed genotype C in 82% and genotype B in 18%. Furthermore, 5/19 cases were negative for HBsAg and were categorized as occult HBV infections. TP53 mutations were detected in 9 cases (34,6% including 7 mutations at codon 249 (AGG to AGT, arginine to serine, considered as ";fingerprint"; of mutagenesis by aflatoxin metabolites. All cases with 249ser mutation had overt HBV infection.

    CTNNB1 mutations were found in 6/26 cases (23%, 4 of whom also had TP53 mutation. There was no significant association between CTTNB1

  2. Synthesis of the enantiomers of [N-methyl-[sup 11]C]PK 11195 and comparison of their behaviours as radioligands for PK binding sites in rats

    Energy Technology Data Exchange (ETDEWEB)

    Shah, Farah; Hume, S.P.; Pike, V.W.; Ashworth, S.; McDermott, J. (Hammersmith Hospital, London (United Kingdom). M.R.C. Cyclotron Unit)

    1994-05-01

    The enantiomers of [N-methyl-[sup 11]C]PK 11195, a radioligand for PET studies of PK (peripheral benzodiazepine) binding sites, have been prepared from the newly synthesized N-desmethyl-enantiomers by [sup 11]C-methylation with N.C.A. [[sup 11]C]iodomethane. The brain uptake and retention of each enantiomer was compared with that of the racemic radioligand after i.v. administration into normal rats and into rats with focal cortical lesions. The observed differences are consistent with the approximately 2-fold greater affinity of the R-enantiomer for PK binding sites reported in vitro and imply that the use of this entantiomer would have advantages over the use of the racemate currently used for PET studies. (author).

  3. 完全二部图的K1,pk-因子分解%K1,pk-FACTORIZATION OF COMPLETE BIPARTITE GRAPHS

    Institute of Scientific and Technical Information of China (English)

    杜北樑

    2001-01-01

    In this paper, it is shown that a sufficient condition for the existence of a K1,pk-factorization of Km,n, whenever p is a prime number and k is a positive integer, is (1) m≤pkn,(2) n≤pkm,(3)pkn-m≡pkm- n≡0(mod(p2k - 1)) and (4)(pkn-m)(pkm- n)≡0(mod(pk - 1)pk×(p2k-1)(m+n)).

  4. Synthesis, Structure and Quantum Chemistry of Scorpionates Oxovanadium Compleses: Tp*VO(OOCHCCHCOOCH3)(pz*H) and Tp*VO(DMSO)(NCS)%蝎型钒氧配合物Tp*VO(OOCHCCHCOOCH3)(pz*H)和Tp*VO(DMSO)(NCS)的合成、结构及量子化学研究

    Institute of Scientific and Technical Information of China (English)

    魏东明; 董斌; 李章鹏; 白凤英; 曹运珠; 邢永恒; 蒲志凤; 葛茂发

    2011-01-01

    Two new half-sandwich monomeric complexes of oxovanadium (Ⅳ), Tp*VO(OOCHCCHCOOCH3)(pz*H)(1) and Tp*VO(DMSO)(NCS) (2) (Tp* =hydrotris(3,5-dimethylpyrazolyl)borate, pz*H=3,5-dimethylpyrazole) have been synthesized from the reaction of VOSO4·nH2O with respective ligands.The complexes were characterized by element analysis, IR spectra and single crystal X-ray diffraction.The electronic structure and the bonding characters of the two complexes were analyzed with ab initio calculations.The calculations results showed that the structural stability of complexes 1 and 2 are close.The atomic net charge distribution in the molecular system indicates obvious covalent interaction between the coordinated atoms (N, O) and vanadium.The results are consistent with the structural analysis of complexes.%本文在室温条件下,甲醇体系中,设计并首次合成了2种蝎型半夹心钒氧配合物Tp*VO(OOCHCCHCOOCH3)(pz*H)(1)和Tp*VO(DMSO)(NCS)(2)(Tp*=三聚3,5-二甲基吡唑硼酸根),通过元素分析、红外光谱对配合物进行了表征,利用X-射线单晶衍射方法对晶体结构进行了测定,并结合从头计算结果进一步分析了配合物的稳定性及分子中配键的共价特征.分析结果表明,配合物1和2的稳定性相近,且中心钒原子周围的价键类型都属于共价键范畴,键序分析结果与晶体结构测定的键长结果是一致的.

  5. TP Atlas: integration and dissemination of advances in Targeted Proteins Research Program (TPRP)-structural biology project phase II in Japan.

    Science.gov (United States)

    Iwayanagi, Takao; Miyamoto, Sei; Konno, Takeshi; Mizutani, Hisashi; Hirai, Tomohiro; Shigemoto, Yasumasa; Gojobori, Takashi; Sugawara, Hideaki

    2012-09-01

    The Targeted Proteins Research Program (TPRP) promoted by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan is the phase II of structural biology project (2007-2011) following the Protein 3000 Project (2002-2006) in Japan. While the phase I Protein 3000 Project put partial emphasis on the construction and maintenance of pipelines for structural analyses, the TPRP is dedicated to revealing the structures and functions of the targeted proteins that have great importance in both basic research and industrial applications. To pursue this objective, 35 Targeted Proteins (TP) Projects selected in the three areas of fundamental biology, medicine and pharmacology, and food and environment are tightly collaborated with 10 Advanced Technology (AT) Projects in the four fields of protein production, structural analyses, chemical library and screening, and information platform. Here, the outlines and achievements of the 35 TP Projects are summarized in the system named TP Atlas. Progress in the diversified areas is described in the modules of Graphical Summary, General Summary, Tabular Summary, and Structure Gallery of the TP Atlas in the standard and unified format. Advances in TP Projects owing to novel technologies stemmed from AT Projects and collaborative research among TP Projects are illustrated as a hallmark of the Program. The TP Atlas can be accessed at http://net.genes.nig.ac.jp/tpatlas/index_e.html .

  6. Increasing the reach of the PK-3R continuous Miner; Desarrollo y Ensayo de un Sistema para aumentar el alcance de la Pina de Rozado en un Minador PK-3R

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-12-01

    The objective of this project is the development and implementation of a system designed to increase the reach of the cutting head of a PK-3R continuous miner working in our coal operations. Justification for the project stems from our method of coal extraction, whereby once the sub-level gallery has been advanced to it`s limit, extraction of the coal is undertaken by retreat mining, using a room and pillar method. In this method the roof is blasted to allow greater coal recovery. Due to it`s short length, the original position of the cutting arm of the PK-3R miner did not permit the total recovery of the blasted coal piled up on the gallery floor. Therefore an increase in the reach of the arm is very beneficial, facilitating the recovery of coal that previously could not be recovered. The system also permits excavation for support methods to be undertaken more rapidly, and a better adaptation of the miner to the irregularities of the wall, thus permitting it to move up or down more quickly, reducing the movements required. The system has not caused significant breakdowns, and the availability of the miner is good. In addition, the substitution of the turret in the case of a breakdown is an easy task, as during the design stage, the ease of mounting and dismounting the turret was considered as a fundamental parameter. (Author)

  7. Defining interactions between DNA-PK and ligase IV/XRCC4

    Energy Technology Data Exchange (ETDEWEB)

    Hsu, Hsin-Ling; Yannone, Steven M.; Chen, David J.

    2001-04-10

    Non-homologous end joining (NHEJ) is a major pathway for the repair of DNA double-strand breaks in mammalian cells. DNA-dependent protein kinase (DNA-PK), ligase IV, and XRCC4 are all critical components of the NHEJ repair pathway. DNA-PK is composed of a heterodimeric DNA-binding component, Ku, and a large catalytic subunit, DNA-PKcs. Ligase IV and XRCC4 associate to form a multimeric complex that is also essential for NHEJ. DNA-PK and ligase IV/XRCC4 interact at DNA termini which results in stimulated ligase activity. Here we define interactions between the components of these two essential complexes, DNA-PK and ligase IV/XRCC4. We find that ligase IV/XRCC4 associates with DNA-PK in a DNA-independent manner. The specific protein-protein interactions that mediate the interaction between these two complexes are further identified. Direct physical interactions between ligase IV and Ku as well as between XRCC4 and DNA-PKcs are shown. No direct interactions are observed between ligase IV and DNA-PKcs or between XRCC4 and Ku. Our data defines the specific protein pairs involved in the association of DNA-PK and ligase IV/XRCC4, and suggests a molecular mechanism for coordinating the assembly of the DNA repair complex at DNA breaks.

  8. THE RESEARCH PROGRESSION OF TUMOR SUPPRESSOR TP53 AND THE NEW FAMILY MEMBERS TP63 AND TP73%抑癌基因TP53及新家族成员TP63和TP73的研究新进展

    Institute of Scientific and Technical Information of China (English)

    陈中; 张嘉玲; 杨歆萍; 吕海; CARTER Van Waes

    2013-01-01

    抑癌基因TP53在调控细胞周期、细胞凋亡和维持基因组稳定的过程中发挥着重要作用.TP63和TP73是TP53家族中包含的另外两个成员,均具有多种亚型,这些亚型通过自身家族或与其它转录因子家族之间的相互作用,从而对广泛的基因群发挥调控作用.本文将综述TP53及其家族成员TP63、TP73的功能学研究上的最新进展,并将重点介绍我们NIH/NIDCD头颈外科实验室的近期的研究工作所取得的新发现.我们近期的研究结果揭示了在肿瘤炎症的微环境中,存在着一种新的可逆转的动态机制为促炎症细胞因子TNF-α诱导NF-kB c-REL/ANp 63α相互作用,协同促进细胞增殖、生存、炎症和迁移相关基因群的调控.并在有突变的TP53肿瘤中,这些相互作用同时使肿瘤抑制基因TAp73的功能失活,促进肿瘤对TNF-α的抗药性和细胞生存.我们的研究阐述了炎症与肿瘤发生、发展的新机制,其中NF-kB和TP53两大转录因子家族基因的相互作用起到了关键性作用.这一新发现或许可为肿瘤的诊断、治疗和预防提供新的策略.

  9. Purification and characterization of exonuclease-free Artemis: Implications for DNA-PK – dependent processing of DNA termini in NHEJ catalyzed DSB repair

    Science.gov (United States)

    Pawelczak, Katherine S.; Turchi, John J.

    2010-01-01

    Artemis is a member of the β–CASP family of nucleases in the metallo-β-lactamase superfamily of hydrolases. Artemis has been demonstrated to be involved in V(D)J-recombination and in the NHEJ-catalyzed repair of DNA DSBs. In vitro, both DNA-PK independent 5’ to 3’ exonuclease activity and DNA-PK dependent endonuclease activity have been attributed to Artemis, though mutational analysis of the Artemis active site only disrupts endonuclease activity. This suggests that either the enzyme contains two different active sites, or the exonuclease activity is not intrinsic to the Artemis polypeptide. To distinguish between these possibilities, we sought to determine if it was possible to biochemically separate Artemis endonuclease activity from exonuclease activity. Recombinant [His]6–Artemis was expressed in a Baculovirus insect-cell expression system and isolated using a three-column purification methodology. Exonuclease and endonuclease activity, the ability to be phosphorylated by DNA-PK, and Artemis antibody reactivity was monitored throughout the purification and to characterize final pools of protein preparation. Results demonstrated the co-elution of exonuclease and endonuclease activity on a Ni-Agarose affinity column but separation of the two enzymatic activities upon fractionation on a hydroxyapatite column. An exonuclease free fraction of Artemis was obtained that retained DNA-PK dependent endonuclease activity, was phosphorylated by DNA-PK and reacted with an Artemis specific antibody. These data demonstrate that the exonuclease activity thought to be intrinsic to Artemis can be biochemically separated from the Artemis endonuclease. PMID:20347402

  10. Purification and characterization of exonuclease-free Artemis: Implications for DNA-PK-dependent processing of DNA termini in NHEJ-catalyzed DSB repair.

    Science.gov (United States)

    Pawelczak, Katherine S; Turchi, John J

    2010-06-04

    Artemis is a member of the beta-CASP family of nucleases in the metallo-beta-lactamase superfamily of hydrolases. Artemis has been demonstrated to be involved in V(D)J-recombination and in the NHEJ-catalyzed repair of DNA DSBs. In vitro, both DNA-PK independent 5'-3' exonuclease activities and DNA-PK dependent endonuclease activity have been attributed to Artemis, though mutational analysis of the Artemis active site only disrupts endonuclease activity. This suggests that either the enzyme contains two different active sites, or the exonuclease activity is not intrinsic to the Artemis polypeptide. To distinguish between these possibilities, we sought to determine if it was possible to biochemically separate Artemis endonuclease activity from exonuclease activity. Recombinant [His](6)-Artemis was expressed in a Baculovirus insect-cell expression system and isolated using a three-column purification methodology. Exonuclease and endonuclease activities, the ability to be phosphorylated by DNA-PK, and Artemis antibody reactivity was monitored throughout the purification and to characterize final pools of protein preparation. Results demonstrated the co-elution of exonuclease and endonuclease activities on a Ni-agarose affinity column but separation of the two enzymatic activities upon fractionation on a hydroxyapatite column. An exonuclease-free fraction of Artemis was obtained that retained DNA-PK dependent endonuclease activity, was phosphorylated by DNA-PK and reacted with an Artemis specific antibody. These data demonstrate that the exonuclease activity thought to be intrinsic to Artemis can be biochemically separated from the Artemis endonuclease. Copyright 2010 Elsevier B.V. All rights reserved.

  11. A novel three primers PCR (TP-PCR) method to obtain recombinant DNA molecule independent of restriction enzyme

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    In this note, we report a novel and efficient three primers PCR (TP-PCR) method to rapidly generate recombinant DNA molecule at precise junction between two arbitrary DNA fragments. TP-PCR method is characterized by its reaction system with two templates and three primers, which can produce a recombinant DNA molecule in one PCR reaction. The main advantages of this method are the independence of sequences at the recombination site, the rapidness, and the easy establishment of adequate conditions. This method has been successfully applied to constructing a fusion protein gene, sck gene.

  12. Analysis the causes of suspicious results for BECKMAN PK 7300 automatic blood inspection device%BECKM AN PK7300全自动血型检测系统可疑结果的原因分析

    Institute of Scientific and Technical Information of China (English)

    刘淼; 王霞; 潘彤

    2016-01-01

    目的:探讨BECKMAN PK7300全自动血型检测系统在血站实验室用于血型筛查时出现结果可疑的原因以及应用中的注意事项。方法选取天津市血液中心2015年5月至2015年8月ABO及Rh血型经微板法鉴定后的无偿献血者的标本14417例,再由PK7300进行检测,统计分析ABO及Rh血型结果判读的正确率、错误率以及对可疑结果的原因进行分析。结果ABO血型结果一次性判读正确率为99.01%,失败率0.99%(其中正反定型不符0.48%),无错误判读;Rh(D)血型正确判读率100%。结论 BECKMAN PK7300全自动血型检测系统结果准确可靠,实现了血型检测的自动化、标准化,减少人为因素对实验的影响,反应图像可长期保存,保证结果的可溯性,节约成本,适用于血站实验室血型批量化检测需要。%Objective To investigate the causes of suspicious results for BECKMAN PK 7300 automatic blood inspection device on blood typing in blood station and the application notes .Methods A total of 11417 samples from unpaid blood donors were re‐cruited from Tianjin Blood Center between May 2015 and August 2015 .Microplate assay was applied in ABO and Rh(D)blood typ‐ing .All the samples were tested by BECKMAN PK7300 automatic blood inspection device .The accuracy and error rates were calcu‐lated for ABO and Rh(D)blood group and causes of suspicious results were analyzed .Results The accuracy and failure rate of ABO blood group were 99 .01% and 0 .99% (of which the inconsistent rate of positive and reverse ABO blood typing was 0 .48% )and there was no false reading .Its accuracy was 100% in Rh(D)blood grouping .Conclusion The results of BECKMAN PK7300 auto‐matic blood inspection device were accurate and reliable .The whole system achieved automation and standardization and reduced the artificial factors for experiments ,which images could be saved for a long period of time ,saving the cost .The

  13. Physiologically based pharmacokinetic (PB-PK) modeling of indoor air pollutant degradation by houseplants

    Energy Technology Data Exchange (ETDEWEB)

    Smith, E.K.; El-Masri, H.A.; Tessari, J.D.; Yang, R.S.H.; Reardon, K.F. [Colorado State Univ., Fort Collins, CO (United States)

    1994-12-31

    In the US, indoor air pollutant levels commonly exceed outdoor levels by a factor of 7 or more. Since people typically spend more than 90% percent of their time indoors, indoor air pollution has the potential for greater consequences on human health. A NASA researcher has reported that certain houseplants will reduce closed chamber concentrations of common indoor air pollutants by more than 75%. The authors are expanding this research; common houseplants and PB-PK modeling can be combined to predict the reduction rates of frequently detected indoor air pollutants, and be used as an environmental remediation approach. The approach to measuring plant gas uptake of indoor air pollutants provides a more quantitative and controlled approach than previous studies. Construction of the closed chamber system linked to a computerized gas chromatograph is complete. This system measures plant uptake of volatile organic chemicals. In experiments using initial concentrations of 21--2,100 ppm of the common indoor air pollutant trichloroethylene (TCE) with peace lily in soil, between 27--34% of TCE was removed during a 12-hour test period. In similar experiments, plants in abiotic potting media removed only 4--13% of TCE from the closed system, suggesting that microbial degradation or soil adsorption of TCE are significant factors.

  14. Increased oxidative damage in carriers of the germline TP53 p.R337H mutation.

    Directory of Open Access Journals (Sweden)

    Gabriel S Macedo

    Full Text Available Germline mutations in TP53 are the underlying defect of Li-Fraumeni Syndrome (LFS and Li-Fraumeni-like (LFL Syndrome, autosomal dominant disorders characterized by predisposition to multiple early onset cancers. In Brazil, a variant form of LFS/LFL is commonly detected because of the high prevalence of a founder mutation at codon 337 in TP53 (p.R337H. The p53 protein exerts multiple roles in the regulation of oxidative metabolism and cellular anti-oxidant defense systems. Herein, we analyzed the redox parameters in blood samples from p.R337H mutation carriers (C, n = 17 and non-carriers (NC, n = 17. We identified a significant increase in erythrocyte GPx activity and in plasma carbonyl content,an indicator of protein oxidative damage, in mutation carriers compared to non-carriers (P = 0.048 and P = 0.035, respectively. Mutation carriers also showed a four-fold increase in plasma malondialdehyde levels, indicating increased lipid peroxidation (NC = 40.20±0.71, C = 160.5±0.88, P<0.0001. Finally, carriers showed increased total antioxidant status but a decrease in plasma ascorbic acid content. The observed imbalance could be associated with deregulated cell bioenergetics and/or with increased inflammatory stress, two effects that may result from loss of wild-type p53 function. These findings provide the first evidence that oxidative damage occurs in carriers of a germline TP53 mutation, and these may have important implications regarding our understanding of the mechanisms responsible for germline TP53 p.R337H mutation-associated carcinogenesis.

  15. Evaluation of sgRNA target sites for CRISPR-mediated repression of TP53.

    Directory of Open Access Journals (Sweden)

    Ingrid E B Lawhorn

    Full Text Available The CRISPR (clustered regularly interspaced short palindromic repeats platform has been developed as a general method to direct proteins of interest to gene targets. While the native CRISPR system delivers a nuclease that cleaves and potentially mutates target genes, researchers have recently employed catalytically inactive CRISPR-associated 9 nuclease (dCas9 in order to target and repress genes without DNA cleavage or mutagenesis. With the intent of improving repression efficiency in mammalian cells, researchers have also fused dCas9 with a KRAB repressor domain. Here, we evaluated different genomic sgRNA targeting sites for repression of TP53. The sites spanned a 200-kb distance, which included the promoter, transcript sequence, and regions flanking the endogenous human TP53 gene. We showed that repression up to 86% can be achieved with dCas9 alone (i.e., without use of the KRAB domain by targeting the complex to sites near the TP53 transcriptional start site. This work demonstrates that efficient transcriptional repression of endogenous human genes can be achieved by the targeted delivery of dCas9. Yet, the efficiency of repression strongly depends on the choice of the sgRNA target site.

  16. Synthesis and Chiral Separation of Dinucleotide(TpAZT) Phosphoramidates

    Institute of Scientific and Technical Information of China (English)

    Chang Xue LIN; Hua FU; Guang Zhong TU; Yu Fen ZHAO

    2003-01-01

    Dinucleotide (TpAZT) phosphoramidates were synthesized by Todd reaction of dinucleoside H-phosphonates and amino acid methyl esters, and their diastereomers (Rp and Sp) were separated by crystallization, and the results showed that natural and cheap methyl esters of alanine and phenylalanine can be used for large-scale synthesis of dinucleotide analogs.

  17. Studying the effectiveness of using pneumoimpulsive technology for cleaning the platen surfaces of the PK-38 boiler at the Nazarovo district power station

    Science.gov (United States)

    Agliulin, S. G.; Nikolaev, S. F.; Zvegintsev, V. I.; Yurkin, I. A.; Shabanov, I. I.; Palkin, V. F.; Sergienko, S. P.; Vlasov, S. M.

    2014-09-01

    A new pneumoimpulsive technology, central to which is an impact effect of air jet on ash deposits, was proposed for carrying out continuous preventive cleaning of the platens installed in the steam superheater primary and secondary paths of the PK-38 boiler at the Nazarovo district power station. The pneumoimpulsive cleaning system was mounted in the PK-38 boiler unit no. 6A, and the cleaning system tests were carried out during field operation of the boiler. Owing to the use of the proposed cleaning system, long-term (for no less than 3 months of observations) slag-free operation of the platen surfaces was achieved in the range of steam loads from 215 to 235 t/h with the average load equal to 225 t/h at furnace gas temperatures upstream of the platens equal to 1220-1250°C.

  18. Simulation of the impact of rifampicin on darunavir/ritonavir PK and dose adjustment strategies in HIV-infected patients: a population PK approach

    Directory of Open Access Journals (Sweden)

    Laura Dickinson

    2014-11-01

    Full Text Available Introduction: Treatment of HIV/TB co-infection is challenging due to high drug–drug interaction potential between antiretrovirals and rifamycins, such as rifampicin (RIF. The PK interaction between darunavir/ritonavir (DRV/RTV and RIF has not been studied. Utilizing other protease inhibitor data, population PK modelling and simulation was applied to assess the impact of RIF on DRV/RTV PK and generate alternative dosing strategies to aid future clinical trial design. Materials and Methods: A previously developed model describing DRV/RTV PK including data from three studies in HIV patients was used [n=51, 7 female, DRV/RTV 800/100 mg (n=32 or 900/100 mg once daily (qd; n=19 (1. The PK interaction between DRV/RTV and RIF was assumed to mimic that observed in HIV-infected, TB negative patients receiving lopinavir (LPV/RTV (n=21 (2. Simulations of DRV/RTV 800/100 mg qd (n=1000 were performed (-RIF. The model was adapted to increase the typical value of apparent oral clearance (CL/F by 71% and 36% and decrease relative bioavailability (F by 20% and 45% for DRV and RTV, respectively (2; 1000 simulations were generated (+RIF. Dose adjustments of DRV/RTV 1200/200 mg qd, 800/100 mg and 1200/150 mg twice daily (bid were simulated to overcome the interaction. DRV trough (Ctrough for each dosing scenario was compared to the reference (-RIF by GMR (90% CI. Results: DRV and RTV were described by a 1 and 2-compartment model, respectively. A maximum effect model, with RTV inhibiting DRV CL/F, best described the relationship between the drugs. Compared to the reference (-RIF, simulated DRV Ctrough was 70%, 46% and 20% lower for 800/100 mg qd, 1200/200 mg qd and 800/100 mg bid all +RIF, respectively. Ctrough was 38% higher with 1200/150 mg bid +RIF (Table 1. Conclusions: Modelling and simulation was used to investigate the theoretical impact of RIF on DRV/RTV PK. Based on simulations, 800/100 mg and 1200/150 mg both bid could largely overcome the impact of the

  19. Structure of Pseudoknot PK26 Shows 3D Domain Swapping in an RNA

    Science.gov (United States)

    Lietzke, Susan E; Barnes, Cindy L.

    1998-01-01

    3D domain swapping provides a facile pathway for the evolution of oligomeric proteins and allosteric mechanisms and a means for using monomer-oligomer equilibria to regulate biological activity. The term "3D domain swapping" describes the exchange of identical domains between two protein monomers to create an oligomer. 3D domain swapping has, so far, only been recognized in proteins. In this study, the structure of the pseudoknot PK26 is reported and it is a clear example of 3D domain swapping in RNA. PK26 was chosen for study because RNA pseudoknots are required structures in several biological processes and they arise frequently in in vitro selection experiments directed against protein targets. PK26 specifically inhibits HIV-1 reverse transcriptase with nanomolar affinity. We have now determined the 3.1 A resolution crystal structure of PK26 and find that it forms a 3D domain swapped dimer. PK26 shows extensive base pairing between and within strands. Formation of the dimer requires the linker region between the pseudoknot folds to adopt a unique conformation that allows a base within a helical stem to skip one base in the stacking register. Rearrangement of the linker would permit a monomeric pseudoknot to form. This structure shows how RNA can use 3D domain swapping to build large scale oligomers like the putative hexamer in the packaging RNA of bacteriophage Phi29.

  20. D6PK AGCVIII kinases are required for auxin transport and phototropic hypocotyl bending in Arabidopsis.

    Science.gov (United States)

    Willige, Björn C; Ahlers, Siv; Zourelidou, Melina; Barbosa, Inês C R; Demarsy, Emilie; Trevisan, Martine; Davis, Philip A; Roelfsema, M Rob G; Hangarter, Roger; Fankhauser, Christian; Schwechheimer, Claus

    2013-05-01

    Phototropic hypocotyl bending in response to blue light excitation is an important adaptive process that helps plants to optimize their exposure to light. In Arabidopsis thaliana, phototropic hypocotyl bending is initiated by the blue light receptors and protein kinases phototropin1 (phot1) and phot2. Phototropic responses also require auxin transport and were shown to be partially compromised in mutants of the PIN-FORMED (PIN) auxin efflux facilitators. We previously described the D6 PROTEIN KINASE (D6PK) subfamily of AGCVIII kinases, which we proposed to directly regulate PIN-mediated auxin transport. Here, we show that phototropic hypocotyl bending is strongly dependent on the activity of D6PKs and the PIN proteins PIN3, PIN4, and PIN7. While early blue light and phot-dependent signaling events are not affected by the loss of D6PKs, we detect a gradual loss of PIN3 phosphorylation in d6pk mutants of increasing complexity that is most severe in the d6pk d6pkl1 d6pkl2 d6pkl3 quadruple mutant. This is accompanied by a reduction of basipetal auxin transport in the hypocotyls of d6pk as well as in pin mutants. Based on our data, we propose that D6PK-dependent PIN regulation promotes auxin transport and that auxin transport in the hypocotyl is a prerequisite for phot1-dependent hypocotyl bending.

  1. Porcine circovirus-2 capsid protein induces cell death in PK15 cells

    Energy Technology Data Exchange (ETDEWEB)

    Walia, Rupali; Dardari, Rkia, E-mail: rdardari@ucalgary.ca; Chaiyakul, Mark; Czub, Markus

    2014-11-15

    Studies have shown that Porcine circovirus (PCV)-2 induces apoptosis in PK15 cells. Here we report that cell death is induced in PCV2b-infected PK15 cells that express Capsid (Cap) protein and this effect is enhanced in interferon gamma (IFN-γ)-treated cells. We further show that transient PCV2a and 2b-Cap protein expression induces cell death in PK15 cells at rate similar to PCV2 infection, regardless of Cap protein localization. These data suggest that Cap protein may have the capacity to trigger different signaling pathways involved in cell death. Although further investigation is needed to gain deeper insights into the nature of the pathways involved in Cap-induced cell death, this study provides evidence that PCV2-induced cell death in kidney epithelial PK15 cells can be mapped to the Cap protein and establishes the need for future research regarding the role of Cap-induced cell death in PCV2 pathogenesis. - Highlights: • IFN-γ enhances PCV2 replication that leads to cell death in PK15 cells. • IFN-γ enhances nuclear localization of the PCV2 Capsid protein. • Transient PCV2a and 2b-Capsid protein expression induces cell death. • Cell death is not dictated by specific Capsid protein sub-localization.

  2. [Proliferation characteristics of a PK-15 cell-adapted strain of porcine parvovirus].

    Science.gov (United States)

    Wu, Yun-Fei; Zhu, Ling; Xu, Zhi-Wen; Fu, Meng-Jin; Chen, Lei; Yang, Ai-Guo; Guo, Wan-Zhu

    2013-06-01

    To study the proliferation characteristics of PPV in differently infected way and the variance of concentrations in different cells. A strain of porcine parvovirus(PPV) was adapted to PK-15 cells, and a Real-time fluorescent quantitative PCR (FQ-PCR) assay was developed based on the specific region of the NS1 gene of PPV to quantify the PPV. The FQ-PCR was used to measure the viral concentration of virus-infected cells by simultaneous or step by step inoculation and plot one-step growth curves. The proliferation characteristics of PPV strain in different cells lines (HeLa, MDBK, PK-15 ,ST, F81, BHK-21 and Marc-145) was also compared. The results showed the PK-15 cell -adapted strain of PPV produced CPE after 12 passages, and maintained stable CPE at the following 10 messages. The one-step growth curve showed that the virus concentration of simultaneous inoculation was higher than that of the step-by-step inoculation, and the proliferation cycle of step-by-step inoculation was shorter. The proliferation ability of PPV strain in different cells showed that CPE appeared first inPK-15, followed by ST, HeLa and MDBK, and the virus concentration was highest in ST, followed byPK-15, MDBK and HeLa. NO proliferation was observed in F81, BHK-21 and Marc-145 cells. These findings lay a material foundation for the basic researches on PPV and the development of vaccine.

  3. Sustained release ophthalmic dexamethasone: In vitro in vivo correlations derived from the PK-Eye.

    Science.gov (United States)

    Awwad, Sahar; Day, Richard M; Khaw, Peng T; Brocchini, Steve; Fadda, Hala M

    2017-04-30

    Corticosteroids have long been used to treat intraocular inflammation by intravitreal injection. We describe dexamethasone loaded poly-DL-lactide-co-glycolide (PLGA) microparticles that were fabricated by thermally induced phase separation (TIPS). The dexamethasone loaded microparticles were evaluated using a two-compartment, in vitro aqueous outflow model of the eye (PK-Eye) that estimates drug clearance time from the back of the eye via aqueous outflow by the anterior route. A dexamethasone dose of 0.20±0.02mg in a 50μL volume of TIPS microparticles resulted in a clearance t1/2 of 9.6±0.3days using simulated vitreous in the PK-Eye. Since corticosteroids can also clear through the retina, it is necessary to account for clearance through the back of the eye. Retinal permeability data, published human ocular pharmacokinetics (PK) and the PK-Eye clearance times were then used to establish in vitro in vivo correlations (IVIVCs) for intraocular clearance times of corticosteroid formulations. A t1/2 of 48h was estimated for the dexamethasone-TIPS microparticles, which is almost 9 times longer than that reported for dexamethasone suspension in humans. The prediction of human clearance times of permeable molecules from the vitreous compartment can be determined by accounting for drug retinal permeation and determining the experimental clearance via the anterior aqueous outflow pathway using the PK-Eye. Copyright © 2017. Published by Elsevier B.V.

  4. PIN1 in hepatocellular carcinoma is associated with TP53 gene status.

    Science.gov (United States)

    Bae, Jun Sang; Noh, Sang Jae; Kim, Kyoung Min; Jang, Kyu Yun; Park, Ho Sung; Chung, Myoung Ja; Park, Byung-Hyun; Moon, Woo Sung

    2016-10-01

    Phosphorylation of proteins on serine/threonine residues that precede proline (pSer/Thr-Pro) is specifically catalyzed by the peptidyl-prolyl cis-trans isomerase PIN1. PIN1-mediated prolyl-isomerization induces cell cycle arrest and growth inhibition through the regulation of target proteins, including TP53. We examined whether PIN1 acts in a different manner according to TP53 gene status in hepatocellular carcinoma (HCC). We investigated the expression of PIN1 and TP53 proteins in 119 HCC tissue samples. We also analyzed PIN1 expression in combination with TP53 gene mutation and its correlation with the clinical outcome. In addition, we used synthetic small interfering RNA to silence PIN1 gene expression in TP53 wild-type and TP53 mutant HCC cell lines, and then evaluated cell proliferation, migration and invasion. Expression of PIN1 was strongly associated with expression of TP53 protein or TP53 mutation of HCC samples. PIN1 and TP53 expression in TP53 mutant HCC cell lines was higher than that in TP53 wild-type HCC cell lines. Silencing of PIN1 in HLE cells containing mutant TP53 significantly decreased cell proliferation, migration and invasion. In contrast to PIN1 silencing in HLE cells, PIN1 silencing in HepG2 cells containing functional wild-type TP53 resulted in enhanced tumor cell proliferation. HCC patients bearing PIN1 expression with wild-type TP53 were predicted to demonstrate favorable relapse-free survival. Our results suggest that PIN1 plays a role in cancer cell proliferation, migration and invasion in a different manner according to the TP53 gene mutation status in HCC. In particular, interaction of PIN1 with mutant TP53 can act as a tumor promoter and increase its oncogenic activities in HCC.

  5. Synthesis of TP3 Fragment via One Pot Strategy and Its Immune Regulatory Activity

    Institute of Scientific and Technical Information of China (English)

    WANG Li-feng; CHEN Jie; SHAN Hui-jie; LI Wei

    2005-01-01

    We have modified the previously described one-pot peptide synthesis method. The modified method has been successfully applied to the synthesis of TP3. Furthermore, the immune regulatory activity of TP3 has been characterized. The results show that the modified one-pot method can be used to synthesize the biological active peptide with the advantages of low cost and high productivity. Moreover, TP3 has a higher immune regulatory activity than TP5.

  6. Profile of TP53 gene mutations in sinonasal cancer

    DEFF Research Database (Denmark)

    Holmila, Reetta; Bornholdt, Jette; Suitiala, Tuula

    2010-01-01

    %) frameshift or nonsense mutations, and 36 (23%) intronic or silent mutations. In coding region, the most common base change detected was C-->T transition (43/125; 34% of base changes in the coding region). G-->T transversions occurred at a frequency of 10% (12/125), which is less than reported in mutation...... not been reported before as frequently mutated in head and neck cancer or human cancer in general. About half of all tumours with TP53 mutations carried more than one mutation. Interestingly, 86% (19/22) of the silent mutations detected had occurred in tumours with multiple mutations.......Genetic alterations underlying the development of the cancer of the nose and paranasal sinuses (sinonasal cancer, SNC), a rare cancer that can be included in the group of head and neck cancers, are still largely unknown. We recently reported that TP53 mutations are a common feature of SNC...

  7. The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases.

    Science.gov (United States)

    Stengel, A; Kern, W; Haferlach, T; Meggendorfer, M; Fasan, A; Haferlach, C

    2017-03-01

    Alterations in TP53 have been described in many cancer types including hematological neoplasms. We aimed at comparing TP53 mutations (mut) and deletions (del) in a large cohort of patients with hematological malignancies (n=3307), including AML (n=858), MDS (n=943), ALL (n=358), CLL (n=1148). Overall, alterations in TP53 were detected in 332/3307 cases (10%). The highest frequency was observed in ALL (total: 19%; mut+del: 6%; mut only: 8%; del only: 5%) and AML (total: 13%; mut+del: 5%; mut only: 7%; del only: 1%), whereas TP53 alterations occurred less frequently in CLL (total: 8%) and MDS (total: 7%). TP53 mutations were significantly more frequent in patients ⩾60 vs TP53 deletion and mutation status.

  8. Study of the Antimicrobial Activity of Tilapia Piscidin 3 (TP3) and TP4 and Their Effects on Immune Functions in Hybrid Tilapia (Oreochromis spp.)

    Science.gov (United States)

    Pan, Chieh-Yu; Tsai, Tsung-Yu; Su, Bor-Chyuan; Hui, Cho-Fat; Chen, Jyh-Yih

    2017-01-01

    To address the growing concern over antibiotic-resistant microbial infections in aquatic animals, we tested several promising alternative agents that have emerged as new drug candidates. Specifically, the tilapia piscidins are a group of peptides that possess antimicrobial, wound-healing, and antitumor functions. In this study, we focused on tilapia piscidin 3 (TP3) and TP4, which are peptides derived from Oreochromis niloticus, and investigated their inhibition of acute bacterial infections by infecting hybrid tilapia (Oreochromis spp.) with Vibrio vulnificus and evaluating the protective effects of pre-treating, co-treating, and post-treating fish with TP3 and TP4. In vivo experiments showed that co-treatment with V. vulnificus and TP3 (20 μg/fish) or TP4 (20 μg/fish) achieved 95.3% and 88.9% survival rates, respectively, after seven days. When we co-injected TP3 or TP4 and V. vulnificus into tilapia and then re-challenged the fish with V. vulnificus after 28 days, the tilapia exhibited survival rates of 35.6% and 42.2%, respectively. Pre-treatment with TP3 (30 μg/fish) or TP4 (20 μg/fish) for 30 minutes prior to V. vulnificus infection resulted in high survival rates of 28.9% and 37.8%, respectively, while post-treatment with TP3 (20 μg/fish or 30 μg/fish) or TP4 (20 μg/fish) 30 minutes after V. vulnificus infection yielded high survival rates of 33.3% and 48.9%. In summary, pre-treating, co-treating, and post-treating fish with TP3 or TP4 all effectively decreased the number of V. vulnificus bacteria and promoted significantly lower mortality rates in tilapia. The minimum inhibitory concentrations (MICs) of TP3 and TP4 that were effective for treating fish infected with V. vulnificus were 7.8 and 62.5 μg/ml, respectively, whereas the MICs of kanamycin and ampicillin were 31.2 and 3.91 μg/ml. The antimicrobial activity of these peptides was confirmed by transmission electron microscopy (TEM) and scanning electron microscopy (SEM), both of which showed

  9. Translational PK/PD modeling to increase probability of success in drug discovery and early development.

    Science.gov (United States)

    Lavé, Thierry; Caruso, Antonello; Parrott, Neil; Walz, Antje

    In this review we present ways in which translational PK/PD modeling can address opportunities to enhance probability of success in drug discovery and early development. This is achieved by impacting efficacy and safety-driven attrition rates, through increased focus on the quantitative understanding and modeling of translational PK/PD. Application of the proposed principles early in the discovery and development phases is anticipated to bolster confidence of successfully evaluating proof of mechanism in humans and ultimately improve Phase II success. The present review is centered on the application of predictive modeling and simulation approaches during drug discovery and early development, and more specifically of mechanism-based PK/PD modeling. Case studies are presented, focused on the relevance of M&S contributions to real-world questions and the impact on decision making.

  10. File list: Oth.PSC.20.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.PSC.20.TP53.AllCell hg19 TFs and others TP53 Pluripotent stem cell SRX189250,SR...X189251,SRX189249 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.PSC.20.TP53.AllCell.bed ...

  11. File list: Oth.ALL.50.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.ALL.50.TP53.AllCell hg19 TFs and others TP53 All cell types SRX189250,SRX275504...672731,SRX396265,SRX396258,SRX396256,SRX275502,SRX278507,SRX612780 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.ALL.50.TP53.AllCell.bed ...

  12. File list: Oth.PSC.10.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.PSC.10.TP53.AllCell hg19 TFs and others TP53 Pluripotent stem cell SRX189250,SR...X189251,SRX189249 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.PSC.10.TP53.AllCell.bed ...

  13. File list: Oth.Bon.05.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bon.05.TP53.AllCell hg19 TFs and others TP53 Bone SRX020768,SRX275504,SRX016980...06,SRX275502,SRX020767,SRX020769,SRX020766 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Bon.05.TP53.AllCell.bed ...

  14. File list: Oth.Lng.50.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Lng.50.TP53.AllCell hg19 TFs and others TP53 Lung SRX208484,SRX208485,SRX208486...,SRX620747,SRX620746,SRX093319 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Lng.50.TP53.AllCell.bed ...

  15. File list: Oth.Lng.05.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Lng.05.TP53.AllCell hg19 TFs and others TP53 Lung SRX208485,SRX208484,SRX208486...,SRX620747,SRX620746,SRX093319 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Lng.05.TP53.AllCell.bed ...

  16. File list: Oth.Lng.10.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Lng.10.TP53.AllCell hg19 TFs and others TP53 Lung SRX208485,SRX208484,SRX208486...,SRX620747,SRX620746,SRX093319 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Lng.10.TP53.AllCell.bed ...

  17. Comprehensive characterization of genes associated with the TP53 signal transduction pathway in various tumors.

    Science.gov (United States)

    Ohnami, Shumpei; Ohshima, Keiichi; Nagashima, Takeshi; Urakami, Kenichi; Shimoda, Yuji; Saito, Junko; Naruoka, Akane; Hatakeyama, Keiichi; Mochizuki, Tohru; Serizawa, Masakuni; Ohnami, Sumiko; Kusuhara, Masatoshi; Yamaguchi, Ken

    2017-03-03

    The TP53 signal transduction pathway is an attractive target for cancer treatments. In this study, we conducted a comprehensive molecular evaluation of 907 patients with cancer in Japan to identify genomic alterations in the TP53 pathway. TP53 mutations were frequently detected in many cancers, except melanoma, thymic tumors, gastrointestinal stromal tumors, and renal cancers. The frequencies of non-synonymous single nucleotide variants (SNVs) in the TP53 family members TP63 and TP73 were relatively low, although genes with increased frequencies of SNVs were as follows: PTEN (11.7%) in breast cancer, CDKN2A (11.1 and 9.6%) in pancreas and head and neck cancers, and ATM (18.0 and 11.1%) in liver and esophageal cancers. MDM2 expression was decreased or increased in patients with mutant or wild-type TP53, respectively. CDKN1A expression was increased with mutant TP53 in head and neck cancers. Moreover, TP63 overexpression was characteristically observed in squamous cell carcinomas of the lung, esophagus, and head and neck region. Additionally, overexpression of TP63 and TP73 was frequently observed in thymomas. Our results reveal a spectrum of genomic alterations in the TP53 pathway that is characteristic of many tumor types, and these data may be useful in the trials of targeted therapies.

  18. File list: Oth.Dig.05.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Dig.05.TP53.AllCell hg19 TFs and others TP53 Digestive tract SRX672732,SRX60337...2,SRX672731,SRX603373,SRX612780 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Dig.05.TP53.AllCell.bed ...

  19. TP53 germline mutations in Portugal and genetic modifiers of age at cancer onset

    NARCIS (Netherlands)

    Pinto, Carla; Veiga, Isabel; Pinheiro, Manuela; Peixoto, Ana; Pinto, Armando; Lopes, Jose M.; Reis, Rui M.; Oliveira, Carla; Baptista, Manuela; Roque, Lucia; Regateiro, Fernando; Cirnes, Luis; Hofstra, Robert M. W.; Seruca, Raquel; Castedo, Sergio; Teixeira, Manuel R.

    2009-01-01

    The Li-Fraumeni syndrome (LFS) is a rare, autosomal dominant disease caused by TP53 germline mutations. This study aimed to characterize the TP53 mutational spectrum in patients suspected to have LFS in Portugal and to evaluate the influence of the MDM2-SNP309 and TP53-72Arg variants and of telomere

  20. File list: Oth.Brs.20.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Brs.20.TP53.AllCell hg19 TFs and others TP53 Breast SRX647704,SRX647706,SRX6477...05,SRX285808,SRX647703,SRX647707 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Brs.20.TP53.AllCell.bed ...

  1. File list: Oth.Dig.10.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Dig.10.TP53.AllCell hg19 TFs and others TP53 Digestive tract SRX672732,SRX60337...3,SRX612780,SRX603372,SRX672731 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Dig.10.TP53.AllCell.bed ...

  2. File list: Oth.PSC.50.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.PSC.50.TP53.AllCell hg19 TFs and others TP53 Pluripotent stem cell SRX189250,SR...X189251,SRX189249 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.PSC.50.TP53.AllCell.bed ...

  3. File list: Oth.ALL.10.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.ALL.10.TP53.AllCell hg19 TFs and others TP53 All cell types SRX020768,SRX189250...647704,SRX285808,SRX647705,SRX189249,SRX672731,SRX647703,SRX278507 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.ALL.10.TP53.AllCell.bed ...

  4. File list: Oth.Dig.50.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Dig.50.TP53.AllCell hg19 TFs and others TP53 Digestive tract SRX603373,SRX67273...2,SRX603372,SRX672731,SRX612780 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Dig.50.TP53.AllCell.bed ...

  5. File list: Oth.ALL.20.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.ALL.20.TP53.AllCell hg19 TFs and others TP53 All cell types SRX189250,SRX275504...285808,SRX361198,SRX189249,SRX647703,SRX647707,SRX612780,SRX278507 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.ALL.20.TP53.AllCell.bed ...

  6. File list: Oth.Lng.20.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Lng.20.TP53.AllCell hg19 TFs and others TP53 Lung SRX208484,SRX208485,SRX208486...,SRX620747,SRX620746,SRX093319 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Lng.20.TP53.AllCell.bed ...

  7. File list: Oth.Bld.20.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.20.TP53.AllCell hg19 TFs and others TP53 Blood SRX278510,SRX278504,SRX27850...6,SRX278507 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Bld.20.TP53.AllCell.bed ...

  8. File list: Oth.Bld.50.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.50.TP53.AllCell hg19 TFs and others TP53 Blood SRX278510,SRX278504,SRX27850...6,SRX278507 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Bld.50.TP53.AllCell.bed ...

  9. File list: Oth.Bon.20.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bon.20.TP53.AllCell hg19 TFs and others TP53 Bone SRX275504,SRX016980,SRX020768...67,SRX020764,SRX020769,SRX020766,SRX361198 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Bon.20.TP53.AllCell.bed ...

  10. File list: Oth.ALL.05.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.ALL.05.TP53.AllCell hg19 TFs and others TP53 All cell types SRX672732,SRX020768...647706,SRX647705,SRX285808,SRX612780,SRX189251,SRX647703,SRX189249 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.ALL.05.TP53.AllCell.bed ...

  11. File list: Oth.PSC.05.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.PSC.05.TP53.AllCell hg19 TFs and others TP53 Pluripotent stem cell SRX189250,SR...X189251,SRX189249 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.PSC.05.TP53.AllCell.bed ...

  12. File list: Oth.Brs.10.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Brs.10.TP53.AllCell hg19 TFs and others TP53 Breast SRX647706,SRX647707,SRX6477...04,SRX285808,SRX647705,SRX647703 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Brs.10.TP53.AllCell.bed ...

  13. File list: Oth.Bld.10.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.10.TP53.AllCell hg19 TFs and others TP53 Blood SRX278510,SRX278504,SRX27850...6,SRX278507 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Bld.10.TP53.AllCell.bed ...

  14. File list: Oth.Bld.05.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.05.TP53.AllCell hg19 TFs and others TP53 Blood SRX278507,SRX278504,SRX27851...0,SRX278506 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Bld.05.TP53.AllCell.bed ...

  15. File list: Oth.Brs.50.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Brs.50.TP53.AllCell hg19 TFs and others TP53 Breast SRX647705,SRX647704,SRX2858...08,SRX647703,SRX647707,SRX647706 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Brs.50.TP53.AllCell.bed ...

  16. File list: Oth.Bon.10.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bon.10.TP53.AllCell hg19 TFs and others TP53 Bone SRX020768,SRX275504,SRX016980...06,SRX020767,SRX275502,SRX020769,SRX020766 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Bon.10.TP53.AllCell.bed ...

  17. File list: Oth.Bon.50.TP53.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bon.50.TP53.AllCell hg19 TFs and others TP53 Bone SRX275504,SRX016980,SRX020768...64,SRX020769,SRX361198,SRX020766,SRX275502 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Bon.50.TP53.AllCell.bed ...

  18. Network File - TP Atlas | LSDB Archive [Life Science Database Archive metadata

    Lifescience Database Archive (English)

    Full Text Available SML format) for each project. One project has one pathway file originally drawn by Cell Illustrator. Data file File name: tp_atlas..._csml.zip File URL: ftp://ftp.biosciencedbc.jp/archive/tp_atlas/LATEST/tp_atlas

  19. Coincident In Vitro Analysis of DNA-PK-Dependent and -Independent Nonhomologous End Joining

    OpenAIRE

    Hendrickson, Cynthia L.; Shubhadeep Purkayastha; Elzbieta Pastwa; Neumann, Ronald D.; Winters, Thomas A.

    2010-01-01

    In mammalian cells, DNA double-strand breaks (DSBs) are primarily repaired by nonhomologous end joining (NHEJ). The current model suggests that the Ku 70/80 heterodimer binds to DSB ends and recruits DNA-PKcs to form the active DNA-dependent protein kinase, DNA-PK. Subsequently, XRCC4, DNA ligase IV, XLF and most likely, other unidentified components participate in the final DSB ligation step. Therefore, DNA-PK plays a key role in NHEJ due to its structural and regulatory functions that media...

  20. Purification, crystallization and preliminary X-ray analysis of TP0435 (Tp17) from the syphilis spirochete Treponema pallidum.

    Science.gov (United States)

    Brautigam, Chad A; Deka, Ranjit K; Norgard, Michael V

    2013-04-01

    Syphilis, caused by the bacterial spirochete Treponema pallidum, remains a prominent sexually transmitted infection worldwide. Despite sequencing of the genome of this obligate human pathogen 15 years ago, the functions of a large number of the gene products of T. pallidum are still unknown, particularly with respect to those of the organism's periplasmic lipoproteins. To better understand their functions, a structural biology approach has been pursued. To this end, the soluble portion of the T. pallidum TP0435 lipoprotein (also known as Tp17) was cloned, hyper-expressed in Escherichia coli and purified to apparent homogeneity. The protein crystals obtained from this preparation diffracted to 2.4 Å resolution and had the symmetry of space group R3. In the hexagonal setting, the unit-cell parameters were a = b = 85.7, c = 85.4 Å.

  1. Numerical evaluation of the weldability of the low alloy ferritic steels T/P23 and T/P24

    Directory of Open Access Journals (Sweden)

    Carlos Roberto Xavier

    2011-03-01

    Full Text Available A model based on transport equations was numerically implemented by the finite volume method (FVM in a computational code in order to simulate the influence of the heat input, base metal thickness and preheating temperature on the thermal evolution and the cooling rate during the welding of the low alloy ferritic steels T/P23 and T/P24. As a consequence, it was possible to evaluate qualitatively the microstructure at the heat affected zone (HAZ of these steels when a single weld bead was deposited on their surface and calculate the maximum hardness reached at this region. Goldakfs double-ellipsoid heat source model for power density distribution was utilized in order to obtain a good estimate of the cooling rate and dimensions of the fusion zone (FZ. The results are discussed in light of previous work and good agreement between experimental and simulated results was verified.

  2. TP53 Gene Status Affects Survival in Advanced Mycosis Fungoides

    DEFF Research Database (Denmark)

    Wooler, Gitte; Melchior, Linea; Ralfkiaer, Elisabeth

    2016-01-01

    TP53 is frequently mutated in different types of neoplasms including leukemia and lymphomas. Mutations of TP53 have also been reported in mycosis fungoides (MF), the most common type of cutaneous lymphoma. However, little is known about the frequency, spectrum of mutations, and their prognostic...... significance in MF. In this study, we have optimized the protocol for Sanger sequencing of TP53 using DNA extracted from archival paraffin-embedded biopsies. Of 19 samples from patients with stage IIB MF or higher, 31% harbored mutations in TP53. Overall survival of the patients with mutated TP53...

  3. Evaluation of a PK/PBAN Analog with an (E)-Alkene, trans-Pro Isostere Identifies the Pro Orientation for Activity in Four Diverse PK/PBAN Bioassays

    Science.gov (United States)

    2009-01-01

    pentapeptide common to the PK/PBAN neuropeptide class retains activity in each of the disparate functions. The functional diversity of the PK/PBAN family...2008;29:268–75. [15] Matsumoto S, Kitamura A, Nagasawa H, Kataoka H, Orikasa C, Mitsui T, et al. Functional diversity of a neurohormone produced by the

  4. The IARC TP53 mutation database: a resource for studying the significance of TP53 mutations in human cancers

    Directory of Open Access Journals (Sweden)

    Magali Olivier

    2007-02-01

    Full Text Available

    The tumor suppressor gene TP53 is frequently inactivated by gene mutations in many types of human sporadic cancers, and inherited TP53 mutations predispose to a wide spectrum of early-onset tumors (Li-Fraumeni et Li-Fraumenilike Syndromes. All TP53 gene variations (somatic and germline mutations, as well as polymorphisms that are reported in the scientific literature or in SNP databases are compiled in the IARC TP53 Database. This database provides structured data and analysis tools to study mutation patterns in human cancers and cell-lines and to investigate the clinical impact of mutations. It contains annotations related to the clinical and pathological characteristics of tumors, as well as the demographics and carcinogen exposure of patients. The IARC TP53 web site (http://www-p53.iarc.fr/ provides a search interface for the core database and includes a comprehensive user guide, a slideshow on TP53 mutations in human cancer, protocols and references for sequencing TP53 gene, and links to relevant publications and bioinformatics databases. The database interface allows download of entire data sets and propose various tools for the selection, analysis and downloads of specific sets of data according to user's query.

    Recently, new annotations on the functional properties of mutant p53 proteins have been integrated in this database. Indeed, the most frequent TP53 alterations observed in cancers (75% are missense mutations that result in the production of a mutant protein that differ from the wildtype by one single amino-acid. The characterization of the biological activities of these mutant proteins is thus very important. Over the last ten years, a great amount of systematic data has been generated from experimental assays performed in

  5. The human DNA-activated protein kinase, DNA-PK: Substrate specificity

    Energy Technology Data Exchange (ETDEWEB)

    Anderson, C.W.; Connelly, M.A.; Zhang, H.; Sipley, J.A. [Brookhaven National Lab., Upton, NY (United States). Biology Dept.; Lees-Miller, S.P.; Lintott, L.G. [Univ. of Calgary, Alberta (Canada). Dept. of Biological Sciences; Sakaguchi, Kazuyasu; Appella, E. [National Institutes of Health, Bethesda, MD (United States). Lab. of Cell Biology

    1994-11-05

    Although much has been learned about the structure and function of p53 and the probable sequence of subsequent events that lead to cell cycle arrest, little is known about how DNA damage is detected and the nature of the signal that is generated by DNA damage. Circumstantial evidence suggests that protein kinases may be involved. In vitro, human DNA-PK phosphorylates a variety of nuclear DNA-binding, regulatory proteins including the tumor suppressor protein p53, the single-stranded DNA binding protein RPA, the heat shock protein hsp90, the large tumor antigen (TAg) of simian virus 40, a variety of transcription factors including Fos, Jun, serum response factor (SRF), Myc, Sp1, Oct-1, TFIID, E2F, the estrogen receptor, and the large subunit of RNA polymerase II (reviewed in Anderson, 1993; Jackson et al., 1993). However, for most of these proteins, the sites that are phosphorylated by DNA-PK are not known. To determine if the sites that were phosphorylated in vitro also were phosphorylated in vivo and if DNA-PK recognized a preferred protein sequence, the authors identified the sites phosphorylated by DNA-PK in several substrates by direct protein sequence analysis. Each phosphorylated serine or threonine is followed immediately by glutamine in the polypeptide chain; at no other positions are the amino acid residues obviously constrained.

  6. The human DNA-activated protein kinase, DNA-PK: Substrate specificity

    Energy Technology Data Exchange (ETDEWEB)

    Anderson, C.W.; Connelly, M.A.; Zhang, H.; Sipley, J.A. [Brookhaven National Lab., Upton, NY (United States). Biology Dept.; Lees-Miller, S.P.; Lintott, L.G. [Univ. of Calgary, Alberta (Canada). Dept. of Biological Sciences; Sakaguchi, Kazuyasu; Appella, E. [National Institutes of Health, Bethesda, MD (United States). Lab. of Cell Biology

    1994-11-05

    Although much has been learned about the structure and function of p53 and the probable sequence of subsequent events that lead to cell cycle arrest, little is known about how DNA damage is detected and the nature of the signal that is generated by DNA damage. Circumstantial evidence suggests that protein kinases may be involved. In vitro, human DNA-PK phosphorylates a variety of nuclear DNA-binding, regulatory proteins including the tumor suppressor protein p53, the single-stranded DNA binding protein RPA, the heat shock protein hsp90, the large tumor antigen (TAg) of simian virus 40, a variety of transcription factors including Fos, Jun, serum response factor (SRF), Myc, Sp1, Oct-1, TFIID, E2F, the estrogen receptor, and the large subunit of RNA polymerase II (reviewed in Anderson, 1993; Jackson et al., 1993). However, for most of these proteins, the sites that are phosphorylated by DNA-PK are not known. To determine if the sites that were phosphorylated in vitro also were phosphorylated in vivo and if DNA-PK recognized a preferred protein sequence, the authors identified the sites phosphorylated by DNA-PK in several substrates by direct protein sequence analysis. Each phosphorylated serine or threonine is followed immediately by glutamine in the polypeptide chain; at no other positions are the amino acid residues obviously constrained.

  7. Data of evolutionary structure change: 1ACMA-3E2PK [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1ACMA-3E2PK 1ACM 3E2P A K ANPLYQKHIISINDLSRDDLNLVLATAAKLKA-----NP...GG HHHHHGGHHHHHHHHHHHHHH - 0 1ACM... A 1ACMA KERLD-PSEYA SER CA 128 VAL CA 222 ALA CA 223 1ACM... A 1ACMA FSDSANTSLGK

  8. Neuroinflammation in bipolar disorder : A [C-11]-(R)-PK11195 positron emission tomography study

    NARCIS (Netherlands)

    Haarman, Bartholomeus C.M.; Riemersma -van der Lek, Rixt; de Groot, Jan Cees; Ruhe, Eric; Klein, Hans C; Zandstra, Tjitske E; Burger, Huibert; Schoevers, Robert A.; de Vries, Erik F.J.; Drexhage, Hemmo A; Nolen, Willem A.; Doorduin, Janine

    2014-01-01

    Background: The "monocyte-T-cell theory of mood disorders" regards neuroinflammation, i.e. marked activation of microglia, as a driving force in bipolar disorder. Microglia activation can be visualized in vivo using [C-11]-(R)-PK11195 PET. Indirect evidence suggests the hippocampus as a potential fo

  9. A Markov approach to characterising the PK-PD relationship of anti-migraine drugs

    NARCIS (Netherlands)

    Maas, Hugo J.

    2007-01-01

    The objective of the investigations described in this thesis was the development of novel PK-PD modelling for the characterisation and prediction of the effects of anti-migraine drugs in clinical investigations. The Markov approach has first been applied to migraine data by Hassani and Ebutt. They

  10. Construction of an integrated map of rose with AFLP, SSR, PK, RGA, SCAR and morphological markers

    NARCIS (Netherlands)

    Yan Zifu, Z.; Denneboom, C.; Hattendorf, A.; Dolstra, O.; Debener, T.; Stam, P.; Visser, P.B.

    2005-01-01

    A high-density genetic map with a number of anchor markers has been created to be used as a tool to dissect genetic variation in rose. Linkage maps for the diploid 94/1 population consisting of 88 individuals were constructed using a total of 520 molecular markers including AFLP, SSR, PK, RGA, RFLP,

  11. Derivation of adsorption parameters for nanofiltration membranes using a 1-pK Basic Stern model

    NARCIS (Netherlands)

    de Lint, W.B.S.; Benes, Nieck Edwin; Higler, A.P.; Verweij, H.

    2002-01-01

    The ion retention and flux of nanofiltration (NF) membranes are to a large extent determined by the membrane surface charge. This surface charge is in turn strongly influenced by adsorption of ions from the solution onto the membrane material. A 1-pK adsorption model with a Basic Stern electrostatic

  12. Application of PK/PD Modeling in Veterinary Field: Dose Optimization and Drug Resistance Prediction

    Directory of Open Access Journals (Sweden)

    Ijaz Ahmad

    2016-01-01

    Full Text Available Among veterinary drugs, antibiotics are frequently used. The true mean of antibiotic treatment is to administer dose of drug that will have enough high possibility of attaining the preferred curative effect, with adequately low chance of concentration associated toxicity. Rising of antibacterial resistance and lack of novel antibiotic is a global crisis; therefore there is an urgent need to overcome this problem. Inappropriate antibiotic selection, group treatment, and suboptimal dosing are mostly responsible for the mentioned problem. One approach to minimizing the antibacterial resistance is to optimize the dosage regimen. PK/PD model is important realm to be used for that purpose from several years. PK/PD model describes the relationship between drug potency, microorganism exposed to drug, and the effect observed. Proper use of the most modern PK/PD modeling approaches in veterinary medicine can optimize the dosage for patient, which in turn reduce toxicity and reduce the emergence of resistance. The aim of this review is to look at the existing state and application of PK/PD in veterinary medicine based on in vitro, in vivo, healthy, and disease model.

  13. Biostable beta-Amino Acid PK/PBAN Analogs: Agonist and Antagonist Properties

    Science.gov (United States)

    2009-01-01

    peptide [1,11,29,30]. The functional diversity of the PK/PBAN family raises many questions regarding the mechanisms by which these neuropeptides operate and...46. [18] Matsumoto S. Functional diversity of a neurohormone produced by the subesophageal ganglion: molecular identity of melanization and reddish

  14. PK11195 effect on steroidogenesis is not mediated through the translocator protein (TSPO).

    Science.gov (United States)

    Tu, Lan N; Zhao, Amy H; Stocco, Douglas M; Selvaraj, Vimal

    2015-03-01

    Translocator protein (TSPO) is a mitochondrial outer membrane protein of unknown function with high physiological expression in steroidogenic cells. Using TSPO gene-deleted mice, we recently demonstrated that TSPO function is not essential for steroidogenesis. The first link between TSPO and steroidogenesis was established in studies showing modest increases in progesterone production by adrenocortical and Leydig tumor cell lines after treatment with PK11195. To reconcile discrepancies between physiological and pharmacological interpretations of TSPO function, we generated TSPO-knockout MA-10 mouse Leydig tumor cells (MA-10:TspoΔ/Δ) and examined their steroidogenic potential after exposure to either dibutyryl-cAMP or PK11195. Progesterone production in MA-10:TspoΔ/Δ after dibutyryl-cAMP was not different from control MA-10:Tspo+/+ cells, confirming that TSPO function is not essential for steroidogenesis. Interestingly, when treated with increasing concentrations of PK11195, both control MA-10:Tspo+/+ cells and MA-10:TspoΔ/Δ cells responded in a similar dose-dependent manner showing increases in progesterone production. These results show that the pharmacological effect of PK11195 on steroidogenesis is not mediated through TSPO.

  15. Comparison of Plasma Tu-M2-PK and CA19-9 in Pancreatic Cancer

    DEFF Research Database (Denmark)

    Joergensen, Maiken Thyregod; Heegaard, Niels H H; Schaffalitzky de Muckadell, Ove B

    2009-01-01

    because of suspicion of pancreatic cancer. Of these, 51 patients had their conditions diagnosed as PDAC, whereas this diagnosis was ruled out in 52 after 12 months of follow-up. The performance of Tu-M2-PK was compared with that of CA19-9 using cutoff values 15 and 37 U/mL, respectively. RESULTS...

  16. TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis.

    Science.gov (United States)

    Loghavi, Sanam; Al-Ibraheemi, Alyaa; Zuo, Zhuang; Garcia-Manero, Guillermo; Yabe, Mariko; Wang, Sa A; Kantarjian, Hagop M; Yin, Cameron C; Miranda, Roberto N; Luthra, Raja; Medeiros, L Jeffrey; Bueso-Ramos, Carlos E; Khoury, Joseph D

    2015-10-01

    Bone marrow (BM) fibrosis is associated with poor prognosis in patients with de novo myelodysplastic syndromes (MDS). TP53 mutations and TP53 (p53) overexpression in MDS are also associated with poor patient outcomes. The prevalence and significance of TP53 mutations and TP53 overexpression in MDS with fibrosis are unknown. We studied 67 patients with de novo MDS demonstrating moderate to severe reticulin fibrosis (MDS-F). Expression of TP53 was evaluated in BM core biopsy specimens using dual-colour CD34/TP53 immunohistochemistry with computer-assisted image analysis. Mutation analysis was performed using next-generation sequencing, or Sanger sequencing methods. TP53 mutations were present in 47·1% of cases. TP53 mutation was significantly associated with TP53 expression (P = 0·0294). High levels of TP53 expression (3 +  in ≥10% cells) were associated with higher BM blast counts (P = 0·0149); alterations of chromosomes 5 (P = 0·0009) or 7 (P = 0·0141); complex karyotype (P = 0·0002); high- and very-high risk IPSS-R groups (P = 0·009); and TP53 mutations (P = 0·0003). High TP53 expression independently predicted shorter overall survival (OS) by multivariate analysis (P = TP53 by CD34-positive cells was associated with shorter OS and leukaemia-free survival (P = 0·0428). TP53 overexpression is a predictor of poor outcome in patients with MDS-F.

  17. c-Myc inhibits TP53INP1 expression via promoter methylation in esophageal carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Weng, Wenhao; Yang, Qinyuan [Department of Laboratory Medicine, Shanghai Tenth People' s Hospital, Tongji University School of Medicine, Shanghai 200072 (China); Huang, Miaolong [Department of Thoracic Surgery, Yuebei People' s Hospital, Shaoguan, Guangdong 512026 (China); Qiao, Yongxia [Department of Preventive Medicine, Tongji University, Shanghai City 200092 (China); Xie, Yuan; Yu, Yongchun [Department of Laboratory Medicine, Shanghai Tenth People' s Hospital, Tongji University School of Medicine, Shanghai 200072 (China); Jing, An, E-mail: Anjing77@gmail.com [Department of Thoracic Surgery, Yuebei People' s Hospital, Shaoguan, Guangdong 512026 (China); Institute of Cancer Research, Southern Medical University, Guangzhou 510515 (China); Li, Zhi, E-mail: lizhiweng2010@163.com [Department of Laboratory Medicine, Shanghai Tenth People' s Hospital, Tongji University School of Medicine, Shanghai 200072 (China)

    2011-02-11

    Research highlights: {yields} TP53INP1 expression is down-regulated in esophageal carcinoma and is associated with CGI-131 methylation. {yields} Inhibition of CGI-131 methylation upregulates TP53INP1 expression in ESCC cell lines. {yields} Ectopic expression of TP53INP1 inhibits growth of ESCC cells by inducing apoptosis and inhibiting cell cycle progression. {yields} c-Myc binds to the promoter of TP53INP1 in vivo and vitro and recruits DNMT3A to TP53INP1 promoter for CGI-131 methylation. -- Abstract: Tumor protein p53-induced nuclear protein 1 (TP53INP1) is a well known stress-induced protein that plays a role in both cell cycle arrest and p53-mediated apoptosis. Loss of TP53INP1 expression has been reported in human melanoma, breast carcinoma, and gastric cancer. However, TP53INP1 expression and its regulatory mechanism in esophageal squamous cell carcinoma (ESCC) remain unclear. Our findings are in agreement with previous reports in that the expression of TP53INP1 was downregulated in 28% (10/36 cases) of ESCC lesions, and this was accompanied by significant promoter methylation. Overexpression of TP53INP1 induced G1 cell cycle arrest and increased apoptosis in ESCC cell lines (EC-1, EC-109, EC-9706). Furthermore, our study showed that the oncoprotein c-Myc bound to the core promoter of TP53INP1 and recruited DNA methyltransferase 3A to methylate the local promoter region, leading to the inhibition of TP53INP1 expression. Our findings revealed that TP53INP1 is a tumor suppressor in ESCC and that c-Myc-mediated DNA methylation-associated silencing of TP53INP1 contributed to the pathogenesis of human ESCC.

  18. Analytical and clinical comparison of Elecsys syphilis (Roche(®)) - Architect syphilis TP and reformulated Architect syphilis TP (Abbott(®)) assay.

    Science.gov (United States)

    De Keukeleire, Steven; Desmet, Stefanie; Lagrou, Katrien; Oosterlynck, Julie; Verhulst, Manon; Van Besien, Jessica; Saegeman, Veroniek; Reynders, Marijke

    2017-03-01

    The performance of Elecsys Syphilis was compared to Architect Syphilis TP and Reformulated Architect Syphilis TP. The overall sensitivity and specificity were 98.4% and 99.5%, 97.7% and 97.1%, and 99.2% and 99.7% respectively. The assays are comparable and considered adequate for syphilis screening.

  19. High frequency of TP53 mutations in juvenile pilocytic astrocytomas indicates role of TP53 in the development of these tumors

    NARCIS (Netherlands)

    Hayes, VM; Dirven, CMF; Verlind, E; Molenaar, WM; Mooij, JJA; Hofstra, RMW; Buys, CHCM; Dam, A.

    1999-01-01

    In adults, the TP53 tumor suppressor gene is frequently mutated in astrocytic brain tumors which is supposed to represent an early event in their development. In juvenile pilocytic and low-grade astrocytomas, however, TP53 mutations have until now been reported as rare, which has led to the suggesti

  20. License - TP Atlas | LSDB Archive [Life Science Database Archive metadata

    Lifescience Database Archive (English)

    Full Text Available [ Credits ] BLAST Search Image Search Home About Archive Update History Contact us TP Atlas License Lice...nce with the terms and conditions of the license described below. The license specifies the license terms re...garding the use of this database and the requirements you must follow in using this database. The lice...rgeted Proteins Research Program licensed under CC Attribution-Share Alike 2.1 Ja...pan . The summary of the Creative Commons Attribution-Share Alike 2.1 Japan is found here . With regard to t

  1. DNA-PK Mediates AKT Activation and Apoptosis Inhibition in Clinically Acquired Platinum Resistance

    Directory of Open Access Journals (Sweden)

    Euan A. Stronach

    2011-11-01

    Full Text Available Clinical resistance to chemotherapy is a frequent event in cancer treatment and is closely linked to poor outcome. High-grade serous (HGS ovarian cancer is characterized by p53 mutation and high levels of genomic instability. Treatment includes platinum-based chemotherapy and initial response rates are high; however, resistance is frequently acquired, at which point treatment options are largely palliative. Recent data indicate that platinumresistant clones exist within the sensitive primary tumor at presentation, implying resistant cell selection after treatment with platinum chemotherapy. The AKT pathway is central to cell survival and has been implicated in platinum resistance. Here, we show that platinum exposure induces an AKT-dependent, prosurvival, DNA damage response in clinically platinum-resistant but not platinum-sensitive cells. AKT relocates to the nucleus of resistant cells where it is phosphorylated specifically on S473 by DNA-dependent protein kinase (DNA-PK, and this activation inhibits cisplatin-mediated apoptosis. Inhibition of DNA-PK or AKT, but not mTORC2, restores platinum sensitivity in a panel of clinically resistant HGS ovarian cancer cell lines: we also demonstrate these effects in other tumor types. Re-sensitization is associated with prevention of AKT-mediated BAD phosphorylation. Strikingly, in patient-matched sensitive cells, we do not see enhanced apoptosis on combining cisplatin with AKT or DNA-PK inhibition. Insulin-mediated activation of AKT is unaffected by DNA-PK inhibitor treatment, suggesting that this effect is restricted to DNA damage–mediated activation of AKT and that, clinically, DNA-PK inhibition might prevent platinum-induced AKT activation without interfering with normal glucose homeostasis, an unwanted toxicity of direct AKT inhibitors.

  2. Quantification of (R)-[{sup 11}C]PK11195 binding in rheumatoid arthritis

    Energy Technology Data Exchange (ETDEWEB)

    Kropholler, M.A.; Boellaard, R.; Kloet, R.W.; Lammertsma, A.A. [VU University Medical Centre, Department of Nuclear Medicine and PET Research, PO Box 7057, Amsterdam (Netherlands); Elzinga, E.H.; Voskuyl, A.E. [VU University Medical Centre, Department of Rheumatology, Amsterdam (Netherlands); Laken, C.J. van der; Dijkmans, B.A.C. [VU University Medical Centre, Department of Rheumatology, Amsterdam (Netherlands); Jan van Breemen Instituut, Amsterdam (Netherlands); Maruyama, K. [Osaka University Graduate School of Medicine, Department of Nuclear Medicine and Tracer Kinetics, Osaka (Japan)

    2009-04-15

    Rheumatoid arthritis (RA) involves migration of macrophages into inflamed areas. (R)-[{sup 11}C]PK11195 binds to peripheral benzodiazepine receptors, expressed on macrophages, and may be used to quantify inflammation using positron emission tomography (PET). This study evaluated methods for the quantification of (R)-[{sup 11}C]PK11195 binding in the knee joints of RA patients. Data from six patients with RA were analysed. Dynamic PET scans were acquired in 3-D mode following (R)-[{sup 11}C]PK11195 injection. During scanning arterial radioactivity concentrations were measured to determine the plasma (R)-[{sup 11}C]PK11195 concentrations. Data were analysed using irreversible and reversible one-tissue and two-tissue compartment models and input functions with various types of metabolite correction. Model preferences according to the Akaike information criterion (AIC) and correlations between measures were evaluated. Correlations between distribution volume (V{sub d}) and standardized uptake values (SUV) were evaluated. AIC indicated optimal performance for a one-tissue reversible compartment model including blood volume. High correlations were observed between V{sub d} obtained using different input functions (R {sup 2}=0.80-1.00) and between V{sub d} obtained with one- and two-tissue reversible compartment models (R {sup 2}=0.75-0.94). A high correlation was observed between optimal V{sub d} and SUV after injection (R {sup 2}=0.73). (R)-[{sup 11}C]PK11195 kinetics in the knee were best described by a reversible single-tissue compartment model including blood volume. Applying metabolite corrections did not increase sensitivity. Due to the high correlation with V{sub d}, SUV is a practical alternative for clinical use. (orig.)

  3. 朗格汉斯细胞组织细胞增生症中TP53蛋白表达及基因突变检测%Detection TP53 Protein Expression and Gene Mutation in Langerhans' Cell Histiocytosis

    Institute of Scientific and Technical Information of China (English)

    孙忠辉; 石梅; 李明; 余红

    2013-01-01

    Objective To determine whether TP53 gene plays a role in the pathogenesis of Langerhans' Cell Histiocytosis (LCH) ,we studied the expression of TP53 protein and mutation of TP53 gene in LCH biopsies. Methods The expression of TP53 protein was detected by immunohistochemical SP method in 38 cases of Langerhans cell histiocytosis. The mutation in TP53 gene exon 2 to 11 was identified by polymerase chain reaction and subsequently conformed by DNA sequencing in the 16 TP53 protein positive biopsies. Results TP53 protein expression was detected in 16/38(42. 11% ) LCH biopsies. In those biopsies, there were no significant difference between the average optical density of multisystem (MS,0. 120 6 ±0.008 8) and single-system (SS,0. 122 1 ±0.0030) respectively(P>0.05). No mutations in the TP53 gene exon 2 to 11 were detected in those positive biopsies. For genetic genotype of the polymorphism of TP53 gene codon 72, there were PRO in 3 cases,ARG in 5 cases, PRO/ARG in 8 cases in LCH group (TP53 protein positive). Compared with 40 normal controls,Chi-square analysis showed there was no significant difference for distribution of the three genotypes( P > 0. 05 ). Then, for the clinical classification, the cases of PRO, ARG and PRO/ ARG were 2,3 ,5 in MS and 1 ,2,3 in SS,respectively. Chi-square analysis also showed no significant differences (P>0. 05). Conclusion The TP53 protein is abnormally expressed in LCH,although there was no significant difference with the clinical classification. There is no TP53 gene mutation in LCH. The TP53 codon 72 genotype distribution was consistent with the normal population and not related with clinical classification. We speculate that the abnormality of TP53 gene expression in LCH may not result from gene mutation but an unknown mechanism.%目的 检测朗格汉斯细胞组织细胞增生症(LCH)中TP53蛋白表达和TP53基因全外显子突变,以探讨TP53在LCH发生发展中的作用机制.方法 应用免疫纽化SP法检测38例LCH中TP

  4. TP-model transformation-based-control design frameworks

    CERN Document Server

    Baranyi, Péter

    2016-01-01

    This book covers new aspects and frameworks of control, design, and optimization based on the TP model transformation and its various extensions. The author outlines the three main steps of polytopic and LMI based control design: 1) development of the qLPV state-space model, 2) generation of the polytopic model; and 3) application of LMI to derive controller and observer. He goes on to describe why literature has extensively studied LMI design, but has not focused much on the second step, in part because the generation and manipulation of the polytopic form was not tractable in many cases. The author then shows how the TP model transformation facilitates this second step and hence reveals new directions, leading to powerful design procedures and the formulation of new questions. The chapters of this book, and the complex dynamical control tasks which they cover, are organized so as to present and analyze the beneficial aspect of the family of approaches (control, design, and optimization). Additionally, the b...

  5. TP53 codon 72 polymorphism in pigmentary phenotypes

    Indian Academy of Sciences (India)

    Kárita Antunes Costa; Lidia Andreu Guillo

    2012-03-01

    The p53 protein exerts different cellular functions, and recent findings have demonstrated its influence on the cascade of skin pigmentation during UV exposure. Among TP53 gene polymorphisms, the most studied is the G to C transversion in exon 4 at codon 72, which results in three distinct genotypes, Arg/Arg, Pro/Pro and Arg/Pro, each one encoding different p53 isoforms. Therefore, this study aimed to determine the relationship between TP53 codon 72 polymorphism and skin protection against sunburn. Genomic DNA was extracted from peripheral blood samples and genotyping was performed by PCR and confirmed by restriction enzyme digestion. The genotype frequency was 50% for Arg/Arg and 14.6% for Pro/Pro genotype. The frequency of heterozygous subjects was 35.4%. In our population, p53 genotypes were in Hardy–Weinberg (HW) equilibrium ($\\chi^{2}_{\\text{HM}}$ < 3.84), showing a predominance of arginine allele (total Arg allele frequency of 68%). No significant association between p53 genotype and skin colour, hair or eye colour and susceptibility to sun exposure was found. However, further analysis demonstrated a significant association between the genotype Pro/Pro and blue/green eyes among participants who presented redness (=0.016). Our findings indicate susceptibility to sun exposure when this phenotype (eye colour) occurs simultaneously with Pro/Pro genotype.

  6. Total and unbound darunavir (DRV pharmacokinetics (PK in HIV-1-infected pregnant women

    Directory of Open Access Journals (Sweden)

    C Zorrilla

    2012-11-01

    Full Text Available Antiretroviral (ARV therapy during pregnancy is recommended to reduce the risk of mother-to-child transmission (MTCT. Physiologic changes during pregnancy can affect PK. We present the PK of total and unbound (pharmacologically active DRV in HIV-1-infected pregnant women receiving twice-daily (bid DRV/ritonavir (rtv. This Phase IIIb study enrolled HIV-1-infected pregnant women≥18 years old in the 2nd trimester of pregnancy receiving DRV/rtv 600/100 mg bid and other ARVs. DRV (total and unbound and rtv (total plasma concentrations were obtained predose and 1, 2, 3, 4, 6, 9 and 12 hours postdose during the 2nd and 3rd trimesters and postpartum. Total DRV and rtv plasma concentrations were determined using a previously validated HPLC-MS/MS assay (lower limit of quantification 5.00 ng/mL. Unbound DRV was determined by fortifying plasma samples with 14-C DRV and separating total and unbound DRV using ultrafiltration. Total and unbound 14-C DRV were measured using liquid scintillation counting. Total and unbound PK parameters were derived using a noncompartmental analysis. Safety and efficacy were investigated at each visit and summarized using descriptive statistics. Sixteen women (10 black, 4 Hispanic, 2 white were enrolled; 11 had evaluable PK data. Total DRV AUC12h was 24% and 17% lower during 2nd and 3rd trimesters, respectively, vs postpartum (Table. Unbound DRV AUC12h was unchanged during 2nd and 3rd trimesters vs postpartum. Total and unbound DRV Cmin increased by 43% and 10%, respectively, during 2nd trimester and by 86% and 14%, respectively, during 3rd trimester vs postpartum. Unbound DRV was above the EC50 (27.5 ng/mL for PI-resistant HIV in all patients. Albumin and α1-acid glycoprotein (AAG concentrations were 22%–29% lower during pregnancy vs postpartum. Viral load decreased and CD4+ count increased over time. One serious adverse event was reported (increased transaminase. Three of 12 infants were born prior to 37 weeks (30, 36 and

  7. BRAF和TP53基因热点突变的构建%Construction of Hot-spot Mutations in Human BRAF and TP53 Genes

    Institute of Scientific and Technical Information of China (English)

    张环宇; 王改平; 李晓芳; 姚谨; 陈倩倩; 樊路娟

    2014-01-01

    目的:构建BRAF和TP53基因多个位点的点突变质粒,为进一步研究其在肿瘤形成中的作用奠定基础.方法:以HEK-293T基因组DNA为模板构建含BRAF600、TP53175和TP53248位点的野生型质粒,利用MutanBESTTM定点突变方法获得含BRAFV600E、TP53R175C和TP53R248W等突变位点的突变型质粒,并进行DNA测序鉴定.结果:DNA测序结果显示构建的三个点突变与实验设计完全一致.结论:成功构建了BRAFV600E、TP53R175C和TP53R248W三个具有不同突变位点的突变型质粒,MutanBESTTM定点突变技术是一种简单、快速、高效的基因定点突变方法.

  8. Common polymorphisms in TP53 and MDM2 and the relationship to TP53 mutations and clinical outcomes in women with ovarian and peritoneal carcinomas.

    Science.gov (United States)

    Galic, Vijaya; Willner, Julia; Wollan, Melissa; Garg, Ruchi; Garcia, Rochelle; Goff, Barbara A; Gray, Heidi J; Swisher, Elizabeth M

    2007-03-01

    The importance of somatic TP53 mutations and germline TP53 codon 72 genotype in the survival of women with epithelial ovarian cancer is controversial. Recent data suggest that a promoter polymorphism in the MDM2 gene may influence age of cancer onset in a gender-specific fashion. We sought to determine the relationship between somatic TP53 mutations, germline genotypes at TP53 codon 72 and MDM2 SNP309, and overall survival and response to chemotherapy in a large series of patients with ovarian and peritoneal carcinomas. Of the 188 cancers, 103 (54.8%) had a TP53 mutation, of which 71% were missense mutations and 29% were null mutations. TP53 mutation status and mutation type (null vs. missense) did not influence response to therapy or overall survival. Women with the codon 72 Pro/Pro had a decreased overall survival (median, 29 months) compared with women with one or two arginine alleles (median, 49 months; P=0.04). Somatic mutation or deletion was equally common for either codon 72 allele. Age of diagnosis was not influenced by codon 72 but showed a trend for younger age in women with somatic TP53 mutations and the MDM2 G/G genotype. Copyright (c) 2006 Wiley-Liss, Inc.

  9. Two Novel Tunnel-based Ring Protection Switching for MPLS-TP Multicast Services

    DEFF Research Database (Denmark)

    Zhang, Jiang; Fu, Rong; Yu, Hao;

    2011-01-01

    This paper investigates and compares the schemes suggested by the ITU and the IETF for MPLS-TP ring protection, and proposes two MPLS-TP ring protections to ensure reliability of MPLS-TP multicast services. The introduced ring protection schemes are named, the SPME-based-Wrapping protection scheme...... and the SPME-based-ROM-Wrapping protection scheme, both of which aim at retaining the advantages of previous MPSL-TP ring protections and avoiding limitations. In the paper, the requirements of designing an efficient and reliable MPLS-TP ring protection, for instance with respect to label consumption......, bandwidth utilization and operation complexity are well considered and also set concrete evaluating criteria for new proposed MPLS-TP ring protection schemes for multicast services....

  10. Specific interaction of IP6 with human Ku70/80, the DNA-binding subunit of DNA-PK.

    Science.gov (United States)

    Hanakahi, Les A; West, Stephen C

    2002-04-15

    In eukaryotic cells, DNA double-strand breaks can be repaired by non-homologous end-joining, a process dependent upon Ku70/80, XRCC4 and DNA ligase IV. In mammals, this process also requires DNA-PK(cs), the catalytic subunit of the DNA-dependent protein kinase DNA-PK. Previously, inositol hexakisphosphate (IP6) was shown to be bound by DNA-PK and to stimulate DNA-PK-dependent end-joining in vitro. Here, we localize IP6 binding to the Ku70/80 subunits of DNA- PK, and show that DNA-PK(cs) alone exhibits no detectable affinity for IP6. Moreover, proteolysis mapping of Ku70/80 in the presence and absence of IP6 indicates that binding alters the conformation of the Ku70/80 heterodimer. The yeast homologue of Ku70/80, yKu70/80, fails to bind IP6, indicating that the function of IP6 in non-homologous end-joining, like that of DNA-PK(cs), is unique to the mammalian end-joining process.

  11. AMPD3-deficient mice exhibit increased erythrocyte ATP levels but anemia not improved due to PK deficiency.

    Science.gov (United States)

    Cheng, Jidong; Morisaki, Hiroko; Toyama, Keiko; Ikawa, Masahito; Okabe, Masaru; Morisaki, Takayuki

    2012-11-01

    AMP deaminase (AMPD) catalyzes AMP to IMP and plays an important role in energy charge and nucleotide metabolism. Human AMPD3 deficiency is a type of erythrocyte-specific enzyme deficiency found in individuals without clinical symptoms, although an increased level of ATP in erythrocytes has been reported. To better understand the physiological and pathological roles of AMPD3 deficiency, we established a line of AMPD3-deficient [A3(-/-)] mice. No AMPD activity and a high level of ATP were observed in erythrocytes of these mice, similar to human RBC-AMPD3 deficiency, while other characteristics were unremarkable. Next, we created AMPD3 and pyruvate kinase (PK) double-deficient [PKA(-/-,-/-)] mice by mating A3(-/-) mice with CBA-Pk-1slc/Pk-1slc mice [PK(-/-)], a spontaneous PK-deficient strain showing hemolytic anemia. In PKA(-/-,-/-) mice, the level of ATP in red blood cells was increased 1.5 times as compared to PK(-/-) mice, although hemolytic anemia in those animals was not improved. In addition, we observed osmotic fragility of erythrocytes in A3(-/-) mice under fasting conditions. In contrast, the ATP level in erythrocytes was elevated in A3(-/-) mice as compared to the control. In conclusion, AMPD3 deficiency increases the level of ATP in erythrocytes, but does not improve anemia due to PK deficiency and leads to erythrocyte dysfunction.

  12. Roles of TP53 in determining therapeutic sensitivity, growth, cellular senescence, invasion and metastasis.

    Science.gov (United States)

    McCubrey, James A; Lertpiriyapong, Kvin; Fitzgerald, Timothy L; Martelli, Alberto M; Cocco, Lucio; Rakus, Dariusz; Gizak, Agnieszka; Libra, Massimo; Cervello, Melchiorre; Montalto, Guiseppe; Yang, Li V; Abrams, Stephen L; Steelman, Linda S

    2017-01-01

    TP53 is a critical tumor suppressor gene that regulates cell cycle progression, apoptosis, cellular senescence and many other properties critical for control of normal cellular growth and death. Due to the pleiotropic effects that TP53 has on gene expression and cellular physiology, mutations at this tumor suppressor gene result in diverse physiological effects. T53 mutations are frequently detected in numerous cancers. The expression of TP53 can be induced by various agents used to treat cancer patients such as chemotherapeutic drugs and ionizing radiation. Radiation will induce Ataxia telangiectasia mutated (ATM) and other kinases that results in the phosphorylation and activation of TP53. TP53 is also negatively regulated by other mechanisms, such as ubiquitination by ligases such as MDM2. While TP53 has been documented to control the expression of many "classical" genes (e.g., p21(Cip-1), PUMA, Bax) by transcriptional mechanisms for quite some time, more recently TP53 has been shown to regulate microRNA (miR) gene expression. Different miRs can promote oncogenesis (oncomiR) whereas others act to inhibit tumor progression (tumor suppressor miRs). Targeted therapies to stabilize TP53 have been developed by various approaches, MDM2/MDM4 inhibitors have been developed to stabilize TP53 in TP53-wild type (WT) tumors. In addition, small molecules have been isolated that will reactivate certain mutant TP53s. Both of these types of inhibitors are in clinical trials. Understanding the actions of TP53 may yield novel approaches to suppress cancer, aging and other health problems.

  13. Prognostic value of TP/PD-ECGF and thrombocytosis in gastric carcinoma.

    Science.gov (United States)

    Wang, L; Huang, X; Chen, Y; Jin, X; Li, Q; Yi, T N

    2012-07-01

    Thymidine phosphorylase/platelet-derived endothelial cell growth factor (TP/PD-ECGF) is upregulated in several cancers and plays an important role in angiogenesis and invasion of solid tumors. In this study, we investigated the expression of TP/PD-ECGF in gastric carcinoma and its correlation with clinicopathological features and thrombocytosis, and also determined their prognostic significance. Ninety-eight tissue specimens were resected from patients with gastric carcinoma. The immunohistochemical staining was used for expression of TP/PD-ECGF, platelet counts (PLT) of all patients before surgery were recorded. Patients were divided into high and low TP/PD-ECGF expression groups. Correlations among TP/PD-ECGF expression, PLT and the clinicopathological features of the patients and their prognostic values were studied statistically. Sixty-one cases of high TP/PD-ECGF expression (62%) and 37 cases of low TP/PD-ECGF expression (38%) were detected. There were 21 patients with thrombocytosis (21%). The results show that high TP/PD-ECGF expression was correlated positively with thrombocytosis (P = 0.046, r = 0.20). The 5-year overall survival rate was 46.0% in patients with low TP/PD-ECGF expression, whereas it was only 14.8% in patients with high TP/PD-ECGF expression (P = 0.000). The 5-year survival rate for patients with and without thrombocytosis were 9.5% and 31.2%, respectively, and there was a significant difference between them (P = 0.0001). The multivariate Cox regression analysis showed that high TP/PD-ECGF expression and thrombocytosis would play a role as independent prognostic factors in patients with gastric carcinoma. High TP/PD-ECGF expression and thrombocytosis can be regarded as valuable tools for predicting overall survival in patients with gastric carcinoma. Copyright © 2012 Elsevier Ltd. All rights reserved.

  14. Nuclear imaging of neuroinflammation: a comprehensive review of [{sup 11}C]PK11195 challengers

    Energy Technology Data Exchange (ETDEWEB)

    Chauveau, Fabien; Camp, Nadja van; Tavitian, Bertrand [Service Hospitalier Frederic Joliot, Laboratoire d' Imagerie Moleculaire Experimentale, CEA, Institut d' Imagerie BioMedicale, Orsay (France); INSERM, U803, Orsay (France); Boutin, Herve [University of Manchester, Faculty of Life Sciences, Manchester (United Kingdom); Dolle, Frederic [Service Hospitalier Frederic Joliot, Laboratoire d' Imagerie Moleculaire Experimentale, CEA, Institut d' Imagerie BioMedicale, Orsay (France)

    2008-12-15

    Neurodegenerative, inflammatory and neoplastic brain disorders involve neuroinflammatory reactions, and a biomarker of neuroinflammation would be useful for diagnostic, drug development and therapy control of these frequent diseases. In vivo imaging can document the expression of the peripheral benzodiazepine receptor (PBR)/translocator protein 18 kDa (TSPO) that is linked to microglial activation and considered a hallmark of neuroinflammation. The prototype positron emission tomography tracer for PBR, [{sup 11}C]PK11195, has shown limitations that until now have slowed the clinical applications of PBR imaging. In recent years, dozens of new PET and SPECT radioligands for the PBR have been radiolabelled, and several have been evaluated in imaging protocols. Here we review the new PBR ligands proposed as challengers of [{sup 11}C]PK11195, critically analyze preclinical imaging studies and discuss their potential as neuroinflammation imaging agents. (orig.)

  15. PaDEL-DDPredictor: open-source software for PD-PK-T prediction.

    Science.gov (United States)

    He, Yuye; Liew, Chin Yee; Sharma, Nitin; Woo, Sze Kwang; Chau, Yi Ting; Yap, Chun Wei

    2013-03-15

    ADMET (absorption, distribution, metabolism, excretion, and toxicity)-related failure of drug candidates is a major issue for the pharmaceutical industry today. Prediction of PD-PK-T properties using in silico tools has become very important in pharmaceutical research to reduce cost and enhance efficiency. PaDEL-DDPredictor is an in silico tool for rapid prediction of PD-PK-T properties of compounds from their chemical structures. It is free and open-source software that, has both graphical user interface and command line interface, can work on all major platforms (Windows, Linux, and MacOS) and supports more than 90 different molecular file formats. The software can be downloaded from http://padel.nus.edu.sg/software/padelddpredictor.

  16. Construction of cytopathic PK-15 cell model of classical swine fever virus

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    No cytopathic effect (CPE) can be observed on classical swine fever virus (CSFV) infected cell culture in vitro. This brings an obstacle to the researches on reciprocity between CSFV and host cells. Based on the construction of full-length genomic infectious Cdna clone of Chinese CSFV standard virulent Shimen strain, partial deletion is intro- duced into genomic Cdna to obtain a 7.5 kb subgenomic Cdna. A new subgenomic CSFV is derived from transfection with the subgenomic Cdna on PK-15 cells pre-infected by CSFV Shimen virus. Typical CPE induced by this subgenomic virus is observed on PK-15 cells. Coexistence of wild- type and subgenomic virus in cytopathic cell culture is dem- onstrated by RT-PCR detection in cytopathic cells. For conclusion, the construction of cytopathic cell model exploited a new way for researches on the molecular mechanism of CSFV pathogenesis.

  17. Low Prevalence of TP53 Mutations and MDM2 Amplifications in Pediatric Rhabdomyosarcoma

    Directory of Open Access Journals (Sweden)

    Simona Ognjanovic

    2012-01-01

    Full Text Available The tumor suppressor gene TP53 is the most commonly mutated gene in human cancer. The reported prevalence of mutations in rhabdomyosarcoma (RMS varies widely, with recent larger studies suggesting that TP53 mutations in pediatric RMS may be extremely rare. Overexpression of MDM2 also attenuates p53 function. We have performed TP53 mutation/MDM2 amplification analyses in the largest series analyzed thus far, including DNA isolated from 37 alveolar and 38 embryonal RMS tumor samples obtained from the Cooperative Human Tissue Network (CHTN. Available samples were frozen tumor tissues (N=48 and histopathology slides. TP53 mutations in exons 4–9 were analyzed by direct sequencing in all samples, and MDM2 amplification analysis was performed by differential PCR on a subset of 22 samples. We found only one sample (1/75, 1.3% carrying a TP53 mutation at codon 259 (p.D259Y and no MDM2 amplification. Two SNPs in the TP53 pathway, associated with accelerated tumor onset in germline TP53 mutation carriers, (TP53 SNP72 (rs no. 1042522 and MDM2 SNP309 (rs no. 2279744, were not found to confer earlier tumor onset. In conclusion, we confirm the extremely low prevalence of TP53 mutations/MDM2 amplifications in pediatric RMS (1.33% and 0%, respectively. The possible inactivation of p53 function by other mechanisms thus remains to be elucidated.

  18. TP53 Mutations and Survival in Osteosarcoma Patients: A Meta-Analysis of Published Data

    Directory of Open Access Journals (Sweden)

    Zhe Chen

    2016-01-01

    Full Text Available Several research groups have examined the association between TP53 mutations and prognosis in human osteosarcoma. However, the results were controversial. The purpose of this study was to evaluate the prognostic value of TP53 mutations in osteosarcoma patients. A meta-analysis was conducted with all eligible studies which quantitatively evaluated the relationship between TP53 mutations and clinical outcome of osteosarcoma patients. Eight studies with a total of 210 patients with osteosarcoma were included in this meta-analysis. The risk ratio (RR with a 95% confidence interval (95% CI was calculated to assess the effect of TP53 mutations on 2-year overall survival. The quantitative synthesis of 8 published studies showed that TP53 mutations were associated with 2-year overall survival in osteosarcoma patients. These data suggested that TP53 mutations had an unfavorable impact on 2-year overall survival when compared to the counterparts with wild type (WT TP53 (RR: 1.79; 95% CI: 1.12 to 2.84; P=0.01; I2=0%. There was no between-study heterogeneity. TP53 mutations are an effective prognostic marker for survival of patients with osteosarcoma. However, further large-scale prospective trials should be performed to clarify the prognostic value of TP53 mutations on 3- or 5-year survival in osteosarcoma patients.

  19. TP53 mutation spectrum in smokers and never smoking lung cancer patients

    Directory of Open Access Journals (Sweden)

    Ann Rita Halvorsen

    2016-05-01

    Full Text Available AbstractBackground: TP53 mutations are among the most common mutations found in lung cancers, identified as an independent prognostic factor in many types of cancers. The purpose of this study was to investigate the frequency and prognostic impact of TP53 mutations in never-smokers and in different histological subtypes of lung cancer.Methods: We analysed tumour tissue from 394 non-small cell carcinomas including adenocarcinomas (n=229, squamous cell carcinomas (n=112, large cell carcinomas (n=30 and others (n=23 for mutations in TP53 by the use of Sanger sequencing (n=394 and next generation sequencing (n=100. Results: TP53 mutations were identified in 47.2% of the samples, with the highest frequency (65% of mutations among squamous cell carcinomas. Among never-smokers, 36% carried a TP53 mutation, identified as a significant independent negative prognostic factor in this subgroup. For large cell carcinomas, a significantly prolonged progression free survival was found for those carrying a TP53 mutation. In addition, the frequency of frameshift mutations was doubled in squamous cell carcinomas (20.3% compared to adenocarcinomas (9.1%.Conclusion: TP53 mutation patterns differ between the histological subgroups of lung cancers, as also influenced by smoking history. This indicates that the histological subtypes in lung cancer are genetically different, and that smoking-induced TP53 mutations may have a different biological impact than TP53 mutations occurring in never-smokers.

  20. TP53 Mutations and Survival in Osteosarcoma Patients: A Meta-Analysis of Published Data.

    Science.gov (United States)

    Chen, Zhe; Guo, Jiayi; Zhang, Kun; Guo, Yanxing

    2016-01-01

    Several research groups have examined the association between TP53 mutations and prognosis in human osteosarcoma. However, the results were controversial. The purpose of this study was to evaluate the prognostic value of TP53 mutations in osteosarcoma patients. A meta-analysis was conducted with all eligible studies which quantitatively evaluated the relationship between TP53 mutations and clinical outcome of osteosarcoma patients. Eight studies with a total of 210 patients with osteosarcoma were included in this meta-analysis. The risk ratio (RR) with a 95% confidence interval (95% CI) was calculated to assess the effect of TP53 mutations on 2-year overall survival. The quantitative synthesis of 8 published studies showed that TP53 mutations were associated with 2-year overall survival in osteosarcoma patients. These data suggested that TP53 mutations had an unfavorable impact on 2-year overall survival when compared to the counterparts with wild type (WT) TP53 (RR: 1.79; 95% CI: 1.12 to 2.84; P = 0.01; I (2) = 0%). There was no between-study heterogeneity. TP53 mutations are an effective prognostic marker for survival of patients with osteosarcoma. However, further large-scale prospective trials should be performed to clarify the prognostic value of TP53 mutations on 3- or 5-year survival in osteosarcoma patients.

  1. Analysis of RPR and TP-ELISA joint inspection for pregnant syphilis%RPR与TP-ELISA联检对产妇梅毒检测结果分析

    Institute of Scientific and Technical Information of China (English)

    陈俊; 楼跃民; 朱笑频; 余斐斐

    2013-01-01

    目的:为了研究RPR与TP-ELISA检测方对产妇梅毒在临床上的检测价值.方法:对3479例产妇,进行RPR、TP-ELISA和TPPA检测.结果:RPR与TP-ELISA检测结果比较有显著性差异,P<0.01.在本组资料中,RPR真阳性15例(0.43%),TP-ELISA真阳性118例(3.39%),TPPA真阳性118例(3.39%).TP-ELISA试验共有6例假阳性,占0.17%,假阴性无,而RPR试验共有12例假阳性,占0.34%,而假阴性103例,占2.96%.在3479例产妇中,RPR的总符合率为96.69%,灵敏度为12.71%,特异度为99.64%;TP-ELISA的总符合率为99.83%,灵敏度为100.00%,特异度为99.82%.结论:TP-ELISA敏感性高于RPR,因此可用高质量的TP-ELISA和RPR试剂对产妇进行筛查,应用TPPA试剂确证,可进一步保证医疗质量.TP-ELISA有高的敏感性和特异性,是产妇梅毒检测中的一个好的筛查方法.%Objective:To evaluate the rapid plasma reagin agglutination test (RPR) and Treponema pallidum enzyme - linked immunosorbent assay (TP - ELJSA) for the detection of pregnant syphilis in a clinical setting. Methods : Plasma and serum samples from 3479 pregnant women were tested for the presence of Treponema pallidum antigens by RPR and TP - ELISA and TPPA. Results: A statistical significant (P <0.01) difference in test results were found between the RPR and TP - ELJSA method. When using the RPR test, 15 cases (0.43%) were found positive, while 118 cases (3.39%) were found positive with the TP - ELISA and TPPA test. When the RPR test was used, there were 12 (0.34%) false positive samples and 103 false negative samples (2.96%), respectively, while 6 (0.17%) false positive samples and no false negative samples were found with TP - ELISA. The total coincidence rate of the RPR test was 96.69%, and the sensitivity was 12.71% and the specificity was 99.64%; The total coincidence rate of the TP - ELISA test was 99.83%, and the sensitivity was 100.00% and the specificity was 99.82%. Conclusion: The TP - ELISA was more

  2. Evolution of asymptotic giant branch stars II. Optical to far-infrared isochrones with improved TP-AGB models

    CERN Document Server

    Marigo, Paola; Bressan, Alessandro; Groenewegen, Martin A T; Silva, Laura; Granato, Gian Luigi

    2007-01-01

    We present a large set of theoretical isochrones, whose distinctive features mostly reside on the greatly improved treatment of the thermally pulsing asymptotic giant branch (TP-AGB) phase. Essentially, we have coupled the TP-AGB tracks described in Paper I, at their stages of pre-flash quiescent H-shell burning, with the evolutionary tracks for the previous evolutionary phases from Girardi et al. (2000). Theoretical isochrones for any intermediate value of age and metallicity are then derived by interpolation in the grids. We take care that the isochrones keep, to a good level of detail, the several peculiarities present in these TP-AGB tracks. Theoretical isochrones are then converted to about 20 different photometric systems -- including traditional ground-based systems, and those of recent major wide-field surveys such as SDSS, OGLE, DENIS, 2MASS, UKIDSS, etc., -- by means of synthetic photometry applied to an updated library of stellar spectra, suitably extended to include C-type stars. Finally, we corre...

  3. Integration of preclinical and clinical knowledge to predict intravenous PK in human: bilastine case study.

    Science.gov (United States)

    Vozmediano, Valvanera; Ortega, Ignacio; Lukas, John C; Gonzalo, Ana; Rodriguez, Monica; Lucero, Maria Luisa

    2014-03-01

    Modern pharmacometrics can integrate and leverage all prior proprietary and public knowledge. Such methods can be used to scale across species or comparators, perform clinical trial simulation across alternative designs, confirm hypothesis and potentially reduce development burden, time and costs. Crucial yet typically lacking in integration is the pre-clinical stage. Prediction of PK in man, using in vitro and in vivo studies in different animal species, is increasingly well theorized but could still find wider application in drug development. The aim of the present work was to explore methods for bridging pharmacokinetic knowledge from animal species (i.v. and p.o.) and man (p.o.) into i.v. in man using the antihistamine drug bilastine as example. A model, predictive of i.v. PK in man, was developed on data from two pre-clinical species (rat and dog) and p.o. in man bilastine trials performed earlier. In the knowledge application stage, two different approaches were used to predict human plasma concentration after i.v. of bilastine: allometry (several scaling methods) and a semi-physiological method. Both approaches led to successful predictions of key i.v. PK parameters of bilastine in man. The predictive i.v. PK model was validated using later data from a clinical study of i.v. bilastine. Introduction of such knowledge in development permits proper leveraging of all emergent knowledge as well as quantification-based exploration of PK scenario, e.g. in special populations (pediatrics, renal insufficiency, comedication). In addition, the methods permit reduction or elimination and certainly optimization of learning trials, particularly those concerning alternative off-label administration routes.

  4. Responses of Bog Vegetation and CO2 Exchange to Experimental N and PK Addition

    Science.gov (United States)

    Juutinen, S.; Bubier, J. L.; Shrestha, P.; Smith, R.; Moore, T.

    2008-12-01

    Atmospheric nitrogen (N) deposition has the potential to alter the structure and functioning of nutrient poor wetland ecosystems. It is important to quantify the effect of N input on ecosystem carbon (C) sequestration in these globally important C storages. We address this issue at the temperate Mer Bleue bog, ON, Canada. After 6 years of experimental fertilization, we saw that high N deposition can change mixed Sphagnum and dwarf shrub dominated communities to taller and denser dwarf shrub communities that are losing moss cover, and which might have even lower net C uptake. Now, after 8 years of fertilization and with new treatments we quantify the relationship between the plant community structure and ecosystem CO2 exchange. Three levels of N fertilization were applied with or without phosphorus and potassium (PK) into triplicate plots. We measured light saturated net ecosystem CO2 exchange (NEE), and its components ecosystem respiration and gross photosynthesis using clear and dark chambers (May-August). Vegetation characteristics were quantified by measuring foliage cover (LAI), amount of woody and foliar biomass, and abundance of moss species (point interception technique), moss growth (cranked wires) and green area of vascular leaves and moss. Addition of PK fertilizer did not alter NEE or its components relative to the control. The 8-year low N addition alone and with PK, and the 4-year fertilization with high N levels resulted in the highest net ecosystem CO2 uptake relative to the control. The ecosystem respiration increased with increasing N input rate. All levels of N fertilization resulted in higher gross photosynthesis than the control, but there was no increasing trend with increasing N input. Vascular foliage increased, while moss cover drastically decreased with increasing levels of N fertilization. At the highest level of N (and PK) addition woody biomass increased at the expense of leaf increment. Dependencies of ecosystem CO2 exchange on the

  5. A Population Pharmacokinetic (Pk- Pharmacodynamic (Pd Analysis Of Peginesatide India Lysis Patients With Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Himanshu Naik

    2012-06-01

    Total bilirubin, body mass index, age, alkaline phosphatase, ethnicity, and serum creatinine (for non-dialysis subjects for PK and age and ESAD for PD were identified as statistically significant (p-value<0.005 covariates. None of these identified covariates were considered to be clinically relevant, based on their impact on simulated peginesatide exposure (<±30% and Hb (<0.2 g/dL levels.

  6. L2TP VPN分析及配置

    Institute of Scientific and Technical Information of China (English)

    陈金莲

    2012-01-01

    在微软的Windows Server 2005中,集成了VPN技术,可以实现Site to Site VPN和L2TPVPN、PPTPVPN两种形式的Eemote Access VPN,其中L2TPVPN、PPTPVPN比较常用。虽然对于大型企业而言,用Windows Server 2003做VPN的可能性不大,但对于小型企业或个人用户来说,用这种VPN实现远程接入不失为一个较好的解决方案。下面,笔者就个人配置经历来详细解析一下L2TP VPN及配置要点。

  7. Applications of TP-AGB synthesis to Mira variables

    Institute of Scientific and Technical Information of China (English)

    Chun-Hua Zhu; Guo-Liang Lü; Zhao-Jun Wang; Jun Zhang

    2009-01-01

    Employing recent TP-AGB synthesis, we have carried out a detailed study of Mira variables by means of a population synthesis code. We estimate that the total number of Mira variables in the Galaxy is from about 100 000 to 600 000 and their average lifetimes are between about 150 000 and 830 000 yr. The ratio of the number of O-Mira variables to that of C-Mira variables ranges from about 0.68 to 6.2. The effects of input physical parameters (mass loss rate, the minimum core mass for the third dredge-up, the third dredge-up efficiency and theoretical criterion for selecting Mira variables) on the Mira population are discussed.

  8. Arabidopsis D6PK is a lipid domain-dependent mediator of root epidermal planar polarity.

    Science.gov (United States)

    Stanislas, Thomas; Hüser, Anke; Barbosa, Inês C R; Kiefer, Christian S; Brackmann, Klaus; Pietra, Stefano; Gustavsson, Anna; Zourelidou, Melina; Schwechheimer, Claus; Grebe, Markus

    2015-11-02

    Development of diverse multicellular organisms relies on coordination of single-cell polarities within the plane of the tissue layer (planar polarity). Cell polarity often involves plasma membrane heterogeneity generated by accumulation of specific lipids and proteins into membrane subdomains. Coordinated hair positioning along Arabidopsis root epidermal cells provides a planar polarity model in plants, but knowledge about the functions of proteo-lipid domains in planar polarity signalling remains limited. Here we show that Rho-of-plant (ROP) 2 and 6, phosphatidylinositol-4-phosphate 5-kinase 3 (PIP5K3), DYNAMIN-RELATED PROTEIN (DRP) 1A and DRP2B accumulate in a sterol-enriched, polar membrane domain during root hair initiation. DRP1A, DRP2B, PIP5K3 and sterols are required for planar polarity and the AGCVIII kinase D6 PROTEIN KINASE (D6PK) is a modulator of this process. D6PK undergoes phosphatidylinositol-4,5-bisphosphate- and sterol-dependent basal-to-planar polarity switching into the polar, lipid-enriched domain just before hair formation, unravelling lipid-dependent D6PK localization during late planar polarity signalling.

  9. PK-PD modeling of β-lactam antibiotics: in vitro or in vivo models?

    Science.gov (United States)

    de Araujo, Bibiana Verlindo; Diniz, Andrea; Palma, Eduardo Célia; Buffé, Cândida; Dalla Costa, Teresa

    2011-06-01

    A modified E(max)-pharmacokinetic-pharmacodynamic (PK-PD) model was previously proposed in literature for describing the antimicrobial activity of β-lactam antibiotics based on in vitro experiments. However, bacteria behave differently in vitro and in vivo. Thus, the aims of this study were to model the killing effect of piperacillin (PIP) against Escherichia coli on immunocompromised infected rats using this model and to compare the parameters obtained in vitro and in vivo for the same bacteria/drug combination. The PK-PD parameters determined in vitro and in vivo were as follows: generation rate constant of 1.30 ± 0.10 and 0.76 ± 0.20 h(-1), maximum killing effect of 3.11 ± 0.27 and 1.38 ± 0.20 h(-1) and concentration to produce 50% of the maximum effect of 5.44 ± 0.03 and 1.31 ± 0.27 μg ml(-1), respectively. The comparison between the in vitro and in vivo parameters was not straightforward and had to take into consideration the intrinsic differences of the models involved. So far, the main application of the PK-PD model evaluated is for the comparison of different antimicrobial agent's potency and efficacy, under equivalent conditions.

  10. Molecular cloning of NHE3 from LLC-PK1 cells and localization in pig kidney.

    Science.gov (United States)

    Shugrue, C A; Obermüller, N; Bachmann, S; Slayman, C W; Reilly, R F

    1999-08-01

    LLC-PK1 cells, an established line from pig kidney, express basolateral and apical Na+/H+ exchangers that can be distinguished by their differing sensitivities to the amiloride analog N-ethyl-N-isopropylamiloride (EIPA). It has been shown previously that the basolateral exchanger is encoded by NHE1. In the present study, a combination of reverse transcription-PCR, 5' RACE, and genomic library screening was used to clone the coding region of the porcine NHE3 gene. There was significant homology between the LLC-PK1 sequence and the previously reported rabbit and rat NHE3 genes, with nucleotide and deduced amino acid identities of 87 and 85% in rabbit, and 85 and 87% in rat, respectively. To study expression patterns, Northern analysis was carried out using an NHE3 cDNA to probe poly(A)+ RNA isolated from LLC-PK1 cells, and from pig kidney cortex. In all three cases, a major transcript of 6.1 kb was detected along with two minor transcripts of 4.7 and 3.8 kb. In situ hybridization with two different NHE3 probes gave intense labeling of the distal convoluted tubule in pig kidney but (unexpectedly) no detectable labeling of the proximal tubule. These studies suggest that there are marked species differences in NHE3 expression in the distal nephron.

  11. TP53 mutations induced by BPDE in Xpa-WT and Xpa-Null human TP53 knock-in (Hupki) mouse embryo fibroblasts.

    Science.gov (United States)

    Kucab, Jill E; van Steeg, Harry; Luijten, Mirjam; Schmeiser, Heinz H; White, Paul A; Phillips, David H; Arlt, Volker M

    2015-03-01

    Somatic mutations in the tumour suppressor gene TP53 occur in more than 50% of human tumours; in some instances exposure to environmental carcinogens can be linked to characteristic mutational signatures. The Hupki (human TP53 knock-in) mouse embryo fibroblast (HUF) immortalization assay (HIMA) is a useful model for studying the impact of environmental carcinogens on TP53 mutagenesis. In an effort to increase the frequency of TP53-mutated clones achievable in the HIMA, we generated nucleotide excision repair (NER)-deficient HUFs by crossing the Hupki mouse with an Xpa-knockout (Xpa-Null) mouse. We hypothesized that carcinogen-induced DNA adducts would persist in the TP53 sequence of Xpa-Null HUFs leading to an increased propensity for mismatched base pairing and mutation during replication of adducted DNA. We found that Xpa-Null Hupki mice, and HUFs derived from them, were more sensitive to the environmental carcinogen benzo[a]pyrene (BaP) than their wild-type (Xpa-WT) counterparts. Following treatment with the reactive metabolite of BaP, benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), Xpa-WT and Xpa-Null HUF cultures were subjected to the HIMA. A significant increase in TP53 mutations on the transcribed strand was detected in Xpa-Null HUFs compared to Xpa-WT HUFs, but the TP53-mutant frequency overall was not significantly different between the two genotypes. BPDE induced mutations primarily at G:C base pairs, with approximately half occurring at CpG sites, and the predominant mutation type was G:C>T:A in both Xpa-WT and Xpa-Null cells. Further, several of the TP53 mutation hotspots identified in smokers' lung cancer were mutated by BPDE in HUFs (codons 157, 158, 245, 248, 249, 273). Therefore, the pattern and spectrum of BPDE-induced TP53 mutations in the HIMA are consistent with TP53 mutations detected in lung tumours of smokers. While Xpa-Null HUFs exhibited increased sensitivity to BPDE-induced damage on the transcribed strand, NER-deficiency did not enhance TP53

  12. TP-ELISA法对梅毒检测的诊断学评价%The diagnostic evaluation of TP-ELISA for detecting syphilis

    Institute of Scientific and Technical Information of China (English)

    杨小华; 李丽莉; 赵夏丰

    2010-01-01

    目的 评估梅毒螺旋体抗体酶联免疫吸附试验(Treponema pallidum antibody enzyme-linked immunosorbent assay TP-ELISA)在梅毒检测中的诊断价值.方法 用梅毒螺旋体明胶凝集法(Treponema pallidum particle agglutination test TPPA)与TP-ELISA法对60例住院及门诊梅毒患者血清和50例健康体检者血清分别进行检测,以TPPA法作为参比方法.结 TP-ELISA法与TPPA法检测梅毒结果差异无显著性(P>0.05),并且两者有极好的一致性(Kw=0.8541.TP-ELISA的诊断敏感性(Se)为90%、诊断特异性(Sp)为96.8%、阳性预告值(+PV)为97.2%、阴性预告值(-PV)为88.77%.结论 TP-ELISA法与TPPA法对梅毒检测结果总体上一致,是临床理想的筛查方法,适用于大批量样本检查.%Objective To evaluate the diagnosis value of TP-ELISA for detecting syphilis. Methods The serum samples from 60 patients with syphilis and 50 healthy individuals were detected by TPPA and TP-ELISA; TPPA was used as a reference test. Results There was no significant difference in the test results between TP-ELISA and TPPA (P>0.05). Two tests had excellent consistency (Kw = 0.854). The sensitivity of TP-ELISA was 90%, specificity was 96.8%, positive predictive value was 97.2%, and negative predictive value was 88.77%. Conclusions The test results of TP-ELISA for detecting syphilis are generally consistent with those of TPPA. TP-ELISA is an ideal test for clinical screening and suitable for large sample detection.

  13. Outcomes in patients with multiple myeloma with TP53 deletion after autologous hematopoietic stem cell transplant.

    Science.gov (United States)

    Gaballa, Sameh; Saliba, Rima M; Srour, Samer; Lu, Gary; Brammer, Jonathan E; Shah, Nina; Bashir, Qaiser; Patel, Krina; Bock, Fabian; Parmar, Simrit; Hosing, Chitra; Popat, Uday; Delgado, Ruby; Rondon, Gabriela; Shah, Jatin J; Manasanch, Elisabet E; Orlowski, Robert Z; Champlin, Richard; Qazilbash, Muzaffar H

    2016-10-01

    TP53 gene deletion is associated with poor outcomes in multiple myeloma (MM). We report the outcomes of patients with MM with and without TP53 deletion who underwent immunomodulatory drug (IMiD) and/or proteasome inhibitor (PI) induction followed by autologous hematopoietic stem cell transplant (auto-HCT). We identified 34 patients with MM and TP53 deletion who underwent IMiD and/or PI induction followed by auto-HCT at our institution during 2008-2014. We compared their outcomes with those of control patients (n = 111) with MM without TP53 deletion. Median age at auto-HCT was 59 years in the TP53-deletion group and 58 years in the control group (P = 0.4). Twenty-one patients (62%) with TP53 deletion and 69 controls (62%) achieved at least partial remission before auto-HCT (P = 0.97). Twenty-three patients (68%) with TP53 deletion and 47 controls (42%) had relapsed disease at auto-HCT (P = 0.01). Median progression-free survival was 8 months for patients with TP53 deletion and 28 months for controls (P TP53 deletion and 56 months for controls (P TP53 deletion (hazard ratio 3.4, 95% confidence interval 1.9-5.8, P TP53 deletion and relapsed disease at the time of auto-HCT are independent predictors of progression. Novel approaches should be evaluated in this high-risk population. Am. J. Hematol. 91:E442-E447, 2016. © 2016 Wiley Periodicals, Inc.

  14. The Tp0684 (MglB-2) Lipoprotein of Treponema pallidum: A Glucose-Binding Protein with Divergent Topology.

    Science.gov (United States)

    Brautigam, Chad A; Deka, Ranjit K; Liu, Wei Z; Norgard, Michael V

    2016-01-01

    Treponema pallidum, the bacterium that causes syphilis, is an obligate human parasite. As such, it must acquire energy, in the form of carbon sources, from the host. There is ample evidence that the principal source of energy for this spirochete is D-glucose acquired from its environment, likely via an ABC transporter. Further, there is genetic evidence of a D-glucose chemotaxis system in T. pallidum. Both of these processes may be dependent on a single lipidated chemoreceptor: Tp0684, also called TpMglB-2 for its sequence homology to MglB of Escherichia coli. To broaden our understanding of this potentially vital protein, we determined a 2.05-Å X-ray crystal structure of a soluble form of the recombinant protein. Like its namesake, TpMglB-2 adopts a bilobed fold that is similar to that of the ligand-binding proteins (LBPs) of other ABC transporters. However, the protein has an unusual, circularly permuted topology. This feature prompted a series of biophysical studies that examined whether the protein's topological distinctiveness affected its putative chemoreceptor functions. Differential scanning fluorimetry and isothermal titration calorimetry were used to confirm that the protein bound D-glucose in a cleft between its two lobes. Additionally, analytical ultracentrifugation was employed to reveal that D-glucose binding is accompanied by a significant conformational change. TpMglB-2 thus appears to be fully functional in vitro, and given the probable central importance of the protein to T. pallidum's physiology, our results have implications for the viability and pathogenicity of this obligate human pathogen.

  15. Anomalous altered expressions of downstream gene-targets in TP53-miRNA pathways in head and neck cancer.

    Science.gov (United States)

    Mitra, Sanga; Mukherjee, Nupur; Das, Smarajit; Das, Pijush; Panda, Chinmay Kumar; Chakrabarti, Jayprokas

    2014-01-01

    The prevalence of head and neck squamous cell carcinoma, HNSCC, continues to grow. Change in the expression of TP53 in HNSCC affects its downstream miRNAs and their gene targets, anomalously altering the expressions of the five genes, MEIS1, AGTR1, DTL, TYMS and BAK1. These expression alterations follow the repression of TP53 that upregulates miRNA-107, miRNA- 215, miRNA-34 b/c and miRNA-125b, but downregulates miRNA-155. The above five so far unreported genes are the targets of these miRNAs. Meta-analyses of microarray and RNA-Seq data followed by qRT-PCR validation unravel these new ones in HNSCC. The regulatory roles of TP53 on miRNA-155 and miRNA-125b differentiate the expressions of AGTR1 and BAK1in HNSCC vis-à-vis other carcinogenesis. Expression changes alter cell cycle regulation, angiogenic and blood cell formation, and apoptotic modes in affliction. Pathway analyses establish the resulting systems-level functional and mechanistic insights into the etiology of HNSCC.

  16. Anomalous altered expressions of downstream gene-targets in TP53-miRNA pathways in head and neck cancer

    Science.gov (United States)

    Mitra, Sanga; Mukherjee, Nupur; Das, Smarajit; Das, Pijush; Panda, Chinmay Kumar; Chakrabarti, Jayprokas

    2014-01-01

    The prevalence of head and neck squamous cell carcinoma, HNSCC, continues to grow. Change in the expression of TP53 in HNSCC affects its downstream miRNAs and their gene targets, anomalously altering the expressions of the five genes, MEIS1, AGTR1, DTL, TYMS and BAK1. These expression alterations follow the repression of TP53 that upregulates miRNA-107, miRNA- 215, miRNA-34 b/c and miRNA-125b, but downregulates miRNA-155. The above five so far unreported genes are the targets of these miRNAs. Meta-analyses of microarray and RNA-Seq data followed by qRT-PCR validation unravel these new ones in HNSCC. The regulatory roles of TP53 on miRNA-155 and miRNA-125b differentiate the expressions of AGTR1 and BAK1in HNSCC vis-à-vis other carcinogenesis. Expression changes alter cell cycle regulation, angiogenic and blood cell formation, and apoptotic modes in affliction. Pathway analyses establish the resulting systems-level functional and mechanistic insights into the etiology of HNSCC. PMID:25186767

  17. A DNA-dependent stress response involving DNA-PK occurs in hypoxic cells and contributes to cellular adaptation to hypoxia.

    Science.gov (United States)

    Bouquet, Fanny; Ousset, Marielle; Biard, Denis; Fallone, Frédérique; Dauvillier, Stéphanie; Frit, Philippe; Salles, Bernard; Muller, Catherine

    2011-06-01

    DNA-dependent protein kinase (DNA-PK) is involved in DNA double-strand break (DSB) signalling and repair. We report that DNA-PK is activated by mild hypoxia conditions (0.1-1% O₂) as shown by (1) its autophosphorylation on Ser2056, and (2) its mobilisation from a soluble nucleoplasmic compartment to a less extractable nuclear fraction. The recruitment of DNA-PK was not followed by activation and recruitment of the XRCC4-DNA-ligase-IV complex, suggesting that DSBs are not responsible for activation of DNA-PK. To unravel the mechanism of DNA-PK activation, we show that exposure of cells to trichostatin A, a histone deacetylase inhibitor, leads to DNA-PK autophosphorylation and relocalisation to DNA. Histone acetylation (mainly H3K14) is increased in hypoxic cells and treatment with anacardic acid, an inhibitor of histone acetyl transferase, prevented both histone modifications and DNA-PK activation in hypoxic conditions. Importantly, in using either silenced DNA-PK cells or cells exposed to a specific DNA-PK inhibitor (NU7026), we demonstrated that hypoxic DNA-PK activation positively regulates the key transcription factor HIF-1 and one subsequent target gene, GLUT1. Our results show that hypoxia initiates chromatin modification and consequently DNA-PK activation, which positively regulate cellular oxygen-sensing and oxygen-signalling pathways.

  18. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations

    DEFF Research Database (Denmark)

    Rausch, Tobias; Jones, David T W; Zapatka, Marc

    2012-01-01

    of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals...

  19. Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study.

    NARCIS (Netherlands)

    Iacopetta, B.; Russo, A.; Bazan, V.; Dardanoni, G.; Gebbia, N.; Soussi, T.; Kerr, D.J.; Elsaleh, H.; Soong, R.; Kandioler, D.; Janschek, E.; Kappel, S.; Lung, M.; Leung, C.S.; Ko, J.M.; Yuen, S.; Ho, J.; Leung, S.Y.; Crapez, E.; Duffour, J.; Ychou, M.; Leahy, D.T.; O'Donoghue, D.P.; Agnese, V.; Cascio, S.; Fede, G. Di; Chieco-Bianchi, L.; Bertorelle, R.; Belluco, C.; Giaretti, W.; Castagnola, P.; Ricevuto, E.; Ficorella, C.; Bosari, S.; Arizzi, C.D.; Miyaki, M.; Onda, M.; Kampman, E.; Diergaarde, B.; Royds, J.; Lothe, R.A.; Diep, C.B.; Meling, G.I.; Ostrowski, J.; Trzeciak, L.; Guzinska-Ustymowicz, K.; Zalewski, B.; Capella, G.M.; Moreno, V.; Peinado, M.A.; Lonnroth, C.; Lundholm, K.; Sun, X.F.; Jansson, A.; Bouzourene, H.; Hsieh, L.L.; Tang, R.; Smith, D.R.; Allen-Mersh, T.G.; Khan, Z.A.; Shorthouse, A.J.; Silverman, M.L.; Kato, S.; Ishioka, C.

    2006-01-01

    BACKGROUND: Loss of TP53 function through gene mutation is a critical event in the development and progression of many tumour types including colorectal cancer (CRC). In vitro studies have found considerable heterogeneity amongst different TP53 mutants in terms of their transactivating abilities. Th

  20. Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study

    NARCIS (Netherlands)

    Iacopetta, B.; Russo, A.; Bazan, V.; Kampman, E.; Diergaarde, B.

    2006-01-01

    Background: Loss of TP53 function through gene mutation is a critical event in the development and progression of many tumour types including colorectal cancer (CRC). In vitro studies have found considerable heterogeneity amongst different TP53 mutants in terms of their transactivating abilities. Th

  1. Bioinformatic dissecting of TP53 regulation pathway underlying butyrate-induced histone modification in epigenetic regulation

    Science.gov (United States)

    Butyrate affects cell proliferation, differentiation and motility. Butyrate inhibits histone deacetylase (HDAC) activities and induces cell cycle arrest and apoptosis. TP53 is one of the most active upstream regulators discovered by IPA in our RNA sequencing data set. The TP53 signaling pathway pl...

  2. Calibrating the role of TP-AGB stars in the cosmic matter cycle

    CERN Document Server

    Marigo, Paola

    2014-01-01

    In the last ten years three main facts about the thermally pulsing asymptotic giant branch (TP-AGB) have become evident: 1) the modelling of the TP-AGB phase is critical for the derivation of basic galaxy properties (e.g. mass and age) up to high redshift, with consequent cosmological implications; 2) current TP-AGB calibrations based on Magellanic Cloud (MC) clusters come out not to work properly for other external galaxies, yielding a likely TP-AGB overestimation; 3) the significance of the TP-AGB contribution in galaxies, hence their derived properties, are strongly debated, with conflicting claims in favour of either a heavy or a light TP-AGB. The only way out of this condition of persisting uncertainty is to perform a reliable calibration of the TP-AGB phase as a function of the star's initial mass (hence age) over a wide range of metallicity, from very low to super-solar values. In this context, I will review recent advancements and ongoing efforts towards a physically-sound TP-AGB calibration that, mov...

  3. Absence of mutations in the coding sequence of the potential tumor suppressor 3pK in metastatic melanoma

    Directory of Open Access Journals (Sweden)

    Houben Roland

    2005-12-01

    Full Text Available Abstract Background Activation of Ras or Raf contributes to tumorigenesis of melanoma. However, constitutive Raf activation is also a characteristic of the majority of benign melanocytic nevi and high intensity signaling of either Ras or Raf was found to induce growth inhibition and senescence rather than transformation. Since the chromosome 3p kinase (3pK is a target of the Ras/Raf/Mek/Erk signaling pathway which antagonizes the function of the oncogene and anti-differentiation factor Bmi-1, 3pK may function as a tumor suppressor in tumors with constitutive Ras/Raf activation. Consequently, we tested whether inactivating 3pK mutations are present in melanoma. Methods 30 metastatic melanoma samples, which were positive for activating mutations of either BRaf or NRas, were analyzed for possible mutations in the 3pk gene. The 10 coding exons and their flanking intron sequences were amplified by PCR and direct sequencing of the PCR products was performed. Results This analysis revealed that besides the presence of some single nucleotide polymorphisms in the 3pk gene, we could not detect any possible loss of function mutation in any of these 30 metastatic melanoma samples selected for the presence of activating mutations within the Ras/Raf/Mek/Erk signaling pathway. Conclusion Hence, in melanoma with constitutively active Ras/Raf inactivating mutations within the 3pk gene do not contribute to the oncogenic phenotype of this highly malignant tumor.

  4. Study on the Clinical Application Value of the tM2-PK in the colorectal cancer%tM2-PK 在结直肠癌的应用价值临床研究

    Institute of Scientific and Technical Information of China (English)

    叶红

    2016-01-01

    Objective To study the tumor pyruvate kinase (tM2-PK)expression and its relationship with clinico-pathological characteristics of colorectal cancer in patients with colorectal cancer.Methods 49 cases of colorectal cancer patients for the study,next to the immunohistochemistry cancer tissue and cancer tissue tM2-PK expression and cancer research organizations tM2-PK and serum tM2-PK levels in patients with correlation analysis tM2-PK colorectal cancer patients with pathological relationship.Results 49 cases of tissue tM2-PK positive rate of colorectal cancer in patients with cancer and adjacent tissues respectively 81.6%,42.9%,there was significant difference (P 0.05)at different ages,gender,and different degrees of differentiation on tM2-PK positive rate;40 cases of colorectal cancer cancer tissues tM2-PK-positive pa-tients,with an average score 7.53 ± 1.94,serum concentrations tM2-PK 26.59 ± 10.24,a positive correlation,r =0.876,P =0.0015,statistically significant (P <0.05).Conclusion tM2-PK in the early diagnosis of colorectal cancer, as well as assess the prognosis of the disease and has good prospects.%目的:研究肿瘤型丙酮酸激酶(tM2-PK)在结直肠癌患者表达情况及其与结直肠癌临床病理特征的关系。方法以49例结直肠癌患者为研究对象,免疫组化检测癌组织以及癌旁组织 tM2-PK 表达情况,并研究癌组织 tM2-PK 与患者血清 tM2-PK 水平相关性,分析 tM2-PK 与结直肠癌患者病理特征关系。结果49例结直肠癌患者癌组织与癌旁组织 tM2-PK 阳性率分别为81.6%、42.9%,两者存在统计学差异(P <0.05);结直肠癌组织最大Φ≥5 cm结直肠癌 tM2-PK 阳性率高于最大Φ<5 cm 结直肠癌,在 TNM 分期中Ⅲ+Ⅳ期 tM2-PK 阳性率高于Ⅰ+Ⅱ期,不同Duck 分期上 C+D 期 tM2-PK 阳性率高于 A+B 期;在不同年龄、性别以及不同分化程度上 tM2-PK 阳性率无统计学差异(P >0.05);40

  5. TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth.

    Science.gov (United States)

    Haricharan, Svasti; Brown, Powel

    2015-06-23

    Breast cancer is a leading cause of cancer-related death, and it is important to understand pathways that drive the disease to devise effective therapeutic strategies. Our results show that Toll-like receptor 4 (TLR4) drives breast cancer cell growth differentially based on the presence of TP53, a tumor suppressor. TP53 is mutationally inactivated in most types of cancer and is mutated in 30-50% of diagnosed breast tumors. We demonstrate that TLR4 activation inhibits growth of TP53 wild-type cells, but promotes growth of TP53 mutant breast cancer cells by regulating proliferation. This differential effect is mediated by changes in tumor cell cytokine secretion. Whereas TLR4 activation in TP53 mutant breast cancer cells increases secretion of progrowth cytokines, TLR4 activation in TP53 wild-type breast cancer cells increases type I IFN (IFN-γ) secretion, which is both necessary and sufficient for mediating TLR4-induced growth inhibition. This study identifies a novel dichotomous role for TLR4 as a growth regulator and a modulator of tumor microenvironment in breast tumors. These results have translational relevance, demonstrating that TP53 mutant breast tumor growth can be suppressed by pharmacologic TLR4 inhibition, whereas TLR4 inhibitors may in fact promote growth of TP53 wild-type tumors. Furthermore, using data generated by The Cancer Genome Atlas consortium, we demonstrate that the effect of TP53 mutational status on TLR4 activity may extend to ovarian, colon, and lung cancers, among others, suggesting that the viability of TLR4 as a therapeutic target depends on TP53 status in many different tumor types.

  6. Isolation and characterization of DkPK genes associated with natural deastringency in C-PCNA persimmon

    Directory of Open Access Journals (Sweden)

    Changfei eGuan

    2016-02-01

    Full Text Available Chinese pollination-constant nonastringent (C-PCNA persimmon (Diospyros kaki Thunb. is considered to be an important germplasm resource for the breeding of PCNA cultivars, though its molecular mechanisms of astringency removal remain to be elucidated. Previously, we showed that the abundance of pyruvate kinase gene (PK transcripts increased rapidly during astringency removal in C-PCNA persimmon fruit. Here, we report the full-length coding sequences (CDS of six novel DkPK genes from C-PCNA persimmon fruit isolated based on a complementary DNA (cDNA library and transcriptome data. The expression patterns of these six DkPK genes and correlations with the soluble proanthocyanidin (PA content were analyzed during various fruit development stages in different types of persimmon, with DkPK1 showing an expression pattern during the last stage in C-PCNA persimmon that was positively correlated with a decrease in soluble PAs. Phylogenetic analysis revealed that DkPK1 belongs to cytosolic-1 subgroup, and subcellular localization analysis confirmed that DkPK1 is located in the cytosol. Notably, tissue expression profiling revealed ubiquitous DkPK1 expression in different persimmon organs, with the highest expression in seeds. Furthermore, transient over-expression of DkPK1 in persimmon leaves resulted in a significant decrease in the content of soluble PAs but a significant increase in the transcript levels of pyruvate decarboxylase genes (DkPDC1, -3, -4, -5, which catalyze the conversion of pyruvate to acetaldehyde. Thus, we propose that an acetaldehyde-based coagulation effect reduces the content of soluble PAs. Taken together, our results suggest that DkPK1 might be involved in the natural removal of astringency at the last developmental stage in C-PCNA persimmon. This is the first report to identify several novel full-length DkPK genes as well as their potential roles in the natural loss of astringency in C-PCNA persimmon.

  7. Fracture toughness evaluations of TP304 stainless steel pipes

    Energy Technology Data Exchange (ETDEWEB)

    Rudland, D.L.; Brust, F.W.; Wilkowski, G.M. [Battelle, Columbus, OH (United States)

    1997-02-01

    In the IPIRG-1 program, the J-R curve calculated for a 16-inch nominal diameter, Schedule 100 TP304 stainless steel (DP2-A8) surface-cracked pipe experiment (Experiment 1.3-3) was considerably lower than the quasi-static, monotonic J-R curve calculated from a C(T) specimen (A8-12a). The results from several related investigations conducted to determine the cause of the observed toughness difference are: (1) chemical analyses on sections of Pipe DP2-A8 from several surface-cracked pipe and material property specimen fracture surfaces indicate that there are two distinct heats of material within Pipe DP2-A8 that differ in chemical composition; (2) SEN(T) specimen experimental results indicate that the toughness of a surface-cracked specimen is highly dependent on the depth of the initial crack, in addition, the J-R curves from the SEN(T) specimens closely match the J-R curve from the surface-cracked pipe experiment; (3) C(T) experimental results suggest that there is a large difference in the quasi-static, monotonic toughness between the two heats of DP2-A8, as well as a toughness degradation in the lower toughness heat of material (DP2-A8II) when loaded with a dynamic, cyclic (R = {minus}0.3) loading history.

  8. [11C]-(R)-PK11195 positron emission tomography in patients with complex regional pain syndrome

    Science.gov (United States)

    Jeon, So Yeon; Seo, Seongho; Lee, Jae Sung; Choi, Soo-Hee; Lee, Do-Hyeong; Jung, Ye-Ha; Song, Man-Kyu; Lee, Kyung-Jun; Kim, Yong Chul; Kwon, Hyun Woo; Im, Hyung-Jun; Lee, Dong Soo; Cheon, Gi Jeong; Kang, Do-Hyung

    2017-01-01

    Abstract Complex regional pain syndrome (CRPS) is characterized by severe and chronic pain, but the pathophysiology of this disease are not clearly understood. The primary aim of our case–control study was to explore neuroinflammation in patients with CRPS using positron emission tomography (PET), with an 18-kDa translocator protein specific radioligand [11C]-(R)-PK11195. [11C]-(R)-PK11195 PET scans were acquired for 11 patients with CRPS (30–55 years) and 12 control subjects (30–52 years). Parametric image of distribution volume ratio (DVR) for each participant was generated by applying a relative equilibrium-based graphical analysis. The DVR of [11C]-(R)-PK11195 in the caudate nucleus (t(21) = −3.209, P = 0.004), putamen (t(21) = −2.492, P = 0.022), nucleus accumbens (t(21) = −2.218, P = 0.040), and thalamus (t(21) = −2.395, P = 0.026) were significantly higher in CRPS patients than in healthy controls. Those of globus pallidus (t(21) = −2.045, P = 0.054) tended to be higher in CRPS patients than in healthy controls. In patients with CRPS, there was a positive correlation between the DVR of [11C]-(R)-PK11195 in the caudate nucleus and the pain score, the visual analog scale (r = 0.661, P = 0.026, R2 = 0.408) and affective subscales of McGill Pain Questionnaire (r = 0.604, P = 0.049, R2 = 0.364). We demonstrated that neuroinflammation of CRPS patients in basal ganglia. Our results suggest that microglial pathology can be an important pathophysiology of CRPS. Association between the level of caudate nucleus and pain severity indicated that neuroinflammation in this region might play a key role. These results may be essential for developing effective medical treatments. PMID:28072713

  9. A PK-PD model of ketamine-induced high-frequency oscillations

    Science.gov (United States)

    Flores, Francisco J.; Ching, ShiNung; Hartnack, Katharine; Fath, Amanda B.; Purdon, Patrick L.; Wilson, Matthew A.; Brown, Emery N.

    2015-10-01

    Objective. Ketamine is a widely used drug with clinical and research applications, and also known to be used as a recreational drug. Ketamine produces conspicuous changes in the electrocorticographic (ECoG) signals observed both in humans and rodents. In rodents, the intracranial ECoG displays a high-frequency oscillation (HFO) which power is modulated nonlinearly by ketamine dose. Despite the widespread use of ketamine there is no model description of the relationship between the pharmacokinetic-pharmacodynamics (PK-PDs) of ketamine and the observed HFO power. Approach. In the present study, we developed a PK-PD model based on estimated ketamine concentration, its known pharmacological actions, and observed ECoG effects. The main pharmacological action of ketamine is antagonism of the NMDA receptor (NMDAR), which in rodents is accompanied by an HFO observed in the ECoG. At high doses, however, ketamine also acts at non-NMDAR sites, produces loss of consciousness, and the transient disappearance of the HFO. We propose a two-compartment PK model that represents the concentration of ketamine, and a PD model based in opposing effects of the NMDAR and non-NMDAR actions on the HFO power. Main results. We recorded ECoG from the cortex of rats after two doses of ketamine, and extracted the HFO power from the ECoG spectrograms. We fit the PK-PD model to the time course of the HFO power, and showed that the model reproduces the dose-dependent profile of the HFO power. The model provides good fits even in the presence of high variability in HFO power across animals. As expected, the model does not provide good fits to the HFO power after dosing the pure NMDAR antagonist MK-801. Significance. Our study provides a simple model to relate the observed electrophysiological effects of ketamine to its actions at the molecular level at different concentrations. This will improve the study of ketamine and rodent models of schizophrenia to better understand the wide and divergent

  10. Phenotypes of PK2/PKR2 heterozygosis mutant mice%前动力蛋白2/前动力蛋白受体2基因杂合突变小鼠表型特征

    Institute of Scientific and Technical Information of China (English)

    肖玲; 周闻白; 周群勇; 胡仁明

    2012-01-01

    目的 观察前动力蛋白(PK2)、前动力蛋白受体2(PKR2)基因单拷贝丢失后小鼠生长发育及生殖系统发育情况.方法 对比观察PK2+/-、PKR2+/-、以及PK2+/-∶PKR2+/-复合杂合突变小鼠与野生型小鼠体重增长、外生殖器发育情况;免疫荧光染色法观察四组小鼠颅内促性腺激素释放激素(GnRH)神经元分布;阴道冲洗细胞涂片评估法观察小鼠动情周期. 结果 三组杂合突变小鼠体重增长、外生殖器发育及颅内GnRH神经元分布与野生型小鼠相比均无显著差异,但杂合突变小鼠动情周期延长、无规律,双基因杂合突变小鼠表现最明显. 结论 PK2、PKR2基因单拷贝丢失后虽不影响小鼠生殖系统和GnRH神经元发育,但雌鼠表现出动情周期紊乱.因此PK2/PKR2通路对生殖系统功能有调节作用.%Objective; To observe the phenotype changes including weight growth and reproductive system development in PK2/PKR2 heterozygosis mutant mice. Methods; The weight gain and external genitalia development were compared between the three heterozygosis mutant mice groups and the wild type group. GnRH neurons distribution was observed by fluorescent staining method in four groups. The stage of estrus cycle was determined by cytologic evaluation of vaginal smears. The vaginal exfoliate cells were smeared on glass slides, and the cytologic features were evaluated under microscopy Results; There were no changes in weight growth, external genitalia development and the GnRH neurons distribution in brain between the three mutant mice groups and the wild type mice group. The length of estrus cycle was extended in heterogeneous mice, especially in PK2/PKR2 heterogeneous mutation mice. Conclusions: Loss of one copy of PK2 or PKR2 gene did not change reproductive system and GnRH neurons development except estrous cycle. So PK2/PKR2 pathway may play roles in the regulation of reproductive system function.

  11. 乳糖诱导胸腺融合肽Tα1-TP5在大肠杆菌中的表达%Expression of Tα1-TP5 fusion peptide in E.coli induced by lactose

    Institute of Scientific and Technical Information of China (English)

    谢琦; 李娟; 王凤山

    2012-01-01

    目的 研究用乳糖替代异丙基-β-D-硫代吡喃半乳糖苷(IPTG)作为诱导剂诱导胸腺融合肽Tα1-TP5表达,并优化诱导表达条件.方法 在摇瓶发酵条件下,以乳糖作为诱导剂,SDS-PAGE电泳和AlphaEase凝胶电泳图像分析系统研究培养基组成、诱导剂浓度、诱导时机、诱导时间、诱导温度和诱导方式等条件对目的肽Tα1 -TP5表达量的影响,并与IPTG诱导结果相比较.结果 选用TB培养基,在菌体对数生长的中后期加入终浓度为1 g/L的乳糖,37℃诱导6h,GST-Tα1 -TP5融合蛋白的表达量约占菌体总蛋白的35%,且主要以可溶形式表达,与IPTG的诱导结果相同.分批流加乳糖4次和一次性加入乳糖诱导,融合蛋白表达量无明显差异.结论 乳糖可以替代IPTG诱导胸腺融合肽Tα1-TP5的表达.%Purpose To study the use of lactose instead of IPTG as the inducer for the expression of recombinant thymosin 1-thymopentin fusion peptide (Tα1-TP5 ), and to optimize the expression conditions. Methods Under the shake flask fermentation conditions, the influence of culture medium, inducer concentration, induction starting time, induction time, induction temperature and induction method on the expression level of target protein was analyzed by SDS-PAGE electrophoresis and AlphaEase gel electro-phoresis image analysis system, and results were compared with those induced by IPTG. Results When using TB as the medium, adding final induction concentration of 1 g/L of lactose to the middle and late logarithmic phase of bacteria to induce for 6 h at 37℃ ,the GST-Tα1-TP5 fusion protein accounted for 35% of the bacterial total protein,mainly in a soluble form,and the expression level was the same as that induced by IPTG. The result of adding lactose once had no significant diffience compared with that of adding four times. Conclusion Lactose can be used as the inducer instead of IPTG for the expression of Tα1-TP5.

  12. Insights into the potential function and membrane organization of the TP0435 (Tp17) lipoprotein from Treponema pallidum derived from structural and biophysical analyses.

    Science.gov (United States)

    Brautigam, Chad A; Deka, Ranjit K; Liu, Wei Z; Norgard, Michael V

    2015-01-01

    The sexually transmitted disease syphilis is caused by the bacterial spirochete Treponema pallidum. This microorganism is genetically intractable, accounting for the large number of putative and undercharacterized members of the pathogen's proteome. In an effort to ascribe a function(s) to the TP0435 (Tp17) lipoprotein, we engineered a soluble variant of the protein (rTP0435) and determined its crystal structure at a resolution of 2.42 Å. The structure is characterized by an eight-stranded β-barrel protein with a shallow "basin" at one end of the barrel and an α-helix stacked on the opposite end. Furthermore, there is a disulfide-linked dimer of the protein in the asymmetric unit of the crystals. Solution hydrodynamic experiments established that purified rTP0435 is monomeric, but specifically forms the disulfide-stabilized dimer observed in the crystal structure. The data herein, when considered with previous work on TP0435, imply plausible roles for the protein in either ligand binding, treponemal membrane architecture, and/or pathogenesis.

  13. TP53 drives invasion through expression of its Δ133p53β variant

    Science.gov (United States)

    Gadea, Gilles; Arsic, Nikola; Fernandes, Kenneth; Diot, Alexandra; Joruiz, Sébastien M; Abdallah, Samer; Meuray, Valerie; Vinot, Stéphanie; Anguille, Christelle; Remenyi, Judit; Khoury, Marie P; Quinlan, Philip R; Purdie, Colin A; Jordan, Lee B; Fuller-Pace, Frances V; de Toledo, Marion; Cren, Maïlys; Thompson, Alastair M

    2016-01-01

    TP53 is conventionally thought to prevent cancer formation and progression to metastasis, while mutant TP53 has transforming activities. However, in the clinic, TP53 mutation status does not accurately predict cancer progression. Here we report, based on clinical analysis corroborated with experimental data, that the p53 isoform Δ133p53β promotes cancer cell invasion, regardless of TP53 mutation status. Δ133p53β increases risk of cancer recurrence and death in breast cancer patients. Furthermore Δ133p53β is critical to define invasiveness in a panel of breast and colon cell lines, expressing WT or mutant TP53. Endogenous mutant Δ133p53β depletion prevents invasiveness without affecting mutant full-length p53 protein expression. Mechanistically WT and mutant Δ133p53β induces EMT. Our findings provide explanations to 2 long-lasting and important clinical conundrums: how WT TP53 can promote cancer cell invasion and reciprocally why mutant TP53 gene does not systematically induce cancer progression. DOI: http://dx.doi.org/10.7554/eLife.14734.001 PMID:27630122

  14. TP53 mutations predict decitabine-induced complete responses in patients with myelodysplastic syndromes.

    Science.gov (United States)

    Chang, Chun-Kang; Zhao, You-Shan; Xu, Feng; Guo, Juan; Zhang, Zheng; He, Qi; Wu, Dong; Wu, Ling-Yun; Su, Ji-Ying; Song, Lu-Xi; Xiao, Chao; Li, Xiao

    2017-02-01

    To identify the molecular signatures that predict responses to decitabine (DAC), we examined baseline gene mutations (28 target genes) in 109 myelodysplastic syndrome (MDS) patients at diagnosis. We determined that TP53 mutations predicted complete response (CR), as 10 of 15 patients (66·7%) who possessed TP53 mutations achieved a CR. Univariate and multivariate analyses showed that TP53 mutations are the only molecular signatures predictive of a CR to DAC in MDS. Among the ten patients with TP53 mutations who achieved a CR, nine presented with complex karyotypes due to abnormalities involving chromosome 5 and/or chromosome 7, and eight possessed monosomies. Although TP53 mutations were associated with a higher frequency of CRs, they were not associated with improved survival. Poor outcomes were attributed to early relapses and transformation to acute myeloid leukaemia after CR. Post-DAC therapy patient gene mutation profiles showed that most CR patients exhibited fewer gene mutations after achieving a CR. It seems that suppression of these gene mutations was facilitated by DAC, resulting in a CR. In summary, TP53 mutations might predict decitabine-induced complete responses in patients with MDS. DAC-induced responses may result from partial suppression of malignant clones containing mutated TP53 genes.

  15. Tracking sub-clonal TP53 mutated tumor cells in human metastatic renal cell carcinoma.

    Science.gov (United States)

    Bousquet, Guilhem; El Bouchtaoui, Morad; Leboeuf, Christophe; Battistella, Maxime; Varna, Mariana; Ferreira, Irmine; Plassa, Louis-François; Hamdan, Diaddin; Bertheau, Philippe; Feugeas, Jean-Paul; Damotte, Diane; Janin, Anne

    2015-08-07

    Renal Cell Carcinomas (RCCs) are heterogeneous tumors with late acquisition of TP53 abnormalities during their evolution. They harbor TP53 abnormalities in their metastases. We aimed to study TP53 gene alterations in tissue samples from primary and metastatic RCCs in 36 patients followed up over a median of 4.2 years, and in xenografted issued from primary RCCs. In 36 primary RCCs systematically xenografted in mice, and in biopsies of metastases performed whenever possible during patient follow-up, we studied p53-expressing tumor cells and TP53 gene abnormalities.We identified TP53 gene alterations in primary tumors, metastases and xenografts. Quantification of tumors cells with TP53 gene alterations showed a significant increase in the metastases compared to the primary RCCs, and, strikingly, the xenografts were similar to the metastases and not to the primary RCCs from which they were derived.Using laser-microdissection of p53-expressing tumor cells, we identified TP53-mutated tumor cells in the xenografts derived from the primary RCC, and in a lung metastasis later developed in one patient. The mutation enabled us to track back their origin to a minority sub-clone in the primary heterogeneous RCC. Combining in situ and molecular analyses, we demonstrated a clonal expansion in a living patient with metastatic RCC.

  16. LAMP3 and TP53 overexpression predicts poor outcome in laryngeal squamous cell carcinoma.

    Science.gov (United States)

    Qiu, Xiaoxia; You, Yiwen; Huang, Jianfei; Wang, Xudong; Zhu, Huijun; Wang, Zhiwei

    2015-01-01

    Lysosomal associated membrane protein 3 (LAMP3) is a newly identified tumor-specific and hypoxia-induced protein. It is a downstream target gene of tumor suppressor TP53 and its expression has been associated with hypoxia-induced metastasis and poor overall survival in cervical, breast and gastrointestinal cancers. However, little is known of LAMP3 protein expression in laryngeal squamous cell carcinoma (LSCC) and its prognostic value. We determined protein expression of LAMP3 and TP53 in LSCC tissues (n=117) by immunohistochemistry analysis on tissue microarray (TMA), their expression was correlated with patients' clinical parameters and overall survival. LAMP3 and TP53 protein expression was significantly higher in cancerous tissues compared to adjacent normal surgical margin tissues. Both high LAMP3 and high TP53 protein expression was significantly associated with tumor stage and size. Significant correlation between LAMP3 and TP53 expression was observed. Patients with high LAMP3 or high TP53 expression had a poor overall survival. Our data suggest that both epithelial LAMP3 expression and TP53 expression are independent prognostic markers for LSCC.

  17. YAF2 promotes TP53-mediated genotoxic stress response via stabilization of PDCD5.

    Science.gov (United States)

    Park, Soo-Yeon; Choi, Hyo-Kyoung; Jo, Seong-Ho; Seo, JaeSung; Han, Eun-Jeong; Choi, Kyung-Chul; Jeong, Jae-Wook; Choi, Youngsok; Yoon, Ho-Geun

    2015-05-01

    Programmed cell death 5 (PDCD5) plays a crucial role in TP53-mediated apoptosis, but the regulatory mechanism of PDCD5 itself during apoptosis remains obscure. We identified YY1-associated factor 2 (YAF2) as a novel PDCD5-interacting protein in a yeast two-hybrid screen for PDCD5-interacting proteins. We found that YY1-associated factor 2 (YAF2) binds to and increases PDCD5 stability by inhibiting the ubiquitin-dependent proteosomal degradation pathway. However, knocking-down of YAF2 diminishes the levels of PDCD5 protein but not the levels of PDCD5 mRNA. Upon genotoxic stress response, YAF2 promotes TP53 activation via association with PDCD5. Strikingly, YAF2 failed to promote TP53 activation in the deletion of PDCD5, whereas restoration of wild-type PDCD5WT efficiently reversed the ineffectiveness of YAF2 on TP53 activation. Conversely, PDCD5 efficiently overcame the knockdown effect of YAF2 on ET-induced TP53 activation. Finally, impaired apoptosis upon PDCD5 ablation was substantially rescued by restoration of PDCD5WT but not YAF2-interacting defective PDCD5E4D nor TP53-interacting defective PDCD5E16D mutant. Our findings uncovered an apoptotic signaling cascade linking YAF2, PDCD5, and TP53 during genotoxic stress responses.

  18. Prevalence of low-penetrant germline TP53 D49H mutation in Japanese cancer patients.

    Science.gov (United States)

    Yamaguchi, Ken; Urakami, Kenichi; Nagashima, Takeshi; Shimoda, Yuji; Ohnami, Shumpei; Ohnami, Sumiko; Ohshima, Keiichi; Mochizuki, Tohru; Hatakeyama, Keiichi; Serizawa, Masakuni; Akiyama, Yasuto; Maruyama, Kouji; Katagiri, Hirohisa; Ishida, Yuji; Takahashi, Kaoru; Nishimura, Seiichiro; Terashima, Masanori; Kawamura, Taiichi; Kinugasa, Yusuke; Yamakawa, Yushi; Onitsuka, Tetsuro; Ohde, Yasuhisa; Sugino, Takashi; Ito, Ichiro; Matsubayashi, Hiroyuki; Horiuchi, Yasue; Mizuguchi, Maki; Yamazaki, Mutsumi; Inoue, Kengo; Wakamatsu, Kimiko; Sugiyama, Misato; Uesaka, Katsuhiko; Kusuhara, Masatoshi

    2016-01-01

    Using whole exome sequencing data obtained from 1,685 Japanese cancer patients, we examined genetic variations of germline TP53 and found 10 types of non-synonymous single nucleotide variants. In the present study, we focused on 6 patients with germline D49H mutation located in the transactivation domain 2 of p53 protein, since the mutation seemed to be prevalent in cancer patients and to be pathogenic. According to the initial survey for family history of the proband with the germline TP53 D49H mutation, one osteosarcoma patient and his pedigree fulfill the criteria for Li-Fraumeni-like syndrome and the 2009 Chompret criteria for germline TP53 mutation screening. Since this patient possesses double germline mutations of TP53 D49H and A159D, further studies are required to evaluate contribution of the D49H mutation in this morbidity. The remaining 5 patients had family histories of cancer, but none fulfills the criteria either for the Li-Fraumeni/Li-Fraumeni-like syndromes or the 2009 Chompret criteria for germline TP53 mutation screening. It is possible to postulate that the germline TP53 D49H mutation is likely to be low-penetrant in some pedigrees. The present study also indicates that the survey for the germline TP53 mutation plays an important role in clinical practice as it will prevent mistaking cancer patients with unusual heredities for sporadic cases.

  19. Transglutaminase 2 contributes to a TP53-induced autophagy program to prevent oncogenic transformation.

    Science.gov (United States)

    Yeo, Shi Yun; Itahana, Yoko; Guo, Alvin Kunyao; Han, Rachel; Iwamoto, Kozue; Nguyen, Hung Thanh; Bao, Yi; Kleiber, Kai; Wu, Ya Jun; Bay, Boon Huat; Voorhoeve, Mathijs; Itahana, Koji

    2016-03-09

    Genetic alterations which impair the function of the TP53 signaling pathway in TP53 wild-type human tumors remain elusive. To identify new components of this pathway, we performed a screen for genes whose loss-of-function debilitated TP53 signaling and enabled oncogenic transformation of human mammary epithelial cells. We identified transglutaminase 2 (TGM2) as a putative tumor suppressor in the TP53 pathway. TGM2 suppressed colony formation in soft agar and tumor formation in a xenograft mouse model. The depletion of growth supplements induced both TGM2 expression and autophagy in a TP53-dependent manner, and TGM2 promoted autophagic flux by enhancing autophagic protein degradation and autolysosome clearance. Reduced expression of both CDKN1A, which regulates the cell cycle downstream of TP53, and TGM2 synergized to promote oncogenic transformation. Our findings suggest that TGM2-mediated autophagy and CDKN1A-mediated cell cycle arrest are two important barriers in the TP53 pathway that prevent oncogenic transformation.

  20. Functional TP53 mutations have no impact on response to cytotoxic agents in metastatic colon cancer.

    Science.gov (United States)

    Netter, Jeanne; Lehmann-Che, Jacqueline; Lambert, Jerome; Tallet, Anne; Lourenco, Nelson; Soliman, Hany; Bertheau, Philippe; Pariente, Benjamin; Chirica, Mircea; Pocard, Marc; Allez, Matthieu; De The, Hugues; Gornet, Jean-Marc

    2015-02-01

    Survival of metastatic colon cancer (mCC) patients has considerably improved with optimization of new drugs regimen. Inactivation of TP53 pathway by TP53 mutations is observed in nearly half of colorectal tumors. The impact of such mutations has been poorly studied in the metastatic setting. The files of 254 mCC treated in a single institution at Saint-Louis hospital between January 1999 and April 2011 were retrospectively reviewed. Tissue samples for analysis of TP53 mutations were available for 68 patients, performed using FASAY. The prognostic value of TP53 status was evaluated by comparing progression free survival (PFS) and overall survival (OS) in the group of TP53-mutated and wild type patients. PFS was 6.9 months and OS 21.7 months in the whole population. There was no statistical difference in TP53-mutated and wild type groups in term of PFS (HR=1.04; IC 95%=0.6-1.79) and OS (HR=0.99; IC 95%=0.53-1.55) whatever the chemotherapy regimen (oxaliplatin- or irinotecan-based). Only BRAF V600 mutation was demonstrated to be a poor prognostic factor for PFS and OS, and CEA level for OS. Routine determination of TP53 mutations, even with a highly sensitive method, cannot be recommended to predict chemotherapy response in mCC. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  1. TP53 Alterations Correlate with Response to VEGF/VEGFR Inhibitors: Implications for Targeted Therapeutics.

    Science.gov (United States)

    Wheler, Jennifer J; Janku, Filip; Naing, Aung; Li, Yali; Stephen, Bettzy; Zinner, Ralph; Subbiah, Vivek; Fu, Siqing; Karp, Daniel; Falchook, Gerald S; Tsimberidou, Apostolia M; Piha-Paul, Sarina; Anderson, Roosevelt; Ke, Danxia; Miller, Vincent; Yelensky, Roman; Lee, J Jack; Hong, David; Kurzrock, Razelle

    2016-10-01

    TP53 tumor-suppressor gene mutations are among the most frequent abnormalities in cancer, affecting approximately 40% of patients. Yet, there is no accepted way to target these alterations in the clinic. At the same time, antagonists of VEGFR or its ligand are best-selling oncology drugs, with multiple, expensive compounds approved. Although only a subset of patients benefit from these antiangiogenesis agents, no relevant biomarker has been identified. Interestingly, TP53 mutations upregulate VEGF-A and VEGFR2. We prospectively enrolled 500 patients, to be interrogated by comprehensive genomic profiling (CGP) (next-generation sequencing, 236 genes), and to be matched, whenever possible, with targeted agents. Herein, we analyze outcomes based on VEGF/VEGFR inhibitor treatment and presence of TP53 mutations. Of the 500 patients, 188 (37.6%; with ≥1 alteration) were treated; 106 (56% of 188) had tumors that harbored TP53 mutations. VEGF/VEGFR inhibitor therapy was independently associated with improvement in all outcome parameters [rate of stable disease (SD) ≥6 months/partial and complete remission (PR/CR); (31% versus 7%; TP53-mutant patients (who received no other molecular-matched agents) treated with versus without VEGF/VEGFR inhibitors), time-to-treatment failure, and overall survival (multivariate analysis: all P ≤ 0.01)] for the patients harboring TP53-mutant cancers, but improvement was not seen in any of these parameters for patients with TP53 wild-type neoplasms. We conclude that TP53 mutations predict sensitivity to VEGF/VEGFR inhibitors in the clinic. TP53 alterations may therefore be a ready biomarker for treatment with antiangiogenesis agents, a finding of seminal importance across the cancer field. Mol Cancer Ther; 15(10); 2475-85. ©2016 AACR.

  2. Prediction of Microcystis Blooms Based on TN:TP Ratio and Lake Origin

    Directory of Open Access Journals (Sweden)

    Yoshimasa Amano

    2008-01-01

    Full Text Available We evaluated the relationship between TN:TP ratio and Microcystis growth via a database that includes worldwide lakes based on four types of lake origin (dammed, tectonic, coastal, and volcanic lakes. We used microcosm and mesocosm for the nutrient elution tests with lake water and four kinds of sediment (nontreated, MgO sprinkling treated, dissolved air flotation [DAF] treated, and combined treated sediment in order to control TN:TP ratio and to suppress Microcystis growth. Microcystis growth was related to TN:TP ratio, with the maximum value at an optimum TN:TP ratio and the minimum values when the TN:TP ratios reached to 0 or ∞. The kurtosis of the distribution curve varied with the type of lake origin; the lowest kurtosis was found in dammed lakes, while the highest was found in volcanic lakes. The lake trophic state could affect the change in the kurtosis, providing much lower kurtosis at eutrophic lakes (dammed lakes than that at oligotrophic lakes (volcanic lakes. The relationship between TN:TP ratio and Microcystis growth could be explained by the nutrient elution tests under controlled TN:TP ratios through the various sediment treatments. A significant suppression of Microcystis growth of 70% could be achieved when the TN:TP ratios exceeded 21. Lake origin could be regarded as an index including morphological and geographical factors, and controlling the trophic state in lakes. The origin rather than trophic state for lakes could be considered as an important factor of TN:TP influences on Microcystis growth.

  3. Application of KCl polysulfonate drilling fluid in the third drilling of well TP338H%KCl聚磺钻井液在TP338H井三开的应用

    Institute of Scientific and Technical Information of China (English)

    范落成; 王杰东; 何小明; 胡林

    2015-01-01

    TP338H井的几口邻井施工时,三开井段均采用常规聚磺钻井液体系,在钻井过程中,PDC钻头泥包、井壁失稳垮塌、下钻大段划眼等复杂情况时有发生,严重影响了钻井施工进度。通过查询和调研相关钻井液资料,决定在TP338H井三开使用KCl聚磺钻井液体系,以聚磺钻井液为基础,通过加入KCl来增强其抑制性和防塌性能。室内性能评价表明,KCl聚磺钻井液的抑制防塌性、高温稳定性、抗污染性、润滑性及流变性能均优于常规聚磺钻井液体系。该井三开井段施工顺利,未出现钻头泥包、严重垮塌等复杂情况,KCl聚磺钻井液体系在该井取得了良好的应用效果,对以后该区块的钻井液施工具有很好的参考意义。%In the construction of adjacent wells of well TP338H, the third drilling sections all adopted the conventional polysulfo⁃nate drilling fluid. In the process of drilling, some complex situations often occurred, including PDC bit balling, wellbore instability and long section reaming, which affected the drilling construction schedule seriously. Through researching the related materials of drilling fluid, in the third drilling of well TP338H, KCl polysulfonate drilling fluid system was adopted. Using polysulfonate drilling fluid as the foundation, the inhibition and anti collapse properties were enhanced by adding KCl. The indoor results show that, the performances of KCl polysulfonate drilling fluid system are superior to those of conventional polysulfonate drilling fluid system, among them, the performances include inhibition and anti collapse, high temperature stability, anti pollution ability, lubricity and rheological properties. The third drilling construction of this well was smooth, and the complex situations including bit balling and serious collapse were not happened. KCl polysulfonate drilling fluid system achieves good results in the well, thereby offering good

  4. LOH rather than genotypes of TP53 codon 72 is associated with disease-free survival in primary breast cancer

    DEFF Research Database (Denmark)

    Kyndi, Marianne; Alsner, Jan; Hansen, Lise Lotte

    2006-01-01

    Mutations in the TP53 gene are a well-documented strong prognostic factor in breast cancer. A prognostic value of the Arg72Pro polymorphism of the TP53 gene is more contradictory. We assessed TP53 mutations and genotypes of the Arg72Pro polymorphism in a study including 204 Danish women. Patients...

  5. Doxycycline down-regulates DNA-PK and radiosensitizes tumor initiating cells: Implications for more effective radiation therapy.

    Science.gov (United States)

    Lamb, Rebecca; Fiorillo, Marco; Chadwick, Amy; Ozsvari, Bela; Reeves, Kimberly J; Smith, Duncan L; Clarke, Robert B; Howell, Sacha J; Cappello, Anna Rita; Martinez-Outschoorn, Ubaldo E; Peiris-Pagès, Maria; Sotgia, Federica; Lisanti, Michael P

    2015-06-10

    DNA-PK is an enzyme that is required for proper DNA-repair and is thought to confer radio-resistance in cancer cells. As a consequence, it is a high-profile validated target for new pharmaceutical development. However, no FDA-approved DNA-PK inhibitors have emerged, despite many years of drug discovery and lead optimization. This is largely because existing DNA-PK inhibitors suffer from poor pharmacokinetics. They are not well absorbed and/or are unstable, with a short plasma half-life. Here, we identified the first FDA-approved DNA-PK inhibitor by "chemical proteomics". In an effort to understand how doxycycline targets cancer stem-like cells (CSCs), we serendipitously discovered that doxycycline reduces DNA-PK protein expression by nearly 15-fold (> 90%). In accordance with these observations, we show that doxycycline functionally radio-sensitizes breast CSCs, by up to 4.5-fold. Moreover, we demonstrate that DNA-PK is highly over-expressed in both MCF7- and T47D-derived mammospheres. Interestingly, genetic or pharmacological inhibition of DNA-PK in MCF7 cells is sufficient to functionally block mammosphere formation. Thus, it appears that active DNA-repair is required for the clonal expansion of CSCs. Mechanistically, doxycycline treatment dramatically reduced the oxidative mitochondrial capacity and the glycolytic activity of cancer cells, consistent with previous studies linking DNA-PK expression to the proper maintenance of mitochondrial DNA integrity and copy number. Using a luciferase-based assay, we observed that doxycycline treatment quantitatively reduces the anti-oxidant response (NRF1/2) and effectively blocks signaling along multiple independent pathways normally associated with stem cells, including STAT1/3, Sonic Hedgehog (Shh), Notch, WNT and TGF-beta signaling. In conclusion, we propose that the efficacy of doxycycline as a DNA-PK inhibitor should be tested in Phase-II clinical trials, in combination with radio-therapy. Doxycycline has excellent

  6. DNA-PK-dependent RPA2 hyperphosphorylation facilitates DNA repair and suppresses sister chromatid exchange.

    Directory of Open Access Journals (Sweden)

    Hungjiun Liaw

    Full Text Available Hyperphosphorylation of RPA2 at serine 4 and serine 8 (S4, S8 has been used as a marker for activation of the DNA damage response. What types of DNA lesions cause RPA2 hyperphosphorylation, which kinase(s are responsible for them, and what is the biological outcome of these phosphorylations, however, have not been fully investigated. In this study we demonstrate that RPA2 hyperphosphorylation occurs primarily in response to genotoxic stresses that cause high levels of DNA double-strand breaks (DSBs and that the DNA-dependent protein kinase complex (DNA-PK is responsible for the modifications in vivo. Alteration of S4, S8 of RPA2 to alanines, which prevent phosphorylations at these sites, caused increased mitotic entry with concomitant increases in RAD51 foci and homologous recombination. Taken together, our results demonstrate that RPA2 hyperphosphorylation by DNA-PK in response to DSBs blocks unscheduled homologous recombination and delays mitotic entry. This pathway thus permits cells to repair DNA damage properly and increase cell viability.

  7. Challenges in application of bioanalytical method on different populations and effect of population on PK.

    Science.gov (United States)

    Kale, Prashant; Shukla, Manoj; Soni, Gunjan; Patel, Ronak; Gupta, Shailendra

    2014-01-01

    Prashant Kale has 22 years of immense experience in the analytical and bioanalytical domain. He is Senior Vice President, Bioequivalence Operations of Lambda Therapeutic Research, India which includes Bioanalytical, Clinics, Clinical data management, Pharmacokinetics and Biostatistics, Protocol writing, Clinical lab and Quality Assurance departments. He has been with Lambda for over 14 years. By qualification he is a M.Sc. and an MBA. Mr. Kale is responsible for the management, technical and administrative functions of the BE unit located at Ahmedabad and Mumbai, India. He is also responsible for leading the process of integration between bioanalytical laboratories and services offered by Lambda at global locations (India and Canada). Mr. Kale has faced several regulatory audits and inspections from leading regulatory bodies including but not limited to DCGI, USFDA, ANVISA, Health Canada, UK MHRA, Turkey MoH, WHO. There are many challenges involved in the application of bioanalytical method on different populations. This includes difference in equipment, material and environment across laboratories, variations in the matrix characteristics in different populations, differences in techniques between analysts such as sample processing and handling and others. Additionally, there is variability in the PK of a drug in different populations. This article shows the effect of different populations on validated bioanalytical method and on the PK of a drug. Hence, the bioanalytical method developed and validated for a specific population may need required modification when applied to another population. Critical consideration of all such aspects is the key to successful implementation of a validated method on different populations.

  8. D6PK AGCVIII Kinases Are Required for Auxin Transport and Phototropic Hypocotyl Bending in Arabidopsis[C][W

    Science.gov (United States)

    Willige, Björn C.; Ahlers, Siv; Zourelidou, Melina; Barbosa, Inês C.R.; Demarsy, Emilie; Trevisan, Martine; Davis, Philip A.; Roelfsema, M. Rob G.; Hangarter, Roger; Fankhauser, Christian; Schwechheimer, Claus

    2013-01-01

    Phototropic hypocotyl bending in response to blue light excitation is an important adaptive process that helps plants to optimize their exposure to light. In Arabidopsis thaliana, phototropic hypocotyl bending is initiated by the blue light receptors and protein kinases phototropin1 (phot1) and phot2. Phototropic responses also require auxin transport and were shown to be partially compromised in mutants of the PIN-FORMED (PIN) auxin efflux facilitators. We previously described the D6 PROTEIN KINASE (D6PK) subfamily of AGCVIII kinases, which we proposed to directly regulate PIN-mediated auxin transport. Here, we show that phototropic hypocotyl bending is strongly dependent on the activity of D6PKs and the PIN proteins PIN3, PIN4, and PIN7. While early blue light and phot-dependent signaling events are not affected by the loss of D6PKs, we detect a gradual loss of PIN3 phosphorylation in d6pk mutants of increasing complexity that is most severe in the d6pk d6pkl1 d6pkl2 d6pkl3 quadruple mutant. This is accompanied by a reduction of basipetal auxin transport in the hypocotyls of d6pk as well as in pin mutants. Based on our data, we propose that D6PK-dependent PIN regulation promotes auxin transport and that auxin transport in the hypocotyl is a prerequisite for phot1-dependent hypocotyl bending. PMID:23709629

  9. Involvement of DNA-PK(sub cs) in DSB Repair Following Fe-56 Ion Irradiation

    Science.gov (United States)

    O'Neill, Peter; Harper, Jane; Anderson, Jennifer a.; Cucinnota, Francis A.

    2007-01-01

    When cells are exposed to radiation, cellular lesions are induced in the DNA including double strand breaks (DSBs), single strand breaks and clustered DNA damage, which if not repaired with high fidelity may lead to detrimental biological consequences. Complex DSBs are induced by ionizing radiation and characterized by the presence of base lesions close to the break termini. They are believed to be one of the major causes of the biological effects of IR. The complexity of DSBs increases with the ionization density of the radiation and these complex DSBs are distinct from the damage induced by sparsely ionizing gamma-radiation. It has been hypothesized that complex DSBs produced by heavy ions in space pose problems to the DNA repair machinery. We have used imm uno-cyto-chemical staining of phosphorylated histone H2AX (gamma-H2AX) foci, as a marker of DSBs. We have investigated the formation and loss of gamma-H2AX foci and RAD51 foci (a protein involved in the homologous recombination pathway) in mammalian cells induced by low fluences of low-LET gamma-radiation and high-LET Fe-56 ions (1GeV/n, 151 keV/micron LET). M059J and M059K cells, which are deficient and proficient in DNA-PK(sub cs) activity respectively, were used to examine the role of DNA-PK(sub cs), a key protein in the non-homologous end joining (NHEJ) pathway of DSB repair, along with HF19 human fibroblasts. Followi ng irradiation with Fe-56 ions the rate of repair was slower in M059J cells compared with that in M059K, indicating a role for DNA-PK(sub cs) in the repair of DSB induced by Fe-56 ions. However a small percentage of DSBs induced are rejoined within 5 h although many DSBs still persist up to 24 h. When RAD51 was examined in M059J/K cells, RAD51 foci are visible 24 hours after irradiation in approximately 40% of M059J cells compared with Vanillin, an inhibitor of DNA-PK(sub cs), reduces significantly the rate of DSB repair in HF19 cells following 1 Gy gamma-radiation but at 0.25 Gy gamma

  10. Involvement of DNA-PK(sub cs) in DSB Repair Following Fe-56 Ion Irradiation

    Science.gov (United States)

    O'Neill, Peter; Harper, Jane; Anderson, Jennifer a.; Cucinnota, Francis A.

    2007-01-01

    When cells are exposed to radiation, cellular lesions are induced in the DNA including double strand breaks (DSBs), single strand breaks and clustered DNA damage, which if not repaired with high fidelity may lead to detrimental biological consequences. Complex DSBs are induced by ionizing radiation and characterized by the presence of base lesions close to the break termini. They are believed to be one of the major causes of the biological effects of IR. The complexity of DSBs increases with the ionization density of the radiation and these complex DSBs are distinct from the damage induced by sparsely ionizing gamma-radiation. It has been hypothesized that complex DSBs produced by heavy ions in space pose problems to the DNA repair machinery. We have used imm uno-cyto-chemical staining of phosphorylated histone H2AX (gamma-H2AX) foci, as a marker of DSBs. We have investigated the formation and loss of gamma-H2AX foci and RAD51 foci (a protein involved in the homologous recombination pathway) in mammalian cells induced by low fluences of low-LET gamma-radiation and high-LET Fe-56 ions (1GeV/n, 151 keV/micron LET). M059J and M059K cells, which are deficient and proficient in DNA-PK(sub cs) activity respectively, were used to examine the role of DNA-PK(sub cs), a key protein in the non-homologous end joining (NHEJ) pathway of DSB repair, along with HF19 human fibroblasts. Followi ng irradiation with Fe-56 ions the rate of repair was slower in M059J cells compared with that in M059K, indicating a role for DNA-PK(sub cs) in the repair of DSB induced by Fe-56 ions. However a small percentage of DSBs induced are rejoined within 5 h although many DSBs still persist up to 24 h. When RAD51 was examined in M059J/K cells, RAD51 foci are visible 24 hours after irradiation in approximately 40% of M059J cells compared with DSB induced by 56Fe ions. Vanillin, an inhibitor of DNA-PK(sub cs), reduces significantly the rate of DSB repair in HF19 cells following 1 Gy gamma

  11. Light energy conversion into H{sub 2} by Anabaena variabilis mutant PK84 dense cultures exposed to nitrogen limitations

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Jianguo [Institute of Oceanology, Chinese Academy of Sciences, 7 Nanhai Road, Qingdao 266071 (China); Bukatin, Vyacheslav E.; Tsygankov, Anatoly A. [Institute of Basic Biological Problem, Russia Academy of Sciences, Pushchino, Moscow Region 142292 (Russian Federation)

    2006-09-15

    Concentrated cultures (25-86mgChl al{sup -1}) of Anabaena variabilis PK84 were incubated under 99% Ar+1% CO{sub 2} atmosphere in the photobioreactor made of coaxial cylinders. Under illumination equal to 353{mu}Em{sup -2}s{sup -1} they produced hydrogen with the rate more than 20mll{sup -1}h{sup -1} for several days. The efficiency of light energy conversion into H{sub 2} was approx. 1% and did not depend significantly on initial Chl a concentration. H{sub 2}/O{sub 2} ratio reached 41.5% of theoretical value for water photolysis. Data indicate that dense cultures might be used for outdoor systems under direct sun light. Supra-optimal temperatures 36{sup |}C were not harmful for cultures even for 2 days period. Short-term incubation of cultures under 36{sup |}C even increased H{sub 2} production rate and efficiency of light energy bioconversion by 1.25 times. (author)

  12. The DNA repair complex DNA-PK, a pharmacological target in cancer chemotherapy and radiotherapy; Le complexe de reparation de l'ADN DNA-PK, une cible pharmacologique en chimiotherapie et radiotherapie anticancereuse

    Energy Technology Data Exchange (ETDEWEB)

    Salles, B.; Calsou, P.; Frit, P.; Muller, C. [Institut de Pharmacologie et Biologie Structurale (IPBS), UMR CNRS 5089, 31 - Toulouse (France)

    2006-05-15

    A line of investigation in the search for sensitizing tumor cells to chemotherapy or radiotherapy relies on the selection of DNA repair inhibitors. In the area of DNA repair mechanisms, DNA-dependent protein kinase (DNA-PK) represents a key complex. Indeed DNA-PK is involved in the non-homologous end joining (NHEJ) process that corresponds to the major activity responsible for cell survival after ionizing radiation or chemotherapeutic treatment producing DNA double strand breaks. DNA-PK belongs to the PI3-K related kinase family and specific inhibitors have been recently selected and evaluated as radio- and chemo-sensitizers. These drugs, along with other ways to inhibit the DSBs repair process, are presented and discussed. (authors)

  13. Detection of TP53 dysfunction in chronic lymphocytic leukemia by an in vitro functional assay based on TP53 activation by the non-genotoxic drug Nutlin-3: a proposal for clinical application

    OpenAIRE

    Pozzo, Federico; Dal Bo, Michele; Peragine, Nadia; Bomben, Riccardo; Zucchetto, Antonella; Rossi, Francesca Maria; Degan, Massimo; Rossi, Davide; Chiarenza, Annalisa; Grossi, Alberto; Di Raimondo, Francesco; Zaja, Francesco; Pozzato, Gabriele; Secchiero, Paola; Gaidano, Gianluca

    2013-01-01

    Background TP53 defects, i.e. 17p13 deletion and/or nucleotide mutations, associate with short survival and chemorefractoriness in chronic lymphocytic leukemia (CLL). In this context, since direct sequencing of the TP53 gene does not evaluate TP53 functionality, a functional assessment of TP53 pathway may be of interest to identify high risk CLL. By taking advantage of a training cohort of 100 CLL and a validation cohort of 40 CLL with different patterns of TP53 mutation/deletion by FISH and ...

  14. PK-SVD Filter for Impulse Noise Based on Non-noisy Pixel Reconstruction%基于非噪声像素重构的PK-SVD脉冲噪声滤波

    Institute of Scientific and Technical Information of China (English)

    黄宴委; 祁冰露

    2014-01-01

    An improved K-SVD method based on non-noisy pixel reconstruction ( PK-SVD) is proposed to filter impulse noise. In the phase of image reconstruction, non-noisy pixels are applied in the construction of optimal function to obtain the reconstructed image and improve the filtering performance, and the optimal function is solved by integrating the hierarchical property into the OMP algorithm. In the phase of dictionary training, PK-SVD uses the iterant K-singular value decomposition to renovate both atoms and their coefficients rather than fixes the coefficients. The simulation results show that compared with the other three methods, PK-SVD obtains the sparsest dictionary and the clearest image with higher peak signal to noise ratio.%提出一种基于非噪声像素重构的K-SVD( Pixel K-SVD)脉冲噪声滤波方法。在图像重构阶段,以非噪声点像素值为优化目标,利用分层重构改进OMP算法求解优化函数,获得重构图像以提高恢复图像质量;在字典训练阶段,PK-SVD不再固定原子的系数,而是使用重复奇异值分解同时更新原子和系数。将PK-SVD与其他3种方法进行比较,实验结果表明,PK-SVD能得到最稀疏化的字典,较好地抑制脉冲噪声,使得滤波图像较清晰且具有较高的峰值信噪比。

  15. The ECMO PK Project: an incremental research approach to advance understanding of the pharmacokinetic alterations and improve patient outcomes during extracorporeal membrane oxygenation

    OpenAIRE

    Shekar, Kiran; Roberts, Jason A; Smith, Maree T.; Fung, Yoke L.; Fraser, John F.

    2013-01-01

    Background Extracorporeal membrane oxygenation (ECMO) is a supportive therapy and its success depends on optimal drug therapy along with other supportive care. Emerging evidence suggests significant interactions between the drug and the device resulting in altered pharmacokinetics (PK) of vital drugs which may be further complicated by the PK changes that occur in the context of critical illness. Such PK alterations are complex and challenging to investigate in critically ill patients on ECMO...

  16. Rapid Determination of Ionization Constants (pK a) by UV Spectroscopy Using 96-Well Microtiter Plates.

    Science.gov (United States)

    Martínez, Carlos H Ríos; Dardonville, Christophe

    2013-01-10

    We have developed a methodology that enables for the rapid measurement of ionization constants (pK a) of series of compounds by UV spectrophotometry. This protocol, which is straightforward to set up, takes advantage of the sensitivity of UV spectroscopy and the throughput enabled by the 96-well microplate (as opposed to the use of 1 cm quartz cuvette). The compounds, in stock solutions in DMSO, are dissolved in several aqueous buffer solutions directly in the microtiter plate, allowing the simultaneous determination of the UV spectra as a function of pH. Further treatment of the data provides the pK a values in a medium-throughput manner. The pK a values of 11 new antitrypanosomal dibasic compounds were determined using this methodology.

  17. DNA-PK inhibition causes a low level of H2AX phosphorylation and homologous recombination repair in Medaka (Oryzias latipes) cells

    Energy Technology Data Exchange (ETDEWEB)

    Urushihara, Yusuke [Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562 (Japan); Kobayashi, Junya [Department of Genome Repair Dynamics, Radiation Biology Center, Kyoto University, Kyoto 606-8501 (Japan); Matsumoto, Yoshihisa [Research Laboratory for Nuclear Reactors, Tokyo Institute of Technology, Tokyo 152-8550 (Japan); Komatsu, Kenshi [Department of Genome Repair Dynamics, Radiation Biology Center, Kyoto University, Kyoto 606-8501 (Japan); Oda, Shoji [Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562 (Japan); Mitani, Hiroshi, E-mail: mitani@k.u-tokyo.ac.jp [Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562 (Japan)

    2012-12-14

    Highlights: Black-Right-Pointing-Pointer We investigated the effect of DNA-PK inhibition on DSB repair using fish cells. Black-Right-Pointing-Pointer A radiation sensitive mutant RIC1 strain showed a low level of DNA-PK activity. Black-Right-Pointing-Pointer DNA-PK dysfunction leads defects in HR repair and DNA-PKcs autophosphorylation. Black-Right-Pointing-Pointer DNA-PK dysfunction leads a slight increase in the number of 53BP1 foci after DSBs. Black-Right-Pointing-Pointer DNA-PK dysfunction leads an alternative NHEJ that depends on 53BP1. -- Abstract: Nonhomologous end joining (NHEJ) and homologous recombination (HR) are known as DNA double-strand break (DSB) repair pathways. It has been reported that DNA-PK, a member of PI3 kinase family, promotes NHEJ and aberrant DNA-PK causes NHEJ deficiency. However, in this study, we demonstrate that a wild-type cell line treated with DNA-PK inhibitor and a mutant cell line with dysfunctional DNA-PK showed decreased HR efficiency in fish cells (Medaka, Oryzias latipes). Previously, we reported that the radiation-sensitive mutant RIC1 strain has a defect in the Histone H2AX phosphorylation after {gamma}-irradiation. Here, we showed that a DNA-PK inhibitor, NU7026, treatment resulted in significant reduction in the number of {gamma}H2AX foci after {gamma}-irradiation in wild-type cells, but had no significant effect in RIC1 cells. In addition, RIC1 cells showed significantly lower levels of DNA-PK kinase activity compared with wild-type cells. We investigated NHEJ and HR efficiency after induction of DSBs. Wild-type cells treated with NU7026 and RIC1 cells showed decreased HR efficiency. These results indicated that aberrant DNA-PK causes the reduction in the number of {gamma}H2AX foci and HR efficiency in RIC1 cells. We performed phosphorylated DNA-PKcs (Thr2609) and 53BP1 focus assay after {gamma}-irradiation. RIC1 cells showed significant reduction in the number of phosphorylated DNA-PKcs foci and no deference in the

  18. Neural network predicts sequence of TP53 gene based on DNA chip

    DEFF Research Database (Denmark)

    Spicker, J.S.; Wikman, F.; Lu, M.L.;

    2002-01-01

    We have trained an artificial neural network to predict the sequence of the human TP53 tumor suppressor gene based on a p53 GeneChip. The trained neural network uses as input the fluorescence intensities of DNA hybridized to oligonucleotides on the surface of the chip and makes between zero...... and four errors in the predicted 1300 bp sequence when tested on wild-type TP53 sequence....

  19. Optimizing an online SPE-HPLC method for analysis of (R)-[{sup 11}C]1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)- 3-isoquinolinecarboxamide [(R)-[{sup 11}C]PK11195] and its metabolites in humans

    Energy Technology Data Exchange (ETDEWEB)

    Greuter, Henri N.J.M. [Department of Nuclear Medicine and PET Research, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam (Netherlands)]. E-mail: hnjm.greuter@vumc.nl; van Ophemert, Patricia L.B. [Department of Nuclear Medicine and PET Research, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam (Netherlands); Luurtsema, Gert [Department of Nuclear Medicine and PET Research, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam (Netherlands); van Berckel, Bart N.M. [Department of Nuclear Medicine and PET Research, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam (Netherlands); Franssen, Eric J.F. [Department of Nuclear Medicine and PET Research, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam (Netherlands); Windhorst, Bert D. [Department of Nuclear Medicine and PET Research, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam (Netherlands); Lammertsma, Adriaan A. [Department of Nuclear Medicine and PET Research, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam (Netherlands)

    2005-04-01

    (R)-[{sup 11}C]PK11195 is used as a positron emission tomography tracer for activated microglia in several neurological disorders. Quantification of specific binding requires a metabolite-corrected plasma input function. In this study, a high-performance liquid chromatography (HPLC) procedure with online solid phase extraction was modified for analyzing (R)-[{sup 11}C]PK11195 plasma samples, yielding total sample recoveries of more than 98%. When applied to human studies, the use of two HPLC systems enabled analysis of up to seven plasma samples under regular conditions. Online radioactivity detection was compared with offline sample measurements of HPLC profiles. Offline measurements provided the most reliable results especially for late plasma samples. In 10 patients, an average decrease of parent compound from 94.6% at 2.5 min to 45.2% at 1 h after administration was observed.

  20. SPM analysis of parametric (R)-[11C]PK11195 binding images: plasma input versus reference tissue parametric methods.

    Science.gov (United States)

    Schuitemaker, Alie; van Berckel, Bart N M; Kropholler, Marc A; Veltman, Dick J; Scheltens, Philip; Jonker, Cees; Lammertsma, Adriaan A; Boellaard, Ronald

    2007-05-01

    (R)-[11C]PK11195 has been used for quantifying cerebral microglial activation in vivo. In previous studies, both plasma input and reference tissue methods have been used, usually in combination with a region of interest (ROI) approach. Definition of ROIs, however, can be labourious and prone to interobserver variation. In addition, results are only obtained for predefined areas and (unexpected) signals in undefined areas may be missed. On the other hand, standard pharmacokinetic models are too sensitive to noise to calculate (R)-[11C]PK11195 binding on a voxel-by-voxel basis. Linearised versions of both plasma input and reference tissue models have been described, and these are more suitable for parametric imaging. The purpose of this study was to compare the performance of these plasma input and reference tissue parametric methods on the outcome of statistical parametric mapping (SPM) analysis of (R)-[11C]PK11195 binding. Dynamic (R)-[11C]PK11195 PET scans with arterial blood sampling were performed in 7 younger and 11 elderly healthy subjects. Parametric images of volume of distribution (Vd) and binding potential (BP) were generated using linearised versions of plasma input (Logan) and reference tissue (Reference Parametric Mapping) models. Images were compared at the group level using SPM with a two-sample t-test per voxel, both with and without proportional scaling. Parametric BP images without scaling provided the most sensitive framework for determining differences in (R)-[11C]PK11195 binding between younger and elderly subjects. Vd images could only demonstrate differences in (R)-[11C]PK11195 binding when analysed with proportional scaling due to intersubject variation in K1/k2 (blood-brain barrier transport and non-specific binding).

  1. A Convenient Radiolabeling of [{sup 11}C](R)-PK11195 Using Loop Method in Automatic Synthesis Module

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hak Jeong; Jeong, Jae Min; Lee, Yun Sang; Kim, Hyung Woo; Choi, Jae Yeon; Lee, Dong Soo; Chung, June Key; Lee, Myung Chul [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2009-08-15

    ((R)-1-(2-chlorophenyl)-N-1-[[{sup 11}C]methyl-N-(1-propyl)-3-isoquinoline carboxamide ((R)-PK11195) is a specific ligand for the peripheral type benzodiazepine receptor and a marker of activated microglia, used to measure inflammation in neurologic disorders. We report here that a direct and simple radiosynthesis of [[{sup 11}C](R)-PK11195 in mild condition using NaH suspension in DMF and one-step loop method. (R)-NDesmethyl- PK11195 (1 mg) in DMSO (0.1 mL) and NaH suspension in DMF (0.1 mL) were injected into a semi-prep HPLC loop. [{sup 11}C]methyl iodide was passed through HPLC loop at room temperature. Purification was performed using semi-preparative HPLC. Aliquots eluted at 11.3 min were collected and analyzed by analytical HPLC and mass spectrometer. The labeling efficiency of [[{sup 11}C](R)-PK11195 was 71.8{+-}8.5%. The specific activity was 11.8{+-}6.4 GBq/{mu}mol and radiochemical purity was higher than 99.2%. The mass spectrum of the product eluted at 11.3 min showed m/z peaks at 353.1 (M+1), indicating the mass and structure of (R)-PK11195. By the one-step loop method with the [[{sup 11}C]CH3I automated synthesis module, [[{sup 11}C](R)-PK11195 could be easily prepared in high radiochemical yield using NaH suspension in DMF.

  2. Cytotoxic and toxicogenomic effects of silibinin in bladder cancer cells with different TP53 status

    Indian Academy of Sciences (India)

    DAIANE TEIXEIRA DE OLIVEIRA; ANDRÉ LUIZ VENTURA SÁVIO; JOÃO PAULO DE CASTRO MARCONDES; TATIANE MARTINS BARROS; LUDMILA CORREIA BARBOSA; DAISY MARIA FAVERO SALVADORI; GLENDA NICIOLI DA SILVA

    2017-03-01

    Silibinin is a natural phenol found in the seeds of the milk thistle plant. Recent data have shown its effectiveness forpreventing/treating bladder tumours. Therefore, in this study we investigated the cytotoxic and toxicogenetic activityof silibinin in bladder cancer cells with different TP53 statuses. Two bladder urothelial carcinoma cell lines were used:RT4 (wild-type TP53 gene) and T24 (mutated TP53 gene). Cell proliferation, clonogenic survival, apoptosis rates,genotoxicity and relative expression profile of FRAP/mTOR, FGFR3, AKT2 and DNMT1 genes and of miR100 andmiR203 were evaluated. Silibinin promoted decreased proliferation and increased late apoptosis in TP53 mutatedcells. Increased early apoptosis rates, primary DNA damage, and decrease of cell colonies in the clonogenic survivalassay were detected in both RT4 and T24 cell lines. Down-regulation of FRAP/mTOR, AKT2, FGFR3, DNMT1 andmiR100 expression occurred in RT4 cells. Modulation of miR203 was observed in both cell lines. In conclusion,despite the reduction of clone formation in both cell lines, the toxicogenomic effect of silibinin on FRAP/mTOR,AKT2, FGFR3, DNMT1 and miR100 was dependent on the TP53 status. Taken together, the data confirmed the role ofsilibinin as an antiproliferative compound, whose mechanism of action was related to the TP53 status.

  3. Three Common TP53 Polymorphisms and the Risk of Breast Cancer among Groups of Iranian Women

    Directory of Open Access Journals (Sweden)

    Mahin Ahangar Oskouee

    2015-11-01

    Full Text Available Background: The TP53 gene is the most important tumor suppressor gene in humans. The aim of our study was to determine the genotype frequency of three common TP53 polymorphisms (codon 72 BstUI and intron 6 MspI, as well as the intron 3 in a group of Iranian women with and without breast cancer. Methods: Paraffin-embedded specimens of 65 malignant breast cancer cases and 65 cases with benign breast lesions were investigated for the presence of three common TP53 polymorphisms by polymerase chain reaction. Samples were genotyped by polymerase chain reaction followed by variant specific restriction enzyme digestion. Results: In our study, age grouping as >50 and ≤50 showed that the highest number of cancerous and non-cancerous patients was in the age group under 50; according to statistical tests, the difference was significant and recessive alleles of all three hot spots of TP53 had the highest frequency in the cancerous group. The majority of the cases with recessive alleles of all three hot spots of TP53 were in the age group ≤ 50. The difference between cancerous and noncancerous groups was statistically significant. Conclusions: Our results indicate that recessive alleles in three hot spots of TP53 gene might play a role in the breast cancer development, especially in women younger than 50 years.

  4. Cytotoxic and toxicogenomic effects of silibinin in bladder cancer cells with different TP53 status.

    Science.gov (United States)

    DE Oliveira, Daiane Teixeira; Savio, Andre Luiz Ventura; Marcondes, Joao Paulo DE Castro; Barros, Tatiane Martins; Barbosa, Ludmila Correia; Salvadori, Daisy Maria Favero; DA Silva, Glenda Nicioli

    2017-03-01

    Silibinin is a natural phenol found in the seeds of the milk thistle plant. Recent data have shown its effectiveness for preventing/treating bladder tumours. Therefore, in this study we investigated the cytotoxic and toxicogenetic activity of silibinin in bladder cancer cells with different TP53 statuses. Two bladder urothelial carcinoma cell lines were used: RT4 (wild-type TP53 gene) and T24 (mutated TP53 gene). Cell proliferation, clonogenic survival, apoptosis rates, genotoxicity and relative expression profile of FRAP/mTOR, FGFR3, AKT2 and DNMT1 genes and of miR100 and miR203 were evaluated. Silibinin promoted decreased proliferation and increased late apoptosis in TP53 mutated cells. Increased early apoptosis rates, primary DNA damage, and decrease of cell colonies in the clonogenic survival assay were detected in both RT4 and T24 cell lines. Down-regulation of FRAP/mTOR, AKT2, FGFR3, DNMT1 and miR100 expression occurred in RT4 cells. Modulation of miR203 was observed in both cell lines. In conclusion, despite the reduction of clone formation in both cell lines, the toxicogenomic effect of silibinin on FRAP/mTOR, AKT2, FGFR3, DNMT1 and miR100 was dependent on the TP53 status. Taken together, the data confirmed the role of silibinin as an antiproliferative compound, whose mechanism of action was related to the TP53 status.

  5. The insidious boosting of TP-AGB stars in intermediate-age Magellanic Cloud clusters

    CERN Document Server

    Girardi, Leo; Bressan, Alessandro; Rosenfield, Philip

    2013-01-01

    (Abridged) In the recent controversy about the role of TP-AGB stars in evolutionary population synthesis (EPS) models of galaxies, one particular aspect is puzzling: TP-AGB models aimed at reproducing the lifetimes and integrated fluxes of the TP-AGB phase in Magellanic Cloud (MC) clusters, when incorporated into EPS models, are found to overestimate the TP-AGB contribution in resolved star counts and integrated spectra of galaxies. In this paper, we call attention to a particular evolutionary aspect that in all probability is the main cause of this conundrum. As soon as stellar populations intercept the ages at which RGB stars first appear, a sudden change in the lifetime of the core He-burning phase causes a temporary boost in the production rate of subsequent evolutionary phases, including the TP-AGB. For a timespan of about 0.1 Gyr, triple TP-AGB branches develop at slightly different initial masses, causing their frequency and contribution to the integrated luminosity of the stellar population to increas...

  6. Normal and functional TP53 in genetically stable myxoid/round cell liposarcoma.

    Directory of Open Access Journals (Sweden)

    Anders Ståhlberg

    Full Text Available Myxoid/round-cell liposarcoma (MLS/RCLS is characterized by either the fusion gene FUS-DDIT3 or the less commonly occurring EWSR1-DDIT3 and most cases carry few or no additional cytogenetic changes. There are conflicting reports concerning the status and role of TP53 in MLS/RCLS. Here we analysed four MLS/RCLS derived cell lines for TP53 mutations, expression and function. Three SV40 transformed cell lines expressed normal TP53 proteins. Irradiation caused normal posttranslational modifications of TP53 and induced P21 expression in two of these cell lines. Transfection experiments showed that the FUS-DDIT3 fusion protein had no effects on irradiation induced TP53 responses. Ion Torrent AmpliSeq screening, using the Cancer Hotspot panel, showed no dysfunctional or disease associated alleles/mutations. In conclusion, our results suggest that most MLS/RCLS cases carry functional TP53 genes and this is consistent with the low numbers of secondary mutations observed in this tumor entity.

  7. PET study of carbon-11-PK 11195 binding to peripheral type benzodiazepine sites in glioblastoma: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Pappata, S.; Cornu, P.; Samson, Y.; Prenant, C.; Benavides, J.; Scatton, B.; Crouzel, C.; Hauw, J.J.; Syrota, A. (INSERM U. 334 Service Hospitalier Frederic Joliot, Paris (France))

    1991-08-01

    The utility of the peripheral type benzodiazepine site ligand 11C-PK 11195, for imaging human glioma in conjunction with Positron Emission Tomography, relies on a high specific binding of the tracer to tumoral peripheral type benzodiazepines sites. In a patient with glioblastoma, the authors found that 11C-PK 11195 binding was two-fold higher in the tumor than in normal gray matter and that 30% of tumoral binding could be displaced by a large excess of unlabeled drug. These findings suggest that tumoral retention of the ligand is due, in part, to specific binding.

  8. Polimorfismo do gene tp53 no códon 72 em pacientes com suspeita de LMC Codon 72 polymorphism of the TP53 gene in patients suspected to have CML

    Directory of Open Access Journals (Sweden)

    Camila S. Hamú

    2007-12-01

    Full Text Available A leucemia mielóide crônica (LMC é uma doença proliferativa do sistema hematopoiético, caracterizada pela expansão clonal de uma célula-tronco primitiva e pluripotente denominada stem cell. Este tipo de leucemia está associado, em 90% dos casos, à translocação t(9;22(q34;q11. Essa alteração cromossômica estrutural codifica para uma proteína quimérica BCR-ABL, que confere às células leucêmicas uma alta resistência à morte, independente do agente indutor desse processo. A proteína p53 é uma reguladora transcricional induzida por danos no DNA, fato que resulta na parada do ciclo celular com conseqüente ativação de mecanismos de reparo ou mesmo na indução à apoptose. As mutações no gene TP53 são as alterações genéticas mais comuns em tumores malignos humanos. O presente estudo teve como objetivo genotipar e determinar a freqüência alélica do polimorfismo do TP53 no códon 72 (arginina - Arg e prolina - Pro, em pacientes com suspeita de LMC, pela Reação em Cadeia da Polimerase. Desta forma, os resultados indicaram que 73,4% (23/30 dos pacientes apresentaram homozigose para arginina (Arg/Arg e 26,6% (7/30 heterozigose (Arg/Pro. Não foi encontrado nenhum paciente homozigoto para prolina (Pro/Pro. Os resultados obtidos sugerem que o polimorfismo do gene TP53 no códon 72 não é um fator de risco importante para a iniciação, promoção e progressão da LMC.Chronic myeloid leukemia (CML is a proliferative disorder of the hematopoietic system characterized by clonal expansion of a primitive and pluripotent stem cell. In this type of leukemia, up to 90% of all cases is associated to a specific chromosomal translocation, t(9;22(q34;q11. The genomic alteration results in a chimeric protein, BCR-ABL, that confers a high resistance leukemia cells to death, independent of the induction mechanism of this process. Protein p53 is a transcriptional factor expressed after DNA damage which ceases cell cycle progression and

  9. Establishment of Tp0259-PCR for diagnosing infection of treponema pallidum%梅毒感染诊断中Tp0259-PCR方法的建立

    Institute of Scientific and Technical Information of China (English)

    杨长顺; 王三虎; 周秀萍

    2015-01-01

    Objective To establish a method for detection Tp0259 gene by PCR .To provide basis of diagnosis infection of trepo‐nema pallidum by detection Tp0259 gene .Methods Gene sequences of Tp0259 was obtained from Genebank and analysis by bioin‐formatics .Specific primers were designed .The whole genome was extracted from testis specimens of the New Zealand rabbits infec‐ted by treponema pallidum and control groups .The gene of Tp0259 was amplified by PCR under the optimization reaction condi‐tions which was selected by many tests ,using the new construction of amplification method to detect the common pathogenic micro‐organism in urinary and reproductive tract infection .Results Specific bands of 646 bp was appeared only in New Zealand rabbits which was infected by treponema pallidum ,while none was in the control group and other pathogenic microorganisms .Conclusion Detection the Tp0259 gene could be used to diagnose infection of treponema pallidum .%目的:建立聚合酶链反应(PCR)方法扩增梅毒螺旋体Tp0259基因,为进一步探讨其在梅毒感染诊断中的作用提供依据。方法从Genbank获取T p0259基因序列,生物信息学分析,设计特异性引物。收集T p Nichols株感染组和对照组的新西兰兔睾丸标本,提取全基因组DNA ,通过优化PCR扩增条件寻找最佳反应体系和反应条件,PCR扩增Tp0259的编码基因,同时通过新构建扩增方法检测泌尿生殖道感染常见病原微生物。结果通过PCR扩增及琼脂糖凝胶电泳,只有感染梅毒螺旋体的新西兰兔标本才能扩增出特异性条带,条带位置约为646 bp ,其他病原微生物未见扩增条带。结论检测 T p0259基因能用于诊断梅毒螺旋体的感染。

  10. TP53 Mutation vis-a-vis Malignant Progression in Astrocytoma WHO Grade Ⅱ%TP53突变与胶质瘤恶性进展

    Institute of Scientific and Technical Information of China (English)

    岳伟英; 俞苏寰; 李志强; 赵世光; 陈忠平

    2008-01-01

    背景与目的:WHO Ⅱ级的星形细胞瘤手术后在部分患者可能复发,而且,复发时多出现恶性程度增加.本研究探讨TP53蛋白质分子的表达与胶质瘤恶性进展之问的关系.方法:收集第一次手术时为星形细胞瘤(WHO Ⅱ级)的石蜡包埋标本53例份,其中10例复发时第二次手术肿瘤仍然为Ⅱ级(复发无进展组);10例复发时肿瘤级别升高(Ⅲ级或Ⅳ级)(复发进展组);另外13例在5年内没有复发(无复发组).免疫组化检测TP53在肿瘤中的表达,并采用DNA测序法分析TP53蛋白阳性标本TP53外显子5、7、8的突变情况.结果:LTP53阳性率为45.5%(15/33).复发恶性进展组TP53高于无复发组和无进展组(P<0.05);TP53无进展组与无复发组之间差异无统计学意义.基因测序共在6例组织中发现7个(共4类)突变,其中1例同时存在2个突变.所有突变者都是恶性进展组病例.结论:TP53突变/蛋白质分子过表达可能是Ⅱ级星形胶质细胞瘤复发恶性进展的预示指标.

  11. Biochemical analysis of fruiting bodies of Volvariella volvacea strain Vv pk, grown on six different substrates

    Directory of Open Access Journals (Sweden)

    Imran Ul Haq, Muhammad Aslam Khan, Sajid Aleem Khan

    2011-11-01

    Full Text Available A local strain of Volvariella volvacea Vv pk, locally known as Chinese mushroom was cultivated on six different agricultural wastes including paddy straw, cotton waste, banana leaves, corn stovers, sugarcane baggasse and pulses straw. The study was conducted to know that how much a substrate contributes in the nutritional value of the fruiting bodies of the mushroom harvested from such substrate and to recommend the best substrate for the commercial cultivation of the mushroom with high levels of protein, crude fibre and certain other elements. The biochemical analysis of the fruiting bodies harvested from the substrates was done to estimate the moisture percentage, crude fat, protein, fiber, and ash contents. Maximum protein (34.17%, ash (10.8 and crude fiber percentage (11.9% was observed in the fruiting bodies harvested from cotton waste. So, cotton waste is recommended as an effective substrate to grow Chinese mushroom on commercial scale.

  12. microRNAs与TP53基因调控网络研究进展%Advances in microRNAs and TP53 Gene Regulatory Network

    Institute of Scientific and Technical Information of China (English)

    龚朝建; 黄宏斌; 徐柯; 梁芳; 李小玲; 熊炜; 曾朝阳; 李桂源

    2012-01-01

    TP53基因(编码p53蛋白)作为一个重要的抑瘤基因,通过调控一系列信号转导通路广泛参与了多种恶性肿瘤的发生发展,一直是肿瘤分子生物学研究领域的热点.最近的研究发现,microRNAs(miRNAs)参与了TP53的信号通路,它们之间存在着复杂的调控网络.一方面,p53通过调控一些miRNAs的转录及转录后成熟,促进细胞周期阻滞、诱导细胞凋亡和衰老,抑制肿瘤发生.另一方面,许多miRNAs,如miR-25、miR-30d、miR-125b和miR-504等可直接调控p53的表达与活性,参与TP53信号通路的调节,还有一些miRNAs则通过调节p53上下游基因,发挥重要的生物学功能.其中,最具有代表性的是miR-34家族,它们受p53直接调控并参与TP53信号通路,通过靶向抑制多个TP53信号通路关键分子的表达,发挥抑瘤作用.此外,它们还可以通过抑制沉默信息调节子,增强p53的活性,反馈调节TP53信号通路.miRNAs与TP53之间调控网络的研究,是对TP53抑瘤机制的重要补充.%The tumor suppressor TP53 gene, which encodes p53 protein, is a hotspot of all time in molecular oncology. p53 suppresses tumor initiation and progression through its regulation of many downstream genes. Recent studies have revealed that microRNAs (miRNAs) interact with the p53 pathway and form a complex regulatory network. On one hand, p53 promotes cell cycle arrest and induces cell apoptosis and senescence to suppress tumorigenesis by regulating the transcription and post-transcriptional maturation of multiple miRNAs. On the other hand, many miRNAs fine-tune the p53 pathway through regulation of TP53 and its upstream regulators or downstream effectors. The miR-34s family, directly transactivated by p53 represents a large number of p53-regulated miRNAs. They exert their tumor suppressing function via targeted inhibition of multiple key molecules in the p53 pathway. Furthermore, miR-34s enhance p53 activity through a feedback loop by inhibiting silent

  13. Prediction of PK-specific phosphorylation site based on information entropy

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Phosphorylation is a crucial way to control the activity of proteins in many eukaryotic organisms in vivo. Experimental methods to determine phosphorylation sites in substrates are usually restricted by the in vitro condition of enzymes and very intensive in time and labor. Although some in silico methods and web servers have been introduced for automatic detection of phosphorylation sites, sophisticated methods are still in urgent demand to further improve prediction performances. Protein primary se-quences can help predict phosphorylation sites catalyzed by different protein kinase and most com-putational approaches use a short local peptide to make prediction. However, the useful information may be lost if only the conservative residues that are not close to the phosphorylation site are consid-ered in prediction, which would hamper the prediction results. A novel prediction method named IEPP (Information-Entropy based Phosphorylation Prediction) is presented in this paper for automatic de-tection of potential phosphorylation sites. In prediction, the sites around the phosphorylation sites are selected or excluded by their entropy values. The algorithm was compared with other methods such as GSP and PPSP on the ABL, MAPK and PKA PK families. The superior prediction accuracies were ob-tained in various measurements such as sensitivity (Sn) and specificity (Sp). Furthermore, compared with some online prediction web servers on the new discovered phosphorylation sites, IEPP also yielded the best performance. IEPP is another useful computational resource for identification of PK-specific phosphorylation sites and it also has the advantages of simpleness, efficiency and con-venience.

  14. Thrombin related peptide TP508 promoted fracture repair in a mouse high energy fracture model

    Directory of Open Access Journals (Sweden)

    Pan Xiao-Hua

    2009-01-01

    Full Text Available Abstract Background Thrombin related peptide (TP508 is a 23 amino-acid synthetic peptide that represents a portion of the receptor-binding domain of thrombin molecule. Previous studies have shown that TP508 can accelerate musculoskeletal tissue repair including fracture healing. Objectives The aim of this study was to investigate the effect of TP508 on fracture healing in a murine fracture model representing high energy fracture situation. Methods Eighty CD 1 mice underwent controlled quadriceps muscle crush and open transverse mid diaphyseal femoral fracture that was then fixed with an external fixator. Animals were randomised into four groups to receive an intra-operative dose of either 100 μg TP508 into the fracture gap; 100 μg TP508 into the surrounding damaged muscle tissues; 10 μg TP508 into the fracture gap, or control equal amount of saline into the fracture gap. Radiographic assessment was performed weekly for 5 weeks; histological analysis was at 3 and 5 weeks post fracture and biomechanical testing of the fractured bone was performed at 5 weeks post fracture. Results Mechanical testing data showed that the fracture stiffness was significantly higher in the group receiving 100 μg TP508 into the fracture gap than other groups. Histological and radiographic analysis revealed a trend of increase in bone formation in the 100 μg TP508 injected into the fracture gap group compared to the saline control group. It was noted that the scar tissues was significantly less in Group II comparing with the saline control group and there was increased blood vessel formation in the crushed muscles and fracture gap areas in the groups receiving TP508 comparing to the saline control group. Conclusion The results from this study demonstrated the use of thrombin related peptide TP508 in the situation of a high energy fracture can promote fracture healing and reduce the potential complications such as muscle fibrosis and fracture delayed or non-union.

  15. Optimized p53 immunohistochemistry is an accurate predictor of TP53 mutation in ovarian carcinoma.

    Science.gov (United States)

    Köbel, Martin; Piskorz, Anna M; Lee, Sandra; Lui, Shuhong; LePage, Cecile; Marass, Francesco; Rosenfeld, Nitzan; Mes Masson, Anne-Marie; Brenton, James D

    2016-10-01

    TP53 mutations are ubiquitous in high-grade serous ovarian carcinomas (HGSOC), and the presence of TP53 mutation discriminates between high and low-grade serous carcinomas and is now an important biomarker for clinical trials targeting mutant p53. p53 immunohistochemistry (IHC) is widely used as a surrogate for TP53 mutation but its accuracy has not been established. The objective of this study was to test whether improved methods for p53 IHC could reliably predict TP53 mutations independently identified by next generation sequencing (NGS). Four clinical p53 IHC assays and tagged-amplicon NGS for TP53 were performed on 171 HGSOC and 80 endometrioid carcinomas (EC). p53 expression was scored as overexpression (OE), complete absence (CA), cytoplasmic (CY) or wild type (WT). p53 IHC was evaluated as a binary classifier where any abnormal staining predicted deleterious TP53 mutation and as a ternary classifier where OE, CA or WT staining predicted gain-of-function (GOF or nonsynonymous), loss-of-function (LOF including stopgain, indel, splicing) or no detectable TP53 mutations (NDM), respectively. Deleterious TP53 mutations were detected in 169/171 (99%) HGSOC and 7/80 (8.8%) EC. The overall accuracy for the best performing IHC assay for binary and ternary prediction was 0.94 and 0.91 respectively, which improved to 0.97 (sensitivity 0.96, specificity 1.00) and 0.95 after secondary analysis of discordant cases. The sensitivity for predicting LOF mutations was lower at 0.76 because p53 IHC detected mutant p53 protein in 13 HGSOC with LOF mutations. CY staining associated with LOF was seen in 4 (2.3%) of HGSOC. Optimized p53 IHC can approach 100% specificity for the presence of TP53 mutation and its high negative predictive value is clinically useful as it can exclude the possibility of a low-grade serous tumour. 4.1% of HGSOC cases have detectable WT staining while harboring a TP53 LOF mutation, which limits sensitivity for binary prediction of mutation to 96%.

  16. Valores, Creencias Y Objectivos: Base del programa de la Escuela Experimental P.K. Yonge. (Values, Beliefs and Objectives: The Basis of Experimental Schools P.K. Yonge's Program.)

    Science.gov (United States)

    Florida Univ., Gainesville. Coll. of Education.

    The values, beliefs, and objectives that form the core of the program at the Experimental School P.K. Yonge in the University of Florida are presented in this paper which is written in Spanish. This experimental school serves approximately 900 students from grades one through twelve. The function of the school is to conduct research to solve…

  17. Proliferation Characteristics of a PK-15 Cell-adapted Strain of Porcine Parvovirus%猪细小病毒PK-15细胞适应株的培育及增殖特性

    Institute of Scientific and Technical Information of China (English)

    吴云飞; 朱玲; 徐志文; 付梦瑾; 陈蕾; 阳爱国; 郭万柱

    2013-01-01

    To study the proliferation characteristics of PPV in differently infected way and the variance of concentrations in different cells.A strain of porcine parvovirus(PPV) was adapted to PK-15 cells,and a Real-time fluorescent quantitative PCR (FQ-PCR) assay was developed based on the specific region of the NS1 gene of PPV to quantify the PPV.The FQ-PCR was used to measure the viral concentration of virusinfected cells by simultaneous or step by step inoculation and plot one-step growth curves.The proliferation characteristics of PPV strain in different cells lines (HeLa,MDBK,PK-15,ST,F81,BHK-21 and Marc-145) was also compared.The results showed the PK-15 cell-adapted strain of PPV produced CPE after 12 passages,and maintained stable CPE at the following 10 messages.The one-step growth curve showed that the virus concentration of simultaneous inoculation was higher than that of the step-by-step inoculation,and the proliferation cycle of step-by-step inoculation was shorter.The proliferation ability of PPV strain in different ceils showed that CPE appeared first inPK-15,followed by ST,HeLa and MDBK,and the virus concentration was highest in ST,followed byPK-15,MDBK and HeLa.NO proliferation was observed in F81,BHK-21 and Marc-145 cells.These findings lay a material foundation for the basic researches on PPV and the development of vaccine.%为了研究猪细小病毒不同接毒方式的增殖规律及在不同细胞的病毒含量差异.本实验利用PK-15细胞对猪细小病毒(Porcine parvovirus,PPV)分离株进行适应性培养.针对PPV的NS1基因设计特异性引物,建立实时荧光定量PCR方法.利用该方法检测PPV分离株同步和分步接毒的病毒含量,绘制一步生长曲线;同时检测PPV在HeLa、MDBK、PK-15、ST、F81、BHK-21和Marc-145细胞上的增殖特性.结果显示,PPV分离株盲传至12代产生CPE,继续传代培养10代仍能产生稳定的细胞病变,成功培育出PK-15细胞适应株.一步生长曲线显示,

  18. Investigation of utilization of nanosuspension formulation to enhance exposure of 1,3-dicyclohexylurea in rats: Preparation for PK/PD study via subcutaneous route of nanosuspension drug delivery

    Science.gov (United States)

    Chiang, Po-Chang; Ran, Yingqing; Chou, Kang-Jye; Cui, Yong; Wong, Harvey

    2011-06-01

    1,3-Dicyclohexylurea (DCU), a potent soluble epoxide hydrolase (sEH) inhibitor has been reported to lower systemic blood pressure in spontaneously hypertensive rats. One limitation of continual administration of DCU for in vivo studies is the compound's poor oral bioavailability. This phenomenon is mainly attributed to its poor dissolution rate and low aqueous solubility. Previously, wet-milled DCU nanosuspension has been reported to enhance the bioavailability of DCU. However, the prosperities and limitations of wet-milled nanosuspension have not been fully evaluated. Furthermore, the oral pharmacokinetics of DCU in rodent are such that the use of DCU to understand PK/PD relationships of sEH inhibitors in preclinical efficacy model is less than ideal. In this study, the limitation of orally delivered DCU nanosuspension was assessed by a surface area sensitive absorption model and pharmacokinetic modeling. It was found that dosing DCU nanosuspension did not provide the desired plasma profile needed for PK/PD investigation. Based on the model and in vivo data, a subcutaneous route of delivery of nanosuspension of DCU was evaluated and demonstrated to be appropriate for future PK/PD studies.

  19. Investigation of utilization of nanosuspension formulation to enhance exposure of 1,3-dicyclohexylurea in rats: Preparation for PK/PD study via subcutaneous route of nanosuspension drug delivery

    Directory of Open Access Journals (Sweden)

    Chiang Po-Chang

    2011-01-01

    Full Text Available Abstract 1,3-Dicyclohexylurea (DCU, a potent soluble epoxide hydrolase (sEH inhibitor has been reported to lower systemic blood pressure in spontaneously hypertensive rats. One limitation of continual administration of DCU for in vivo studies is the compound's poor oral bioavailability. This phenomenon is mainly attributed to its poor dissolution rate and low aqueous solubility. Previously, wet-milled DCU nanosuspension has been reported to enhance the bioavailability of DCU. However, the prosperities and limitations of wet-milled nanosuspension have not been fully evaluated. Furthermore, the oral pharmacokinetics of DCU in rodent are such that the use of DCU to understand PK/PD relationships of sEH inhibitors in preclinical efficacy model is less than ideal. In this study, the limitation of orally delivered DCU nanosuspension was assessed by a surface area sensitive absorption model and pharmacokinetic modeling. It was found that dosing DCU nanosuspension did not provide the desired plasma profile needed for PK/PD investigation. Based on the model and in vivo data, a subcutaneous route of delivery of nanosuspension of DCU was evaluated and demonstrated to be appropriate for future PK/PD studies.

  20. Evaluation of the recombinant protein TpF1 of Treponema pallidum for serodiagnosis of syphilis.

    Science.gov (United States)

    Jiang, Chuanhao; Zhao, Feijun; Xiao, Jinhong; Zeng, Tiebing; Yu, Jian; Ma, Xiaohua; Wu, Haiying; Wu, Yimou

    2013-10-01

    Syphilis is a chronic infection caused by Treponema pallidum subsp. pallidum, and diagnosis with sensitive and specific methods is a challenging process that is important for its prevention and treatment. In the present study, we established a recombinant protein TpF1-based indirect immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) and a Western blot assay for human and rabbit sera. The 20-kDa recombinant protein TpF1 was detected by Western blotting performed with sera from rabbits immunized with recombinant TpF1 and infected with the T. pallidum Nichols strain and T. pallidum clinical isolates but was not detected by Western blotting with sera from uninfected rabbits. The sensitivity of the recombinant protein was determined by screening sera from individuals with primary, secondary, latent, and congenital syphilis (n = 82). The specificity of the recombinant protein was determined by screening sera from uninfected controls (n = 30) and individuals with potentially cross-reactive infections, including Lyme disease (n = 30) and leptospirosis (n = 5). The sensitivities of TpF1-based ELISAs were 93.3%, 100%, 100%, and 100% for primary, secondary, latent, and congenital syphilis, respectively, and the specificities were all 100% for sera from uninfected controls and individuals with potentially cross-reactive infections. In Western blot assays, the sensitivities and specificities of TpF1 for human sera were all 100%. The reactivities of TpF1 with syphilitic sera were proportional to the titers of the T. pallidum particle agglutination (TPPA) assay. These data indicate that the recombinant protein TpF1 is a highly immunogenic protein in human and rabbit infections and a promising marker for the screening of syphilis.

  1. Glucagon-Secreting Alpha Cell Selective Two-Photon Fluorescent Probe TP-α: For Live Pancreatic Islet Imaging.

    Science.gov (United States)

    Agrawalla, Bikram Keshari; Chandran, Yogeswari; Phue, Wut-Hmone; Lee, Sung-Chan; Jeong, Yun-Mi; Wan, Si Yan Diana; Kang, Nam-Young; Chang, Young-Tae

    2015-04-29

    Two-photon (TP) microscopy has an advantage for live tissue imaging which allows a deeper tissue penetration up to 1 mm comparing to one-photon (OP) microscopy. While there are several OP fluorescence probes in use for pancreatic islet imaging, TP imaging of selective cells in live islet still remains a challenge. Herein, we report the discovery of first TP live pancreatic islet imaging probe; TP-α (Two Photon-alpha) which can selectively stain glucagon secreting alpha cells. Through fluorescent image based screening using three pancreatic cell lines, we discovered TP-α from a TP fluorescent dye library TPG (TP-Green). In vitro fluorescence test showed that TP-α have direct interaction and appear glucagon with a significant fluorescence increase, but not with insulin or other hormones/analytes. Finally, TP-α was successfully applied for 3D imaging of live islets by staining alpha cell directly. The newly developed TP-α can be a practical tool to evaluate and identify live alpha cells in terms of localization, distribution and availability in the intact islets.

  2. TP53 intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome.

    Science.gov (United States)

    Ribi, Sebastian; Baumhoer, Daniel; Lee, Kristy; Edison; Teo, Audrey S M; Madan, Babita; Zhang, Kang; Kohlmann, Wendy K; Yao, Fei; Lee, Wah Heng; Hoi, Qiangze; Cai, Shaojiang; Woo, Xing Yi; Tan, Patrick; Jundt, Gernot; Smida, Jan; Nathrath, Michaela; Sung, Wing-Kin; Schiffman, Joshua D; Virshup, David M; Hillmer, Axel M

    2015-04-10

    Somatic mutations of TP53 are among the most common in cancer and germline mutations of TP53 (usually missense) can cause Li-Fraumeni syndrome (LFS). Recently, recurrent genomic rearrangements in intron 1 of TP53 have been described in osteosarcoma (OS), a highly malignant neoplasm of bone belonging to the spectrum of LFS tumors. Using whole-genome sequencing of OS, we found features of TP53 intron 1 rearrangements suggesting a unique mechanism correlated with transcription. Screening of 288 OS and 1,090 tumors of other types revealed evidence for TP53 rearrangements in 46 (16%) OS, while none were detected in other tumor types, indicating this rearrangement to be highly specific to OS. We revisited a four-generation LFS family where no TP53 mutation had been identified and found a 445 kb inversion spanning from the TP53 intron 1 towards the centromere. The inversion segregated with tumors in the LFS family. Cancers in this family had loss of heterozygosity, retaining the rearranged allele and resulting in TP53 expression loss. In conclusion, intron 1 rearrangements cause p53-driven malignancies by both germline and somatic mechanisms and provide an important mechanism of TP53 inactivation in LFS, which might in part explain the diagnostic gap of formerly classified "TP53 wild-type" LFS.

  3. A physiologically based pharmacokinetic (PB/PK) model for multiple exposure routes for soman in multiple species

    NARCIS (Netherlands)

    Sweeney, R.E.; Langenberg, J.P.; Maxwell, D.M.

    2006-01-01

    A physiologically based pharmacokinetic (PB/PK) model has been developed in advanced computer simulation language (ACSL) to describe blood and tissue concentration-time profiles of the C(±)P(-) stereoisomers of soman after inhalation, subcutaneous and intravenous exposures at low (0.8-1.0 × LD50), m

  4. The radiosynthesis of ( sup 18 F)PK 14105 as an alternative radioligand for peripheral type benzodiazepine binding sites

    Energy Technology Data Exchange (ETDEWEB)

    Pascali, C.; Luthra, S.K.; Pike, V.W.; Price, G.W.; Ahier, R.G.; Hume, S.P.; Myers, R.; Manjil, L.; Cremer, J.E. (Hammersmith Hospital, London (UK). M.R.C. Cyclotron Unit)

    1990-01-01

    A method has been developed for labelling PK 14105 (N-methyl-N-(1-methyl-propyl)-1(2-fluoro-5-nitrophenyl)isoquinoline-3-carboxamide ), a ligand that has high affinity and selectivity for peripheral type benzodiazepine binding sites (PBBS), with NCA fluorine-18 (t{sub 1/2}=109.8 min, {beta}{sup +} = 96.9%). The method involves treating the 2-chloro-analogue with cyclotron-produced NCA ({sup 18}F)fluoride in dimethyl sulphoxide, with rubidium carbonate as base, at 140{sup 0}C for 20 min. Purification is achieved by separation on a reverse phase Sep-Pak followed by HPLC on a silica gel column, to give chemically and radiochemically pure product with a specific activity of ca 7.4 GBq/{mu}mol (200 mCi{mu}mol), decay-corrected to the end of radionuclide production (EOB). The radiosynthesis requires 210 min, giving a radiochemical yield of 10-20%, decay-corrected to EOB. ({sup 18}F)PK 14105 was found to bind avidly to sites associated with kainic acid-induced unilateral lesions of rat striata. Such binding was blocked by pre-dosing the rat with PK 11195, so providing evidence for specific binding to PBBS. These results suggest that ({sup 18}F)PK 14105 has potential for studying phenomena associated with PBBS in man by PET. (author).

  5. Comparison of the proteomes of three yeast wild type strains: CEN.PK2, FY1679 and W303

    DEFF Research Database (Denmark)

    Rogowska-Wrzesinska, A.; Mose Larsen, P.; Blomberg, A.

    2001-01-01

    Yeast deletion strains created during gene function analysis projects very often show drastic phenotypic differences depending on the genetic background used. These results indicate the existence of important molecular differences between the CEN.PK2, FY1679 and W303 wild type strains. To charact...

  6. The apparent positive cooperativity of in vivo [{sup 3}H]PK-11195 binding in mouse fibrosarcoma

    Energy Technology Data Exchange (ETDEWEB)

    Momosaki, Sotaro [Course of Allied Health Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871 (Japan)]. E-mail: momosaki@sahs.med.osaka-u.ac.jp; Hosoi, Rie [Course of Allied Health Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871 (Japan); Takai, Nobuhiko [Heavy-Ion Radiobiology Research Group, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Gee, Antony [GlaxoSmithKline, Clinical Research Unit, ACCI, Addenbrookes Hospital, Cambridge CB2 2GC (United Kingdom); Inoue, Osamu [Course of Allied Health Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871 (Japan)

    2006-08-15

    To evaluate the binding properties of peripheral benzodiazepine receptor (PBR) in mouse fibrosarcoma, [{sup 3}H]PK-11195 binding, in vitro and in vivo, was investigated using either tissue dissection or autoradiographic method. The binding characteristics in fibrosarcoma were compared with those in the kidney. The results of an in vitro saturation study revealed that the maximal numbers of PBR binding sites (B {sub max}) in fibrosarcoma and in the kidney were almost the same (kidney: 5.2 pmol/mg protein; fibrosarcoma: 5.0 pmol/mg protein). On the other hand, the binding affinity (K {sub d}) in fibrosarcoma was lower than that in the kidney (kidney: 0.45 nM; fibrosarcoma: 1.34 nM). It is noteworthy that the in vivo binding of [{sup 3}H]PK-11195 in fibrosarcoma increased with increasing doses of [{sup 3}H]PK-11195 (in the dose range of 0.03-1 mg/kg), whereas that in the kidney decreased with competitive inhibition. The apparent positive cooperativity of [{sup 3}H]PK-11195 binding in fibrosarcoma was only observed under in vivo conditions and might be possibly related to the incoordination of PBR subunits.

  7. IMPLEMENTASI PEMERINTAHAN YANG BERSIH DALAM KERANGKA RENCANA AKSI DAERAH PEMBERANTASAN KORUPSI (RAD-PK (Studi Di Kabupaten Pemalang

    Directory of Open Access Journals (Sweden)

    Muhammad Fauzan

    2012-03-01

    Full Text Available This research related to the implementation of good governance, free from corruption, collusion and nepotism. The approach used in this research is a descriptive qualitative approach. The Location of research conducted in the District of Pemalang. Based on the research results can presented that the District of Pemalang is committed and fully supports the government policy in eradicating corruption. District of Pemalang support to efforts to more information accelerate the eradication of corruption stated in the the Regional Action Plan to Accelerate the Eradication of Corruption (RAD-PK in 2011 -2016 which refers to the Medium Term Development Plan (RPJM District of Pemalang from 2011 to 2016 and the National Action Plan for Eradication of Corruption (RAN-PK and the President of Republic of Indonesia Instruction No. 5 Year 2004 on Accelerating the eradication of corruption. RAD-PK 2011-2016 District of Pemalang is a document that contains an action program that aims to accelerate the eradication of corruption. RAD-PK as a program of action containing concrete measures that have been agreed by the stakeholders in the area, so it has been a commitment of local governments prevention efforts corruption through the development of programs and activities aimed at improving public services and the application of the principles of good governance.

  8. Rapid and efficient radiosynthesis of [{sup 123}I]I-PK11195, a single photon emission computed tomography tracer for peripheral benzodiazepine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Pimlott, Sally L. [Department of Clinical Physics, West of Scotland Radionuclide Dispensary, Western Infirmary, G11 6NT Glasgow (United Kingdom)], E-mail: s.pimlott@clinmed.gla.ac.uk; Stevenson, Louise [Department of Chemistry, WestCHEM, University of Glasgow, G12 8QQ Glasgow (United Kingdom); Wyper, David J. [Institute of Neurological Sciences, Southern General Hospital, G51 4TF Glasgow (United Kingdom); Sutherland, Andrew [Department of Chemistry, WestCHEM, University of Glasgow, G12 8QQ Glasgow (United Kingdom)

    2008-07-15

    Introduction: [{sup 123}I]I-PK11195 is a high-affinity single photon emission computed tomography radiotracer for peripheral benzodiazepine receptors that has previously been used to measure activated microglia and to assess neuroinflammation in the living human brain. This study investigates the radiosynthesis of [{sup 123}I]I-PK11195 in order to develop a rapid and efficient method that obtains [{sup 123}I]I-PK11195 with a high specific activity for in vivo animal and human imaging studies. Methods: The synthesis of [{sup 123}I]I-PK11195 was evaluated using a solid-state interhalogen exchange method and an electrophilic iododestannylation method, where bromine and trimethylstannyl derivatives were used as precursors, respectively. In the electrophilic iododestannylation method, the oxidants peracetic acid and chloramine-T were both investigated. Results: Electrophilic iododestannylation produced [{sup 123}I]I-PK11195 with a higher isolated radiochemical yield and a higher specific activity than achievable using the halogen exchange method investigated. Using chloramine-T as oxidant provided a rapid and efficient method of choice for the synthesis of [{sup 123}I]I-PK11195. Conclusions: [{sup 123}I]I-PK11195 has been successfully synthesized via a rapid and efficient electrophilic iododestannylation method, producing [{sup 123}I]I-PK11195 with a higher isolated radiochemical yield and a higher specific activity than previously achieved.

  9. The pkI gene encoding pyruvate kinase I links to the luxZ gene which enhances bioluminescence of the lux operon from Photobacterium leiognathi.

    Science.gov (United States)

    Lin, J W; Lu, H C; Chen, H Y; Weng, S F

    1997-10-09

    Partial 3'-end nucleotide sequence of the pkI gene (GenBank accession No. AF019143) from Photobacterium leiognathi ATCC 25521 has been determined, and the encoded pyruvate kinase I is deduced. Pyruvate kinase I is the key enzyme of glycolysis, which converts phosphoenol pyruvate to pyruvate. Alignment and comparison of pyruvate kinase Is from P. leiognathi, E. coli and Salmonella typhimurium show that they are homologous. Nucleotide sequence reveals that the pkI gene is linked to the luxZ gene that enhances bioluminescence of the lux operon from P. leiognathi. The gene order of the pkI and luxZ genes is-pk1-ter-->-R&R"-luxZ-ter"-->, whereas ter is transcriptional terminator for the pkI and related genes, and R&R" is the regulatory region and ter" is transcriptional terminator for the luxZ gene. It clearly elicits that the pkI gene and luxZ gene are divided to two operons. Functional analysis confirms that the potential hairpin loop omega T is the transcriptional terminator for the pkI and related genes. It infers that the pkI and related genes are simply linked to the luxZ gene in P. leiognathi genome.

  10. Inhibition of autophagy attenuates pancreatic cancer growth independent of TP53/TRP53 status.

    Science.gov (United States)

    Yang, Annan; Kimmelman, Alec C

    2014-09-01

    Basal levels of autophagy are elevated in most pancreatic ductal adenocarcinomas (PDAC). Suppressing autophagy pharmacologically using chloroquine (CQ) or genetically with RNAi to essential autophagy genes inhibits human pancreatic cancer growth in vitro and in vivo, which presents possible treatment opportunities for PDAC patients using the CQ-derivative hydroxychloroquine (HCQ). Indeed, such clinical trials are ongoing. However, autophagy is a complex cellular mechanism to maintain cell homeostasis under stress. Based on its biological role, a dual role of autophagy in tumorigenesis has been proposed: at tumor initiation, autophagy helps maintain genomic stability and prevent tumor initiation; while in advanced disease, autophagy degrades and recycles cellular components to meet the metabolic needs for rapid growth. This model was proven to be the case in mouse lung tumor models. However, in contrast to prior work in various PDAC model systems, loss of autophagy in PDAC mouse models with embryonic homozygous Trp53 deletion does not inhibit tumor growth and paradoxically increases progression. This raised concerns whether there may be a genotype-dependent reliance of PDAC on autophagy. In a recent study, our group used a Trp53 heterozygous mouse PDAC model and human PDX xenografts to address the question. Our results demonstrate that autophagy inhibition was effective against PDAC tumors irrespective of TP53/TRP53 status.

  11. Analysis of ECG Tp and Te interval on the clinical value of coronary heart disease%心电图 Tp-Te 间期对冠心病患者的临床诊断价值

    Institute of Scientific and Technical Information of China (English)

    丁莹; 刘海; 张民

    2014-01-01

    目的:探讨心电图T波峰末( Tp-Te )间期对冠心病患者的临床诊断价值。方法回顾性分析2010年5月-2013年5月入住的110例心脏病患者的临床资料,其中62例为冠心病患者( CHD组),48例为非冠心病患者(非CHD组)。对2组患者Tp-Te 间期、Tp-Te 间期离散度及J波进行测量,并对心电图进行记录。结果(1)2组V2导联Tp-Te 间期、V6导联Tp-Te 间期比较,差异具有统计学意义( P <0|.05, P <0.01),但Tp-Te 间期离散度比较,差异无统计学意义( P >0.05);(2)不同支数冠状动脉狭窄组间V2导联Tp-Te 间期、V6导联Tp-Te间期及Tp-Te 间期离散度比较,差异均无统计学意义( P >0.05);(3)冠心病患者中,有J波组与无J波组V2导联Tp-Te 间期、V6导联Tp-Te 间期及Tp-Te 间期离散度比较,差异均无统计学意义( P >0.05)。结论心电图Tp-Te 间期对冠心病的诊断具有一定的临床价值;冠脉狭窄支数或缺血性J波对Tp-Te 间期并非惟一的影响因素。%Objective To explore the electrocardiogram T wave end ( Tp-Te ) interval of coronary heart disease in clinical diagnostic value .Methods Retrospective analysis of May 2010 to May 2013 110 cases clinical data of inpatients with heart disease , including 62 cases of coronary heart disease ( CHD group ) , 48 cases of non-coronary heart disease ( non-CHD group).On two groups of patients T p-Te interval, Tp-Te interval dispersion and J wave measurements , and ECG recording.Re-sults (1) 2 group V2 lead Tp-Te interval, V6 lead Tp-Te interval value, the difference was statistically significant ( P 0.05);(2)Diffe rent counts coronary stenosis group V2 lead Tp-Te interval, V6 lead Tp-Te interval and Tp-Te interval dispersion,the difference was not statistically significant ( P >0.05) ;(3)Coronary artery disease patients, J wave group and non-J wave group V2 J wave ECG Tp-Te interval, V6 lead Tp-Te interval

  12. Genetic variation in the TP53 pathway and bladder cancer risk. a comprehensive analysis.

    Directory of Open Access Journals (Sweden)

    Silvia Pineda

    Full Text Available INTRODUCTION: Germline variants in TP63 have been consistently associated with several tumors, including bladder cancer, indicating the importance of TP53 pathway in cancer genetic susceptibility. However, variants in other related genes, including TP53 rs1042522 (Arg72Pro, still present controversial results. We carried out an in depth assessment of associations between common germline variants in the TP53 pathway and bladder cancer risk. MATERIAL AND METHODS: We investigated 184 tagSNPs from 18 genes in 1,058 cases and 1,138 controls from the Spanish Bladder Cancer/EPICURO Study. Cases were newly-diagnosed bladder cancer patients during 1998-2001. Hospital controls were age-gender, and area matched to cases. SNPs were genotyped in blood DNA using Illumina Golden Gate and TaqMan assays. Cases were subphenotyped according to stage/grade and tumor p53 expression. We applied classical tests to assess individual SNP associations and the Least Absolute Shrinkage and Selection Operator (LASSO-penalized logistic regression analysis to assess multiple SNPs simultaneously. RESULTS: Based on classical analyses, SNPs in BAK1 (1, IGF1R (5, P53AIP1 (1, PMAIP1 (2, SERINPB5 (3, TP63 (3, and TP73 (1 showed significant associations at p-value≤0.05. However, no evidence of association, either with overall risk or with specific disease subtypes, was observed after correction for multiple testing (p-value≥0.8. LASSO selected the SNP rs6567355 in SERPINB5 with 83% of reproducibility. This SNP provided an OR = 1.21, 95%CI 1.05-1.38, p-value = 0.006, and a corrected p-value = 0.5 when controlling for over-estimation. DISCUSSION: We found no strong evidence that common variants in the TP53 pathway are associated with bladder cancer susceptibility. Our study suggests that it is unlikely that TP53 Arg72Pro is implicated in the UCB in white Europeans. SERPINB5 and TP63 variation deserve further exploration in extended studies.

  13. Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of the hypothalamic-pituitary-gonadal axis following treatment with GnRH analogues

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Senderovitz, Thomas;

    2007-01-01

    Aims To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of the hypothalamic-pituitary-gonadal (HPG) axis describing the changes in luteinizing hormone (LH) and testosterone concentrations following treatment with the gonadotropin-releasing hormone (GnRH) agonist triptorelin...... and the GnRH receptor blocker degarelix. Methods Fifty-eight healthy subjects received single subcutaneous or intramuscular injections of 3.75 mg of triptorelin and 170 prostate cancer patients received multiple subcutaneous doses of degarelix of between 120 and 320 mg. All subjects were pooled...... for the different dynamic responses observed after administration of both GnRH agonists and GnRH receptor blockers, suggesting that the model adequately characterizes the underlying physiology of the endocrine system....

  14. Search for a narrow baryonic state decaying to ${pK^0_S}$ and ${\\overline{p}K^0_S}$ in deep inelastic scattering at HERA

    CERN Document Server

    Abramowicz, H.; Adamczyk, L.; Adamus, M.; Antonelli, S.; Aushev, V.; Behnke, O.; Behrens, U.; Bertolin, A.; Bhadra, S.; Bloch, I.; Boos, E.G.; Brock, I.; Brook, N.H.; Brugnera, R.; Bruni, A.; Bussey, P.J.; Caldwell, A.; Capua, M.; Catterall, C.D.; Chwastowski, J.; Ciborowski, J.; Ciesielski, R.; Cooper-Sarkar, A.M.; Corradi, M.; Dementiev, R.K.; Devenish, RCE; Dusini, S.; Foster, B.; Gach, G; Gallo, E.; Garfagnini, A.; Geiser, A.; Gizhko, A.; Gladilin, L.K.; Golubkov, Yu.A.; Grzelak, G.; Guzik, M.; Gwenlan, C.; Hain, W.; Hlushchenko, O.; Hochman, D.; Hori, R.; Ibrahim, Z.A.; Iga, Y.; Ishitsuka, M.; Januschek, F.; Jomhari, N.Z.; Kadenko, I.; Kananov, S.; Karshon, U.; Kaur, P.; Kisielewska, D.; Klanner, R.; Klein, U.; Korzhavina, I.A.; Kotański, A.; Kötz, U.; Kovalchuk, N.; Kowalski, H.; Krupa, B.; Kuprash, O.; Kuze, M; Levchenko, B.B.; Levy, A.; Limentani, S.; Lisovyi, M.; Lobodzinska, E.; Löhr, B.; Lohrmann, E.; Longhin, A.; Lontkovskyi, D.; Lukina, O.Yu.; Makarenko, I.; Malka, J.; Mastroberardino, A.; Mohamad Idris, F.; Mohammad Nasir, N; Myronenko, V.; Nagano, K.; Nobe, T.; Nowak, R.J.; Onishchuk, Yu.; Paul, E.; Perlański, W.; Pokrovskiy, N.S.; Polini, A.; Przybycien, M.; Roloff, P.; Ruspa, M.; Saxon, D.H.; Schioppa, M.; Schneekloth, U.; Schörner-Sadenius, T.; Shcheglova, L.M.; Shevchenko, R.; Shkola, O.; Shyrma, Yu.; Singh, I.; Skillicorn, I.O.; Słomiński, W.; Solano, A.; Stanco, L.; Stefaniuk, N.; Stern, A.; Stopa, P.; Sztuk-Dambietz, J.; Tassi, E.; Tokushuku, K.; Tomaszewska, J.; Tsurugai, T.; Turcato, M.; Turkot, O.; Tymieniecka, T.; Verbytskyi, A.; Wan Abdullah, W.A.T.; Wichmann, K.; Wing, M.; Yamada, S.; Yamazaki, Y.; Zakharchuk, N.; Żarnecki, A.F.; Zawiejski, L.; Zenaiev, O.; Zhautykov, B.O.; Zotkin, D.S.; Mastroberardino, A

    2016-01-01

    A search for a narrow baryonic state in the $pK^0_S$ and $\\overline{p}K^0_S$ system has been performed in $ep$ collisions at HERA with the ZEUS detector using an integrated luminosity of 358 pb$^{-1}$ taken in 2003-2007. The search was performed with deep inelastic scattering events at an $ep$ centre-of-mass energy of 318 GeV for exchanged photon virtuality, $Q^2$, between 20 and 100 $\\rm{} GeV^{2}$. Contrary to evidence presented for such a state around 1.52 GeV in a previous ZEUS analysis using a sample of 121 pb$^{-1}$ taken in 1996-2000, no resonance peak was found in the $p(\\overline{p})K^0_S$ invariant-mass distribution in the range 1.45-1.7 GeV. Upper limits on the production cross section are set.

  15. TP receptor as a therapeutic target in atherosclerosis and related cardiovascular diseases.

    Science.gov (United States)

    Ishizuka, Toshiaki; Higashino, Hideaki

    2006-11-01

    It had already showed that several thromboxane A(2) receptor (TP receptor) antagonists might be utilized in the treatment of cardiovascular diseases. In addition, recent reports suggested that TP receptor antagonism may be able to restrict vascular inflammation in atherosclerotic vessels. In particular, S18886 has been developed as a non-prostanoid TP receptor antagonist derived from sulotroban that is characterized by a tetrahydronaphthalene ring as a spacer between the 4-cholophenylsulfonamide group and carboxylic acid. Several reports using experimental animal models of atherosclerosis indicated that S18886 caused a regression of advanced atherosclerosis. More recently, several studies and patents showed that new thromboxane modulators combined with another pharmacological activities have been developed. Ohtake et al. discovered TRA-418 (a benzene-condensed heterocyclic derivative) having a TP receptor antagonistic activity and a prostaglandin I(2) receptor agonistic activity. Cesagrande found that 4-methyl-N- (4-trans-nitrooxycyclohexyl)-N-(3-pyridinylmethyl)-1,3- benzenedicarboxamide is endowed with anti-thromboxane and NO-donor actions. Oketani et al. discovered that E3040, a novel benzothiazole derivative, inhibited TXA(2) synthase and 5-LO activities. EK112, a combined angiotensin II and TP receptor antagonist, was developed. These new compounds may be able to restrict further infiltration of inflammatory cells in atherosclerotic vessels, thus stabilizing vulnerable plaques in the related cardiovascular diseases.

  16. Gaining insights into the codon usage patterns of TP53 gene across eight mammalian species.

    Directory of Open Access Journals (Sweden)

    Tarikul Huda Mazumder

    Full Text Available TP53 gene is known as the "guardian of the genome" as it plays a vital role in regulating cell cycle, cell proliferation, DNA damage repair, initiation of programmed cell death and suppressing tumor growth. Non uniform usage of synonymous codons for a specific amino acid during translation of protein known as codon usage bias (CUB is a unique property of the genome and shows species specific deviation. Analysis of codon usage bias with compositional dynamics of coding sequences has contributed to the better understanding of the molecular mechanism and the evolution of a particular gene. In this study, the complete nucleotide coding sequences of TP53 gene from eight different mammalian species were used for CUB analysis. Our results showed that the codon usage patterns in TP53 gene across different mammalian species has been influenced by GC bias particularly GC3 and a moderate bias exists in the codon usage of TP53 gene. Moreover, we observed that nature has highly favored the most over represented codon CTG for leucine amino acid but selected against the ATA codon for isoleucine in TP53 gene across all mammalian species during the course of evolution.

  17. The TP53 dependence of radiation-induced chromosome instability in human lymphoblastoid cells

    Science.gov (United States)

    Schwartz, Jeffrey L.; Jordan, Robert; Evans, Helen H.; Lenarczyk, Marek; Liber, Howard

    2003-01-01

    The dose and TP53 dependence for the induction of chromosome instability were examined in cells of three human lymphoblastoid cell lines derived from WIL2 cells: TK6, a TP53-normal cell line, NH32, a TP53-knockout created from TK6, and WTK1, a WIL2-derived cell line that spontaneously developed a TP53 mutation. Cells of each cell line were exposed to (137)Cs gamma rays, and then surviving clones were isolated and expanded in culture for approximately 35 generations before the frequency and characteristics of the instability were analyzed. The presence of dicentric chromosomes, formed by end-to-end fusions, served as a marker of chromosomal instability. Unexposed TK6 cells had low levels of chromosomal instability (0.002 +/- 0.001 dicentrics/cell). Exposure of TK6 cells to doses as low as 5 cGy gamma rays increased chromosome instability levels nearly 10-fold to 0.019 +/- 0.008 dicentrics/cell. There was no further increase in instability levels beyond 5 cGy. In contrast to TK6 cells, unexposed cultures of WTK1 and NH32 cells had much higher levels of chromosome instability of 0.034 +/- 0.007 and 0.041 +/- 0.009, respectively, but showed little if any effect of radiation on levels of chromosome instability. The results suggest that radiation exposure alters the normal TP53-dependent cell cycle checkpoint controls that recognize alterations in telomere structure and activate apoptosis.

  18. Genetic variants in TP53 and MDM2 associated with male infertility in Chinese population

    Institute of Scientific and Technical Information of China (English)

    Cong Huang; Wei Liu; Gui-Xiang Ji; Ai-Hua Gu; Jian-Hua Qu; Ling Song; Xin-Ru Wang

    2012-01-01

    The TP53,a transcriptional regulator and tumor suppressor,is functionally important in spermatogenesis.MDM2 is a key regulator of the p53 pathway and modulates p53 activity.Both proteins have been functionally linked to germ cell apoptosis,which may affect human infertility,but very little is known on how common polymorphisms in these genes may influence germ cell apoptosis and the risk of male infertility.Thus,this study was designed to test whether three previously described polymorphisms 72Arg>Pro (rs1042522) and the Ex2+ 19C>T (rs2287498) in TP53,and the 5' untranslated region (5' UTR) 309T>G (rs937283) in MDM2,are associated with idiopathic male infertility in a Chinese population.The three polymorphisms were genotyped using OpenArray assay in a hospital-based case-control study,including 580 infertile patients and 580 fertile controls.Our analyses revealed that TP53 Ex2+ 19C>T and MDM2309T>G polymorphisms are associated with mate infertility.Furthermore,we detected a nearly statistically significant additive interaction between TP53 rs2287498 and MDM2 rs937283 for the development of male.infertility (Pinteraction=0.055).In summary,this study found preliminary evidence,demonstrating that genetic variants in genes of the TP53 pathway are risk factors for male infertility.

  19. TP0262 is a modulator of promoter activity of tpr Subfamily II genes of Treponema pallidum ssp. pallidum.

    Science.gov (United States)

    Giacani, Lorenzo; Godornes, Charmie; Puray-Chavez, Maritza; Guerra-Giraldez, Cristina; Tompa, Martin; Lukehart, Sheila A; Centurion-Lara, Arturo

    2009-06-01

    Transcriptional regulation in Treponema pallidum ssp. pallidum is poorly understood, primarily because this organism cannot be cultivated in vitro or genetically manipulated. We have recently shown a phase variation mechanism controlling transcription initiation of Subfamily II tpr (T. pallidumrepeat) genes (tprE, tprG and tprJ), a group of virulence factor candidates. Furthermore, the same study suggested that additional mechanisms might influence the level of transcription of these tprs. The T. pallidum genome sequence has revealed a few open reading frames with similarity to known bacterial transcription factors, including four catabolite activator protein homologues. In this work, sequences matching the Escherichia coli cAMP receptor protein (CRP) binding motif were identified in silico upstream of tprE, tprG and tprJ. Using elecrophoretic mobility shift assay and DNaseI footprinting assay, recombinant TP0262, a T. pallidum CRP homologue, was shown to bind specifically to amplicons obtained from the tpr promoters containing putative CRP binding motifs. Using a heterologous reporter system, binding of TP0262 to these promoters was shown to either increase (tprE and tprJ) or decrease (tprG) tpr promoter activity. This is the first characterization of a T. pallidum transcriptional modulator that influences tpr promoter activity.

  20. TP0262 is a modulator of promoter activity of tpr Subfamily II genes of Treponema pallidum subsp. pallidum

    Science.gov (United States)

    Giacani, Lorenzo; Godornes, Charmie; Puray-Chavez, Maritza; Guerra-Giraldez, Cristina; Tompa, Martin; Lukehart, Sheila A.; Centurion-Lara, Arturo

    2009-01-01

    Transcriptional regulation in Treponema pallidum subsp. pallidum is poorly understood, primarily because this organism cannot be cultivated in vitro or genetically manipulated. We have recently shown a phase variation mechanism controlling transcription initiation of Subfamily II tpr (T. pallidum repeat) genes (tprE, tprG, and tprJ), a group of virulence factor candidates. Furthermore, the same study suggested that additional mechanisms might influence the level of transcription of these tprs. The T. pallidum genome sequence has revealed a few open reading frames (ORFs) with similarity to known bacterial transcription factors (TFs), including four catabolite activator protein (CAP) homologs. In this work, sequences matching the E. coli cAMP receptor protein (CRP) binding motif were identified in silico upstream of tprE, tprG, and tprJ. Using elecrophoretic mobility shift assay (EMSA) and DNaseI footprinting assay, recombinant TP0262, a T. pallidum CRP homolog, was shown to bind specifically to amplicons obtained from the tpr promoters containing putative CRP binding motifs. Using a heterologous reporter system, binding of TP0262 to these promoters was shown to either increase (tprE and tprJ) or decrease (tprG) tpr promoter activity. This is the first characterization of a T. pallidum transcriptional modulator which influences tpr promoter activity. PMID:19432808

  1. Drug Distribution to Human Tissues: Prediction and Examination of the Basic Assumption in In Vivo Pharmacokinetics-Pharmacodynamics (PK/PD) Research.

    Science.gov (United States)

    Poulin, Patrick

    2015-06-01

    mathematical correction to the basic assumption of similar free drug concentration in plasma and tissues can be derived from the tissue composition-based model. Note that this assumption will be further challenged in a dynamic in vivo system in a companion manuscript. Overall, this study was a first attempt to predict the in vivo Kp values for specific human tissues by considering separately the effect of fup and fut , with the aim of facilitating the use of physiologically-based PK (PBPK) model in PK/PD studies. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  2. EXPRESSION AND SUBCELLULAR LOCALIZATION OF DNA-PK IN NASOPHARYNGEAL CARCINOMA CELL LINES CNE1 AND CNE2 WITH DIFFERENT RADIOSENSITIVITY

    Institute of Scientific and Technical Information of China (English)

    ZHONG Ping-ping; HE Yu-xiang; XIA Yun-fei; YAN Shan-shan

    2006-01-01

    Objective: Radiosensitivity is mainly determined by the number of DNA double-strand breaks (DSBs) induced by ionizing radiation and the extent of its repair. The DNA-PK complex formation is one of the major pathways by which the mammalian cells respond to DSBs repairing. Our previous study suggested that CNE1 is more radioresistant than CNE2. This study was designed to answer whether the radiosensitive difference of Nasopharyngeal Carcinoma cell lines CNE 1/CNE2 was related to the expression and localization of Ku70/Ku80/DNA-PKcs. Methods: Immunohistochemistry was performed to detect the subcellular localization of Ku70/Ku80/DNA-PKcs in NPC cells lines CNE1 and CNE2. Western-blot was used to determine the expression of Ku protein in total extract of CNE1 and CNE2 and semi-quantitative assay of protein expression was performed to estimate the optic density (OD) value of each band using automatic image analysis system. Results:Ku70/Ku80/DNA-PKcs primarily located in the nuclei. A part of nucleolus in CNE1 and CNE2 showed positive dyeing of DNA-PKcs. Protein expression of Ku70/Ku80/DNA-PKcs was detected in CNE1 and CNE2, and the integral optical density (IOD) of Ku70 protein was 22.03 ± 7.56 and 19.98 ± 6.04 respectively (t=0.021, P>0.05), while the IODs of Ku80 protein in the two cell lines were 33.44 ± 12.87 and 28.98 ± 9.24 respectively (t=0.24, P>0.05), and the IODs of DNA-PKcs protein were 45.03 ± 1.77 and 40.87 ± 4.19 (t=1.58, P>0.05). The above results suggested that the basic expression of Ku70/Ku80/DNA-PKcs had no statistic difference between the different radiosensitive NPC cell lines CNE1 and CNE2.Conclusion: The variation of radiosensitivity in NPC cell lines CNE1 and CNE2 has no obviously correlation with the subcellular localization and basic expression of DNA-PK protein. So we presumed that the difference of radiosensitivity between CNE1 and CNE2 may be on account of some other factors than subcellular localization and basic expression of

  3. Molecular characterisation of cAMP-dependent protein kinase (PK-A) catalytic subunit isoforms in the male tick, Amblyomma hebraeum.

    Science.gov (United States)

    Tabish, Mohammad; Clegg, Roger A; Turner, Philip C; Jonczy, Jan; Rees, Huw H; Fisher, Michael J

    2006-12-01

    The cAMP-dependent protein kinase (protein kinase A, PK-A) plays a central role in the regulation of diverse aspects of cellular activity. Specifically, PK-A appears to play a key controlling role in the maturation of spermatids. Using a PCR-based approach, with degenerate primers from the highly conserved regions of the PK-A catalytic (C) subunit in combination with 5' and 3' RACE, we have cloned three cDNAs for the PK-A C-subunit of the male tick, Amblyomma hebraeum. The three cDNAs have open reading frames of 1059, 1275 and 1404bp which encode proteins of 40.6, 48.2 and 52.5kDa, respectively. These transcripts appear to arise from 5' alternative splicing of RNA derived from a single gene for the PK-A C-subunit. One isoform (AH-PK-A C1), in common with PK-A C-subunits from a range of species, contains a consensus sequence for N-myristoylation. RT-PCR and Western blot experiments suggest that the three splice variants are expressed ubiquitously; however, expression of the myristoylatable AH-PK-A C1 isoform is predominant in all investigated tissues (accessory gland, midgut, Malpighian tubules, salivary gland, testis and immature spermatids). There is no evidence for a sperm-specific PK-A C-subunit (Cs) in tick sperm; however, tyrosine protein phosphorylation, previously shown to be modulated by PK-A activity during mammalian sperm maturation, was observed in tick sperm.

  4. 99Tcm-TP1093的制备及其在健康动物体内的生物分布及动力学特点%Preparation of 99Tcm-TP1093 and its bio-distribution and kinetic characteristics in healthy animals

    Institute of Scientific and Technical Information of China (English)

    任浩; 查林; 冯世斌; 唐波; 李前伟

    2013-01-01

    test and oil-water distribution test, respectively. The tracer kinetics in healthy rabbits and bio-distribution of 99Tcm-TP1093 in normal mice were observed through caudal vein injection of the labeled peptides. The dynamic distribution of 99Tcm-TP1093 in organs of the rabbits was observed by SPECT imaging, and the time-activity curve (TAC) of the main organs was drawn using region of interest(ROI) technology. Results The labeling rate and specific activity of 99Tcm-TP1093 was (97.23 ±0.87)% and 15.91 ±0.62 TBq/mmol, respectively. The radiochemi-cal purity of 99Tcm-TP1093 was (93. 34 ±0.91)% after placed at room temperature for 4 h. There was no significant combination between labeled peptide and serum albumin, and the oil-water partition coefficient was lg P= -(1.68±0.09). The kinetics characteristics of the radiolabeled peptide in healthy rabbits was in accordance with a two-compartment model with a weight factor of 1/c, and the t1/2α , t1/2βand CL were 2. 689 ±0. 541 min, 69.156 ±20. 342 min and 5. 029 ±4. 381 mL/kg, respectively. The bio-distribution and SPECT imaging showed that the blood clearance of 99Tcm-TP1093 was rapid, the radioactivity faded rapidly in soft tissues, a radioactive defect area was observed in the stomach and thyroid, and a low radioactive area was observed in the brain. The radioactivity in vivo was excreted mainly through urinary system and slighdy through gastrointestinal and hepatobiliary systems. Conclusion 99Tcm-TP1093 can be easily labeled with a high labeling rate and specific activity. 99Tcm-TP1093 can be prepared into a one-step lyophilized kit due to its good stability, bio-distribution in vivo and kinetic characteristics.

  5. TP53 Mutational Status and Prediction of Benefit from Adjuvant 5-Fluorouracil in Stage III Colon Cancer Patients.

    Science.gov (United States)

    Kandioler, Daniela; Mittlböck, Martina; Kappel, Sonja; Puhalla, Harald; Herbst, Friedrich; Langner, Cord; Wolf, Brigitte; Tschmelitsch, Jörg; Schippinger, Walter; Steger, Günther; Hofbauer, Friedrich; Samonigg, Hellmut; Gnant, Michael; Teleky, Bela; Kührer, Irene

    2015-08-01

    We investigated the hypothesis that the varying treatment efficacy of adjuvant 5-fluorouracil (5FU) in stage III colon cancer is linked to the TP53 mutational status. ABCSG-90 was a prospective randomized trial in which effect of adjuvant 5FU was studied in stage III colon cancer patients. Tumor material of 70% of these patients (389/572) was available for analysis of the biomarker TP53 using a TP53-gene-specific Sanger sequencing protocol. Median follow-up was 88 months. TP53 mutation frequency was 33%. A significant interaction between TP53 status, outcomes and nodal category was found (P = 0.0095). In the N1 category, TP53 wildtype patients had significantly better overall survival than TP53 mutated (81.0% vs. 62.0% overall survival at 5 years; HR = 2.131; 95% CI: 1.344-3.378; P = 0.0010). In the N2 category, the TP53 status did not affect survival (P = 0.4992). In TP53 wildtype patients, the prognostic significance of N category was significantly enhanced (P = 0.0002). In TP53 mutated patients, survival curves of N1 and N2 patients overlapped and nodal category was no longer prognostic. The biomarker TP53 independently predicted effect of adjuvant 5FU in N1 colon cancer patients. TP53 was not predictive in N2 patients, in whom 5FU is known to have no effect.

  6. TP53 mutations in clinically normal mucosa adjacent to oral carcinomas

    DEFF Research Database (Denmark)

    Thode, Christenze; Bilde, Anders; von Buchwald, Christian;

    2010-01-01

    products were separated by denatured gradient gel electrophoresis. Fragments with a deviant DGEE pattern were sequenced. RESULTS: TP53 mutations were found in six of 18 tumours. Fourteen specimens contained histologically normal mucosa adjacent to the tumour; 13 of these showed small clusters of p53...... positive cells. Seven specimens contained both histological normal and dysplastic epithelial tissues adjacent to the tumour. A TP53 mutation was found in only one specimen; this mutation appeared in the normal mucosa, the adjacent tumour, and the epithelial dysplasia. CONCLUSION: We found that upregulation...... of p53 was a frequent event in histological normal mucosa adjacent to OSCC; however, it was rarely associated with a mutation in the TP53 gene....

  7. MHA-Tp testing on HIV positive and negative women in vigilance home at Madurai.

    Science.gov (United States)

    Ganapathysundaram, S; Mallika, M; Chandrasekaran, S; Mohan, G

    1992-01-01

    In the study group of 94 cases of female prostitutes and their children 55 cases showed positive for HIV infection by ELISA and Western Blot tests. They showed positive also for syphilis in 37 cases by VDRL and in 43 cases by MHA-Tp tests among HIV positive and negative women. The association of HIV infection and syphilis was observed in this study due to sexual transmission of these infections. But congenital spread from infected mother to their children was not observed in this study since both mothers and their children were negative for these infections. MHA-Tp testing confirmed VDRL test results in 27 cases and also increased specificity of MHA-Tp test result over VDRL result in 16 cases and exclusion of biological false positive by VDRL in 10 cases were noticed in this study.

  8. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy

    DEFF Research Database (Denmark)

    Eskelund, Christian W; Dahl, Christina; Hansen, Jakob W

    2017-01-01

    Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable and we are still unable to identify patients who will not benefit from the current standard-of-care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM...... to relapse. TP53-mutated cases had a dismal outcome with a median OS of 1.8 years and 50% relapsed at 1.0 years (compared to not reached (NR) and 12.7 years, respectively, for TP53-unmutated cases, p30%, blastoid morphology, MIPI high......-risk and inferior responses to both induction- and high-dose chemotherapy. In conclusion, we show that TP53 mutations identify a phenotypically distinct and highly aggressive form of MCL with poor or no response to regimens including cytarabine, rituximab and autologous stem-cell transplant (ASCT). We suggest...

  9. Association of the germline TP53 R337H mutation with breast cancer in southern Brazil

    Directory of Open Access Journals (Sweden)

    Srivastava Kumar

    2008-12-01

    Full Text Available Abstract Background The germline TP53-R337H mutation is strongly associated with pediatric adrenocortical tumors (ACT in southern Brazil; it has low penetrance and limited tissue specificity in most families and therefore is not associated with Li-Fraumeni syndrome. However, other tumor types, mainly breast cancer, have been observed in carriers of several unrelated kindreds, raising the possibility that the R337H mutation may also contribute to breast tumorigenesis in a genetic background-specific context. Methods We conducted a case-control study to determine the prevalence of the R337H mutation by sequencing TP53 exon 10 in 123 women with breast cancer and 223 age- and sex-matched control subjects from southern Brazil. Fisher's test was used to compare the prevalence of the R337H. Results The R337H mutation was found in three patients but in none of the controls (p = 0.0442. Among the carriers, two had familial history of cancer meeting the Li-Fraumeni-like criteria. Remarkably, tumors in each of these three cases underwent loss of heterozygosity by eliminating the mutant TP53 allele rather than the wild-type allele. Polymorphisms were identified within the TP53 (R72P and Ins16 and MDM2 (SNP309 genes that may further diminish TP53 tumor suppressor activity. Conclusion These results demonstrate that the R337H mutation can significantly increase the risk of breast cancer in carriers, which likely depends on additional cooperating genetic factors. These findings are also important for understanding how low-penetrant mutant TP53 alleles can differentially influence tumor susceptibility.

  10. Insertion products from photolysis of Tp{prime}(CO){sub 3}WH and alkynes

    Energy Technology Data Exchange (ETDEWEB)

    Frohnapfel, D.S.; White, P.S.; Templeton, J.L.

    2000-04-17

    Irradiation of Tp{prime}(CO){sub 3}WH in the presence of alkynes produces a diverse array of products, including {eta}{sup 2}-vinyl, {eta}{sup 2}-acyl, metallafuran, and carbyne complexes. A common mechanistic feature consistent with the observed distribution of products is cis insertion of alkynes into a photogenerated Tp{prime}(CO){sub 2}WH species. Initial cis 2,1-insertion of the alkynes leads to {eta}{sup 2}-vinyl and {eta}{sup 3}-allyl products, while cis 1,2-insertion ultimately produces {eta}{sup 2}-acyl, metallafuran, and carbyne products. An X-ray structure of a metallafuran product, Tp{prime}(CO){sub 2}W({eta}{sup 2}(C,O)-C(Bu{sup n})CHC({double_bond}O)CH{double_bond}CHBu{sup n}), shows trans stereochemistry for the double bond of the pendant 1-hexenyl group, which indicates that cis 1,2-insertion of the first equivalent of alkyne forms an intermediate {eta}{sup 1}-vinyl complex. Additional support for {eta}{sup 1}-vinyl intermediates is present in the {eta}{sup 2}-acyl product Tp{prime}(CO){sub 2}W({eta}{sup 2}(C,O)-C({double_bond}O)CH{double_bond}CHC(CH{sub 3}){sub 3}), which evinces a trans double bond as assayed via {sup 1}H NMR. Irradiation of Tp{prime}(CO){sub 3}WH in the presence of Me{sub 3}SiC{triple_bond}CCH{sub 3} produces two isomers of Tp{prime}(CO){sub 2}W({eta}{sup 3}-syn-CH{sub 2}CHCHSiMe{sub 3}) which differ in the orientation of the allyl fragment relative to the metal center. Heating of the allyl complex results in an unusual {eta}{sup 3}-allyl to carbyne rearrangement.

  11. Knockdown of HSPA9 induces TP53-dependent apoptosis in human hematopoietic progenitor cells.

    Science.gov (United States)

    Liu, Tuoen; Krysiak, Kilannin; Shirai, Cara Lunn; Kim, Sanghyun; Shao, Jin; Ndonwi, Matthew; Walter, Matthew J

    2017-01-01

    Myelodysplastic syndromes (MDS) are the most common adult myeloid blood cancers in the US. Patients have increased apoptosis in their bone marrow cells leading to low peripheral blood counts. The full complement of gene mutations that contribute to increased apoptosis in MDS remains unknown. Up to 25% of MDS patients harbor and acquired interstitial deletion on the long arm of chromosome 5 [del(5q)], creating haploinsufficiency for a large set of genes including HSPA9. Knockdown of HSPA9 in primary human CD34+ hematopoietic progenitor cells significantly inhibits growth and increases apoptosis. We show here that HSPA9 knockdown is associated with increased TP53 expression and activity, resulting in increased expression of target genes BAX and p21. HSPA9 protein interacts with TP53 in CD34+ cells and knockdown of HSPA9 increases nuclear TP53 levels, providing a possible mechanism for regulation of TP53 by HSPA9 haploinsufficiency in hematopoietic cells. Concurrent knockdown of TP53 and HSPA9 rescued the increased apoptosis observed in CD34+ cells following knockdown of HSPA9. Reduction of HSPA9 below 50% results in severe inhibition of cell growth, suggesting that del(5q) cells may be preferentially sensitive to further reductions of HSPA9 below 50%, thus providing a genetic vulnerability to del(5q) cells. Treatment of bone marrow cells with MKT-077, an HSPA9 inhibitor, induced apoptosis in a higher percentage of cells from MDS patients with del(5q) compared to non-del(5q) MDS patients and normal donor cells. Collectively, these findings indicate that reduced levels of HSPA9 may contribute to TP53 activation and increased apoptosis observed in del(5q)-associated MDS.

  12. Mutations in TP53 and CTNNB1 in Relation to Hepatitis B and C Infections in Hepatocellular Carcinomas from Thailand

    Directory of Open Access Journals (Sweden)

    Olivier Galy

    2011-01-01

    Full Text Available Hepatocellular carcinoma (HCC may develop according to two major pathways, one involving HBV infection and TP53 mutation and the other characterized by HCV infection and CTNNB1 mutation. We have investigated HBV/HCV infections and TP53/CTNNB1 mutations in 26 HCC patients from Thailand. HBV DNA (genotype B or C was detected in 19 (73% of the cases, including 5 occult infections and 3 coinfections with HCV. TP53 and CTNNB1 mutations were not mutually exclusive, and most of TP53 mutations were R249S, suggesting a significant impact of aflatoxin-induced mutagenesis in HCC development.

  13. TP53 and CDKN1A mutation analysis in families with Li-Fraumeni and Li-Fraumeni like syndromes.

    Science.gov (United States)

    Andrade, Raissa Coelho; Dos Santos, Anna Claudia Evangelista; de Aguirre Neto, Joaquim Caetano; Nevado, Julián; Lapunzina, Pablo; Vargas, Fernando Regla

    2017-04-01

    Li-Fraumeni and Li-Fraumeni like syndromes (LFS/LFL) represent rare cancer-prone conditions associated mostly with sarcomas, breast cancer, brain tumors, and adrenocortical carcinomas. TP53 germline mutations are present in up to 80 % of families with classic Li-Fraumeni syndrome, and in 20-60 % of families with Li-Fraumeni like phenotypes. The frequency of LFS/LFL families with no TP53 mutations detected suggests the involvement of other genes in the syndrome. In this study, we searched for mutations in TP53 in 39 probands from families with criteria for LFS/LFL. We also searched for mutations in the gene encoding the main mediator of p53 in cell cycle arrest, CDKN1A/p21, in all patients with no mutations in TP53. Eight probands carried germline disease-causing mutations in TP53: six missense mutations and two partial gene deletions. No mutations in CDKN1A coding region were detected. TP53 partial deletions in our cohort represented 25 % (2/8) of the mutations found, a much higher frequency than usually reported, emphasizing the need to search for TP53 rearrangements in patients with LFS/LFL phenotypes. Two benign tumors were detected in two TP53 mutation carriers: an adrenocortical adenoma and a neurofibroma, which raises a question about the possible implication of TP53 mutations on the development of such lesions.

  14. TP53 mutations are early events in chronic lymphocytic leukemia disease progression and precede evolution to complex karyotypes.

    Science.gov (United States)

    Lazarian, Gregory; Tausch, Eugen; Eclache, Virginie; Sebaa, Amel; Bianchi, Vincent; Letestu, Remi; Collon, Jean-Francois; Lefebvre, Valerie; Gardano, Laura; Varin-Blank, Nadine; Soussi, Thierry; Stilgenbauer, Stephen; Cymbalista, Florence; Baran-Marszak, Fanny

    2016-10-15

    TP53 abnormalities lead to resistance to purine analogues and are found in over 40% of patients with refractory chronic lymphocytic leukemia (CLL). At diagnosis, no more than 5% of patients carry the 17p deletion, most cases harbour mutations within the other TP53 allele. The incidence of a TP53 mutation as the only alteration is approximately 5%, but this depends on the sensitivity of the technique. Recently, having a complex karyotype has been considered a strong adverse prognostic factor. However, there are no longitudinal studies simultaneously examining the presence of the 17p deletion, TP53 mutations and karyotype abnormalities. We conducted a retrospective longitudinal study of 31 relapsed/refractory CLL patients. Two to six blood samples per patient were analyzed, with a median follow-up of 8 years. In this report, we assessed the sequence of events of TP53 clonal evolution and correlated the presence of TP53 abnormalities to genetic instability during progression and treatment. Next-generation sequencing allowed the early detection of TP53 mutated clones and was able to be performed on a routine basis, demonstrating an excellent correlation between the Illumina and Ion Torrent technologies. We concluded that TP53 mutations are early events and precede clonal evolution to complex karyotypes. We strongly recommend the early and iterated detection of TP53 mutations in progressive cases.

  15. Detection of TP53 mutation, loss of heterozygosity and DNA content in fine-needle aspirates of breast carcinoma.

    Science.gov (United States)

    Lavarino, C.; Corletto, V.; Mezzelani, A.; Della Torre, G.; Bartoli, C.; Riva, C.; Pierotti, M. A.; Rilke, F.; Pilotti, S.

    1998-01-01

    Recent preclinical and clinical data suggest that TP53 status and TP53 mutations may be important in determining tumour aggressiveness and therapy response. In this study we investigate the feasibility of a structural and quantitative analysis of TP53 on fine-needle aspiration (FNA) material obtained from 31 consecutive female patients with breast carcinoma, enrolled in a primary chemotherapy protocol. Tumours were screened for p53 protein overexpression and TP53 mutations (exons 5-8) using immunocytochemistry, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and DNA sequencing analyses, and finally using fluorescence in situ hybridization (FISH) analysis. Positive nuclear staining was identified in six cases whereas mutations were detected in nine. Although the immunoreactive pattern fitted fully with the characterized TP53 mutation type, the considerable number of null p53 mutations (i.e. four) coupled with the lack of information regarding the localization of TP53 mutations make immunocytochemistry an inadequate indicator of TP53 function deregulation. Combining molecular and FISH analyses, we detected three cases with TP53 deletion and one case with deletion and mutation. Finally, DNA static-image analysis performed on 29 cases showed aneuploidy in 26 cases, which included all TP53-mutated cases. The present results show that FNA may assist clinical decisions by allowing the evaluation of a variety of biological parameters relevant for prognosis and treatment planning. Images Figure 1 PMID:9459157

  16. Based on combination of L2TP and IPSec VPN security technology research

    Directory of Open Access Journals (Sweden)

    Ya-qin Fan

    2012-01-01

    Full Text Available This report is written to provide a method of building secure VPN by combination of L2TP and IPSec in order to meet the requirements of secure transmission of data and improve the VPN security technology. It remedies the secured short comes of L2TP Tunneling Protocol Tunneling Protocol and IPSec security. Simulation and analysis show that the construction method can improve the security of data transmission, and the simulation results of VPN is valuable for security professionals to refer.

  17. Rescue of DNA-PK Signaling and T-Cell Differentiation by Targeted Genome Editing in a prkdc Deficient iPSC Disease Model.

    Directory of Open Access Journals (Sweden)

    Shamim H Rahman

    2015-05-01

    Full Text Available In vitro disease modeling based on induced pluripotent stem cells (iPSCs provides a powerful system to study cellular pathophysiology, especially in combination with targeted genome editing and protocols to differentiate iPSCs into affected cell types. In this study, we established zinc-finger nuclease-mediated genome editing in primary fibroblasts and iPSCs generated from a mouse model for radiosensitive severe combined immunodeficiency (RS-SCID, a rare disorder characterized by cellular sensitivity to radiation and the absence of lymphocytes due to impaired DNA-dependent protein kinase (DNA-PK activity. Our results demonstrate that gene editing in RS-SCID fibroblasts rescued DNA-PK dependent signaling to overcome radiosensitivity. Furthermore, in vitro T-cell differentiation from iPSCs was employed to model the stage-specific T-cell maturation block induced by the disease causing mutation. Genetic correction of the RS-SCID iPSCs restored T-lymphocyte maturation, polyclonal V(DJ recombination of the T-cell receptor followed by successful beta-selection. In conclusion, we provide proof that iPSC-based in vitro T-cell differentiation is a valuable paradigm for SCID disease modeling, which can be utilized to investigate disorders of T-cell development and to validate gene therapy strategies for T-cell deficiencies. Moreover, this study emphasizes the significance of designer nucleases as a tool for generating isogenic disease models and their future role in producing autologous, genetically corrected transplants for various clinical applications.

  18. Cell cycle dependence of DNA-PK phosphorylation in response to DNAdouble strand breaks

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Benjamin P.C.; Chan, Doug W.; Kobayashi, Junya; Burma,Sandeep; Asaithamby, Aroumougame; Morotomi-Yano, Keiko; Quin, Jun; Chen,David J.

    2004-03-25

    DNA-dependent protein kinase (DNA-PK), consisting of Ku and DNA-PKcs subunits, is the key component of the non-homologous end joining (NHEJ) pathway of DNA double strand breaks (DSBs) repair. Though the kinase activity of DNA-PKcs is essential for NHEJ, thus far, no in vivo substrate has been conclusively identified except for an autophosphorylation site on DNA-PKcs itself (threonine 2609). Here we report the IR-induced autophosphorylation of DNA-PKcs at a novel site,serine 2056, and phosphorylation at this site is required for the repair of DSBs by NHEJ. Interestingly, IR-induced DNA-PKcs autophosphorylation is regulated in a cell cycle-dependent manner with attenuated phosphorylation in the S phase. In contrast, DNA replication-associated DSBs result in DNA-PKcs autophosphorylation and localization to DNA damage sites. These results indicate that, while IR-induced DNA-PKcs phosphorylation is attenuated in S phase, DNA-PKcs is preferentially activated by the physiologically relevant DNA replication-associated DSBs at the sites of DNA synthesis.

  19. Calcidiol and vitamin D binding protein uptake by LLC-PK/sub 1/ cells

    Energy Technology Data Exchange (ETDEWEB)

    Keenan, M.J.; Holmes, R.P.

    1986-03-01

    The process by which target cells take up vitamin D and its metabolites is not known. The authors studied the uptake of both /sup 3/H-calcidiol and /sup 125/I-Vitamin D Binding Protein (DBP) by LLC-PK/sub 1/ cells. Uptake was directly related to their extracellular concentrations. In the presence of 55 serum in the growth media cells previously incubated with 10 nM calcitriol for 4 hr had a greater uptake of calcidiol than those cells not incubated with calcitriol. This effect of calcitriol on calcidiol uptake was absent when cells were grown in hormone-supplemented, serum-free media, despite these cells having a cytosolic calcitriol receptor. Equal uptake of calcidiol occurred when DBP was absent and when DBP was present in a one to one molar ratio to calcidiol. With a 1:1 ratio of DBP to calcidiol and a measured K/sub D/ of 2 x 10/sup -8/M, the uptake of calcidiol could not be accounted for by uptake of the free ligand alone. A large excess of DBP (100:1) in relation to calcidiol suppressed uptake of calcidiol by approx. 90%. The authors have not been able to identify a saturable, specific uptake of either calcidiol or DBP despite DBP appearing to facilitate calcidiol uptake.

  20. Ectopic TLX1 expression accelerates malignancies in mice deficient in DNA-PK.

    Directory of Open Access Journals (Sweden)

    Konstantin Krutikov

    Full Text Available The noncluster homeobox gene HOX11/TLX1 (TLX1 is detected at the breakpoint of the t(10;14(q24;q11 chromosome translocation in patients with T cell acute lymphoblastic leukemia (T-ALL. This translocation results in the inappropriate expression of TLX1 in T cells. The oncogenic potential of TLX1 was demonstrated in IgHμ-TLX1(Tg mice which develop mature B cell lymphoma after a long latency period, suggesting the requirement of additional mutations to initiate malignancy. To determine whether dysregulation of genes involved in the DNA damage response contributed to tumor progression, we crossed IgHμ-TLX1(Tg mice with mice deficient in the DNA repair enzyme DNA-PK (Prkdc(Scid/Scid mice. IgHµ-TLX1(TgPrkdc(Scid/Scid mice developed T-ALL and acute myeloid leukemia (AML with reduced latency relative to control Prkdc(Scid/Scid mice. Further analysis of thymi from premalignant mice revealed greater thymic cellularity concomitant with increased thymocyte proliferation and decreased apoptotic index. Moreover, premalignant and malignant thymocytes exhibited impaired spindle checkpoint function, in association with aneuploid karyotypes. Gene expression profiling of premalignant IgHµ-TLX1(TgPrkdc(Scid/Scid thymocytes revealed dysregulated expression of cell cycle, apoptotic and mitotic spindle checkpoint genes in double negative 2 (DN2 and DN3 stage thymocytes. Collectively, these findings reveal a novel synergy between TLX1 and impaired DNA repair pathway in leukemogenesis.

  1. The pK0Σ+ final state in proton-proton collisions

    Science.gov (United States)

    Abdel-Bary, M.; Abdel-Samad, S.; Brinkmann, K.-Th.; Clement, H.; Dietrich, J.; Doroshkevich, E.; Dshemuchadse, S.; Ehrhardt, K.; Erhardt, A.; Eyrich, W.; Filippi, A.; Freiesleben, H.; Fritsch, M.; Gast, W.; Georgi, J.; Gillitzer, A.; Gottwald, J.; Hesselbarth, D.; Jäger, H.; Jakob, B.; Jäkel, R.; Karsch, L.; Kilian, K.; Koch, H.; Krapp, M.; Kreß, J.; Kuhlmann, E.; Lehmann, A.; Marcello, S.; Marwinski, S.; Mauro, S.; Meyer, W.; Michel, P.; Möller, K.; Morsch, H. P.; Mörtel, H.; Naumann, L.; Paul, N.; Pinna, L.; Pizzolotto, C.; Plettner, Ch.; Reimann, S.; Richter, M.; Ritman, J.; Roderburg, E.; Schamlott, A.; Schönmeier, P.; Schroeder, W.; Schulte-Wissermann, M.; Sefzick, T.; Stinzing, F.; Steinke, M.; Sun, G. Y.; Teufel, A.; Ullrich, W.; Wagner, G. J.; Wagner, M.; Wenzel, R.; Wilms, A.; Wintz, P.; Wirth, S.; Wüstner, P.; Zupranski, P.

    2012-02-01

    This paper reports results from a study of the reaction pp → pK0Σ+ at beam momenta of p beam = 2950, 3059, and 3200 MeV/ c (excess energies of ɛ = 126, 161, and 206 MeV. Total cross-sections were determined for all energies; a set of differential cross-sections (Dalitz plots; invariant-mass spectra of all two-body subsystems; angular distributions of all final-state particles; distributions in helicity and Jackson frames) are presented for ɛ = 161 MeV. The total cross-sections are proportional to the volume of available three-body phase space indicating that the transition matrix element does not change significantly in this range of excess energies. It is concluded from the differential data that the reaction proceeds dominantly via the N(1710) P 11- and/or N(1720) P 13-resonance(s); N(1650) S 11 and Δ(1600) P 33 could also contribute.

  2. Experimental Study on the Cryopreservation of LLC-PK1 Epithelial Cells with Hypoxic UW Solution

    Institute of Scientific and Technical Information of China (English)

    WAN Chidan; WANG Chunyou; LIU Tao; WANG Hongbo; YANG Zhiyong

    2007-01-01

    The effects of oxygen partial pressure on cryopreservation of the cells with organ preservation solution were explored. Hypoxic UW solution was made by purging the UW solution with argon. The pig proximal tubule epithelial cells (LLC-PK1 cells) were cryopreserved in hypoxic UW solution (Ar-UW group) or standard UW solution (UW group) at 4℃ for 48 h. Trypan blue staining and LDH detection were performed to evaluate the injury of the cells. The results showed that the oxygen partial pressure in Ar-UW group was significantly declined from 242±6 mmHg to 83±10 mmHg. After cryopreservation at 4℃ for 48 h, LDH leakage rate and Trypan blue-stained rate in Ar-UW group were (11.3±3.4)% and (10.5±4.7)%, respectively, which were significantly lower than in UW group [(49.5±6.9)% and (47.6±9.3)% respectively, both P<0.01]. It was concluded that lower oxygen partial pressure of UW solution was more beneficial to the cryopreservation of LLC.

  3. Semi quantification study of [{sup 11}C]-(R)-PK11195 PET brain images in multiple sclerosis; Estudo da semiquantificacao de imagens PET cerebrais de [{sup 11}C]-(R)-PK11195 na esclerose multipla

    Energy Technology Data Exchange (ETDEWEB)

    Narciso, Lucas D.L.; Schuck, Phelipi N.; Dartora, Caroline M.; Matushita, Cristina S.; Becker, Jefferson; Silva, Ana M. Marques da, E-mail: lucas.narciso@acad.pucrs.br [Pontificia Universidade Catolica do Rio Grande do Sul (PUC-RS), Porto Alegre, RS (Brazil)

    2016-07-01

    PET brain images with [{sup 11}C]-(R)-PK11195 are being widely used to visualize microglial activation in vivo in neuro degenerative diseases, such as multiple sclerosis (MS). The aim of this study is to investigate the uptake behavior in justacortical and periventricular regions of [{sup 11}C]-(R)-PK11195 PET brain images reformatted in different time intervals by applying three methods, seeking method and time interval that significantly differentiate MS patients from healthy controls. Semi-quantitative SUV and uptake relative to a reference region methods were applied to PET images from different time intervals acquired from 10 patients with MS and 5 healthy controls. The results show significant SUV values difference (p = 0.01, 40 to 60 min) in justacortical and periventricular regions between groups and using the normalization method in which the uptake is relative to the mean concentration activity in the white matter (p <0.01, 10 to 60 min). (author)

  4. The expression of one ankyrin pk2 allele of the WO prophage is correlated with the Wolbachia feminizing effect in isopods

    Directory of Open Access Journals (Sweden)

    Pichon Samuel

    2012-04-01

    Full Text Available Abstract Background The maternally inherited α-Proteobacteria Wolbachia pipientis is an obligate endosymbiont of nematodes and arthropods, in which they induce a variety of reproductive alterations, including Cytoplasmic Incompatibility (CI and feminization. The genome of the feminizing wVulC Wolbachia strain harboured by the isopod Armadillidium vulgare has been sequenced and is now at the final assembly step. It contains an unusually high number of ankyrin motif-containing genes, two of which are homologous to the phage-related pk1 and pk2 genes thought to contribute to the CI phenotype in Culex pipiens. These genes encode putative bacterial effectors mediating Wolbachia-host protein-protein interactions via their ankyrin motifs. Results To test whether these Wolbachia homologs are potentially involved in altering terrestrial isopod reproduction, we determined the distribution and expression of both pk1 and pk2 genes in the 3 Wolbachia strains that induce CI and in 5 inducing feminization of their isopod hosts. Aside from the genes being highly conserved, we found a substantial copy number variation among strains, and that is linked to prophage diversity. Transcriptional analyses revealed expression of one pk2 allele (pk2b2 only in the feminizing Wolbachia strains of isopods. Conclusions These results reveal the need to investigate the functions of Wolbachia ankyrin gene products, in particular those of Pk2, and their host targets with respect to host sex manipulation.

  5. Expression, purification and characterization of recombinant Tp0136 from Treponema pallidum%梅毒螺旋体外膜蛋白Tp0136的制备及在血清学诊断中的应用

    Institute of Scientific and Technical Information of China (English)

    王磊阳; 陈政卓; 富梦楚; 何君梅; 李婷婷; 沈琳; 杨珺

    2011-01-01

    Objective:To study the significance of Treponema Pallidum outer membrane protein Tp0136 in the serodiagnosis of primary syphilis, prepare recombinant Tp0136 and study the immune activity. Methods: The Tp0136 gene was inserted in pET28a( + ). The recombinant plasmid was expressed in E. coli BL21. After nickel ion metal afiinity chromatography and gel filtration chromatography, the antigenic and immune reactivity of rTp0136 was confirmed. Then indirect ELISA with the rTp0136 as coating antigen was performed to detect the anti -Tp0136 antibody in sera from 50 normal human controls and 131 primary syphilis patients. Results: The rTp0136 was expressed in form of inclusion bodies as 46000(Mr) and was obtained with a purity of >98% by chromatography. Western blot proved that the rTp0136 could specifically react with anti -Tp0136 polyclonal antibody.Specific humoral response was elicited by the recombinant protein in Japan rabbits and the titers were 1:32 by double agar diffusion. The detection result in sera from normal human was negative. The positive detection rate in sera from primary syphilis patients was 75.1%. Conclusion: This result suggested that the recombinant Tp0136 have a satisfactory immunoc o mpetence, which may have applications in the serodiagnosis of primary syphilis.%目的:为探索梅毒螺旋体(Treponema Pallidum,Tp)外膜蛋白Tp0136在早期梅毒诊断中的价值,利用基因重组技术制备Tp0136蛋白,用于血清抗体的检测.方法:采用PCR扩增Tp0136基因,构建不含信号肽序列的Tp0136基因原核表达载体,SDS-PAGE检测目的蛋白的表达情况,镍离子亲和凝胶分子筛二步法纯化目的蛋白,Western blot检测其免疫反应性,免疫日本大耳白兔评价其免疫原性,免疫双扩检测其效价,以rTp0136为包被抗原的间接ELISA检测早期梅毒血清抗体.结果:重组工程菌包涵体形式表达相对分子质量约为46 KDa的rTp0136,表达率为15%,制备得到纯度大于98%的rTp0136.纯化的rTp

  6. Latanoprost systemic exposure in pediatric and adult patients with glaucoma

    DEFF Research Database (Denmark)

    Raber, Susan; Courtney, Rachel; Maeda-Chubachi, Tomoko

    2011-01-01

    To evaluate short-term safety and steady-state systemic pharmacokinetics (PK) of latanoprost acid in pediatric subjects with glaucoma or ocular hypertension who received the adult latanoprost dose.......To evaluate short-term safety and steady-state systemic pharmacokinetics (PK) of latanoprost acid in pediatric subjects with glaucoma or ocular hypertension who received the adult latanoprost dose....

  7. Synthesis and evaluation of sup 11 C-PK 11195 for in vivo study of peripheral-type benzodiazepine receptors using positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Hashimoto, Kenji (Fukuyama Univ., Hiroshima (Japan). Faculty of Pharmacy and Pharmaceutical Sciences); Inoue, Osamu; Suzuki, Kazutoshi; Yamasaki, Toshiro; Kojima, Masaharu

    1989-07-01

    The biodistribution of {sup 3}H-PK 11195, an antagonist of the peripheral-type benzodiazepine receptors, was studied in mice. High accumulations of radioactivity in the heart, lung, spleen, kidney and adrenal were observed after intravenous injection of tracer amounts of {sup 3}H-PK 11195 into the mice. The radioactivity in the heart, lung, spleen, kidney and adrenal was significantly decreased by the coadministration of carrier PK 11195, which indicated that PK 11195 specifically binds to the receptors. No radioactive metabolites were observed in the heart, lung and brain 20 min after intravenous administration of {sup 3}H-PK 11195. The accumulation of {sup 3}H-PK 11195 in the lung was not affected by pretreatment with either {alpha}-methyl benzylamine or imipramine, suggesting that {sup 3}H-PK 11195 specifically binds to the receptors. The ratios of radioactivity of the kidney, adrenal and spleen to blood increased as a function of time, whereas that of the lung and heart rapidly reached to a steady state. {sup 11}C-PK 11195 was synthesized by the N-methylation of desmethyl precursor yielding more than 100 mCi with high specific activity (more than 1.4 Ci/{mu}mol). The lebeling and purification procedure was completed within 23 min after the end of bombardment (EOB). The {sup 11}C-PK 11195 solution for injection seems to have a high potential for the in vivo study of the peripheral-type benzodiazepine receptors in the living human by means of positron emission tomography (PET). (author).

  8. Application of PK/PD modeling and simulation to dosing regimen optimization of high-dose human regular U-500 insulin.

    Science.gov (United States)

    de la Peña, Amparo; Ma, Xiaosu; Reddy, Shobha; Ovalle, Fernando; Bergenstal, Richard M; Jackson, Jeffrey A

    2014-07-01

    Pharmacokinetic/pharmacodynamic (PK/PD) studies of human regular U-500 insulin (U-500R) at high doses commonly used in clinical practice (>100 units) have not been performed. The current analysis applied PK/PD modeling/simulation to fit the data and simulate single-dose and steady-state PK/PD of U-500R high-dose regimens. Data from 3 single-dose euglycemic clamp studies in healthy obese and normal-weight patients, and normal-weight patients with type 1 diabetes were used to build the model. The model was sequential (PK inputs fed into PD component). PK was described using a 1-compartment model with first-order absorption and elimination. The model estimated separate absorption rate constants for U-500R and human regular U-100 insulin. The PD component used an effect compartment model, parameterized in terms of maximum pharmacologic effect (E(max)) and concentration to achieve 50% of E(max). The model described the data well. Steady-state PK for once-daily (QD), twice-daily (BID), or thrice-daily (TID) administration appeared to be reached 24 hours after the first dose. At steady-state, QD dosing showed the greatest fluctuations in PK/PD. BID dosing showed a gradual increase in insulin action with each dose and a fairly stable basal insulin effect. For TID dosing, activity was maintained throughout the dosing interval. PK/PD modeling/simulation of high U-500R doses supports BID or TID administration with an extended duration of activity relative to QD. TID dosing may provide slightly better full-day insulin effect. Additional PK/PD studies and randomized controlled trials of U-500R are needed to validate model predictions in patients with insulin-resistant diabetes requiring high-dose insulin.

  9. [Using CTS and PK-PD models to predict the effect of uncertainty about population parameters on clinical trial power].

    Science.gov (United States)

    Zhu, Ling; Shi, Xinling; Liu, Yajie

    2009-02-01

    The traditional clinical trail designs always depend on expert opinions and lack statistical evaluations. In this article, we present a method and illustrate how population parameter uncertainty may be incorporated in the overall simulation model. Using the techniques of clinical trail simulation (CTS) and setting up predictions on the basis of pharmacokinetics-pharmacodynamics (PK-PD) models, we advance the modeling methods for simulation, for treatment effects, and for the clinical trail power under the given PK-PD conditions. Then we discuss the model of uncertainty, suggest an ANOVA-based method, add eta2 statistics for sensitivity analysis, and canvass the effect of uncertainty about population parameters on clinical trail power. The results from simulations and the indices derived from this type of sensitivity analysis may be used for grading the influence on the prediction quality of uncertainty about different population parameters. The experiment results are satisfactory and the approach presented has practical value in clinical trails.

  10. Integration of biostatistics and pharmacometrics computing platforms for efficient and reproducible PK/PD analysis: a case study.

    Science.gov (United States)

    Ou, Ying C; Lo, Arthur; Lee, Brian; Liu, Phillip; Kimura, Karen; Eary, Charisse; Hopkins, Alan

    2013-11-01

    Results of pharmacometric analyses influence high-level decisions such as clinical trial design, drug approval, and labeling. Key challenges for timely delivery of pharmacometric analyses are the data assembly process and tracking and documenting the modeling process and results. Since clinical efficacy and safety data typically reside in the biostatistics computing area, an integrated computing platform for pharmacometric and biostatistical analyses would be ideal. A case study is presented integrating a pharmacometric modeling platform into an existing statistical computing environment (SCE). The feasibility and specific configurations of running common PK/PD programs such as NONMEM and R inside of the SCE are provided. The case study provides an example of an integrated repository that facilitates efficient data assembly for pharmacometrics analyses. The proposed platform encourages a good pharmacometrics working practice to maintain transparency, traceability, and reproducibility of PK/PD models and associated data in supporting drug development and regulatory decisions.

  11. Porcine parvovirus infection induces apoptosis in PK-15 cells through activation of p53 and mitochondria-mediated pathway

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Hongling; Huang, Yong; Du, Qian; Luo, Xiaomao; Zhang, Liang; Zhao, Xiaomin; Tong, Dewen, E-mail: dwtong@nwsuaf.edu.cn

    2015-01-09

    Highlights: • PPV reduces PK-15 cells viability by inducing apoptosis. • PPV infection induces apoptosis through mitochondria-mediated pathway. • PPV infection activates p53 to regulate the mitochondria apoptotic signaling. - Abstract: Porcine parvovirus (PPV) infection has been reported to induce the cytopathic effects (CPE) in some special host cells and contribute the occurrence of porcine parvovirus disease, but the molecular mechanisms underlying PPV-induced CPE are not clear. In this study, we investigated the morphological and molecular changes of porcine kidney cell line (PK-15 cells) infected with PPV. The results showed that PPV infection inhibited the viability of PK-15 cells in a time and concentration dependent manner. PPV infection induced typical apoptotic features including chromatin condensation, apoptotic body formation, nuclear fragmentation, and Annexin V-binding activity. Further studies showed that Bax was increased and translocated to mitochondria, whereas Bcl-2 was decreased in PPV-infected cells, which caused mitochondrial outer-membrane permeabilization, resulting in the release of mitochondrial cytochrome c, followed by caspase-9 and caspase-3 activation. However, the expression of Fas and Fas ligand (FasL) did not appear significant changes in the process of PPV-induced apoptosis. Moreover, PPV infection activated p53 signaling, which was involved in the activation of apoptotic signaling induced by PPV infection via regulation of Bax and Bcl-2. Taken together, our results demonstrated that PPV infection induced apoptosis in PK-15 cells through activation of p53 and mitochondria-mediated apoptosis pathway. This study may contribute to shed light on the molecular pathogenesis of PPV infection.

  12. Field test results for steam oxidation of TP347H FG - growth of inner oxide

    DEFF Research Database (Denmark)

    Montgomery, Melanie; Jianmin, Jia; Larsen, OH;

    2005-01-01

    A series of field tests have been conducted with TP347H FG in test superheater loops in coal-fired and biomass fired boilers of steam pressure 256 and 91 bar respectively. The exposure times are from 3,500 to 30,000 hours and the temperature range is from 450-630¢XC. The morphology, composition...

  13. Mutations in TP53 tumor suppressor gene in wood dust-related sinonasal cancer

    DEFF Research Database (Denmark)

    Holmila, Reetta; Bornholdt, Jette; Heikkilä, Pirjo

    2010-01-01

    to wood dust, using capillary electrophoresis single-strand conformation polymorphism analysis and direct sequencing. A significant association between wood-dust exposure and adenocarcinoma histology was observed [adjusted odds ratio (OR) 12.6, 95% confidence interval (CI), 5.0-31.6]. TP53 mutations...

  14. Analysis of the collar-whisker structure of temperate lactococcal bacteriophage TP901-1

    DEFF Research Database (Denmark)

    Vegge, Christina Skovgaard; Neve, Horst; Brøndsted, Lone;

    2006-01-01

    Proteins homologous to the protein NPS (neck passage structure) are widespread among lactococcal phages. We investigated the hypothesis that NPS is involved in the infection of phage TP901-1 by analysis of an NPS mutant. NPS was determined to form a collar-whisker complex but was shown to be none...

  15. A genomic region of lactococcal temperate bacteriophage TP901-1 encoding major virion proteins

    DEFF Research Database (Denmark)

    Johnsen, Mads G.; Appel, Karen Fuglede; Madsen, Hans Peter Lynge;

    1996-01-01

    Two major structural proteins, MHP (major head protein) and MTP (major tail protein), from the lactococcal temperate phage TP901-1 were sequenced at their amino acid termini, and derived degenerate oligonucleotides were used to locate the corresponding genes in the phage genome. This genomic regi...

  16. The LF of TP-AGB stars in the LMC/SMC

    Science.gov (United States)

    Bruzual, Gustavo; Charlot, Stephane; GonzalezLopezlira, Rosa; Srinivasan, Sundar; Boyer, Martha L.

    2013-01-01

    We show that Monte Carlo simulations of the TP-AGB stellar population in the LMC and SMC galaxies using the CB. models produce LF and color distributions that are in closer agreement with observations than those obtained with the BC03 and CB07 models. This is a progress report of work that will be published elsewhere.

  17. TP53 GENE MUTATIONS – FROM GUARDIAN OF THE GENOME TO ONCOGENE

    Directory of Open Access Journals (Sweden)

    Petar Babović

    2010-03-01

    Full Text Available TP53 tumor suppressor gene mutations are the most frequent genetic alterations in human cancer affecting a specific gene. The occurrence of TP53 mutations is considerably influenced by cancer-initiating events, such as DNA damage, the aftermath of which is the promotion of cancer development through the loss of anti-proliferative activities, including apoptosis and cellular senescence. Over 27.000 TP53 gene mutations have been discovered and found in more than 50% of human cancers. The most frequent alterations are the point mutations with a single base substitution in gene segment encoding for DNA-binding domaine of p53 molecule, leading to the production of mutant protein that differs from the wild-type protein by one amino acid (missense mutations usually causing the change in tertiary structure of gene product, thus preventing p53 to bind to DNA and activate transcription of target genes. The result of the mutations may also be the proteins with new, abnormal functions, and the ability to modulate expression of genes responsible for neoangiogenesis, resistance to chemotherapeutics and prevention of tumor initiation and promotion. In such circumstances, not only the mutant TP53 loses its tumor suppressive function, but acquires oncogenic potential and becomes an active participant in the neoplastic transformation of the cell.Vast heterogeneity of mutations and methodological approaches in p53 status assessment represent the main difficulties in rapid and effective integration of basic p53 research into clinical practice.

  18. Wood dust-related mutational profile of TP53 in intestinal-type sinonasal adenocarcinoma.

    Science.gov (United States)

    Pérez-Escuredo, Jhudit; Martínez, Jorge García; Vivanco, Blanca; Marcos, César Álvarez; Suárez, Carlos; Llorente, José Luis; Hermsen, Mario A

    2012-11-01

    Intestinal-type sinonasal adenocarcinoma represents 8% to 25% of all malignant sinonasal cancer and is etiologically related to occupational exposure to wood dust. Despite its clear etiology, the mechanisms behind the carcinogenic effects of wood dust are unclear. Because it is known that carcinogens can leave specific mutational fingerprints, we aimed to analyze the spectrum of TP53 mutations and to relate the findings to the wood dust etiology of the patients. Forty-four primary tumors were examined for TP53 mutations by direct sequencing. In addition, p53 protein expression was analyzed by immunohistochemistry using a tissue microarray consisting of 92 tumors. We report a frequency of 41% (18/44) TP53 mutations and 72% (66/92) p53 immunopositivity in intestinal-type sinonasal adenocarcinoma, significantly related to wood dust, but not to tobacco etiology. G→A transition (50%, 9/18 cases) was the most common alteration detected, almost exclusively found in nonsmokers, whereas G→T (27%, 5/18 cases) was detected in smokers only. These data point to wood dust exposure as the causal factor in the mutagenesis of TP53, possibly caused by reactive nitrogen species generated through a chronic inflammatory process.

  19. TP53 and outcome in DLBCL: not only the coding region.

    Science.gov (United States)

    Jardin, Fabrice; Coiffier, Bertrand

    2013-05-30

    In this issue of Blood, Li et al report mutations in the 3′ untranslated region (3′UTR) of TP53 that modify the expression of p53 and thus its effect on response to therapy in diffuse large B-cell lymphoma (DLBCL) patients.

  20. TMACS test procedure TP009: Acromag driver. Revision 5

    Energy Technology Data Exchange (ETDEWEB)

    Bass, R.B.; Washburn, S.J.

    1994-09-01

    The TMACS Software Project Test Procedures translate the project`s acceptance criteria into test steps. Software releases are certified when the affected Test Procedures are successfully performed and the customers authorize installation of these changes. This Test Procedure addresses the testing of the functionality of the TMACS Acromag driver software in conjunction with a new bridge for the Panalarm Annunciator system.

  1. Modification of polyethylene glycol onto solid lipid nanoparticles encapsulating a novel chemotherapeutic agent (PK-L4 to enhance solubility for injection delivery

    Directory of Open Access Journals (Sweden)

    Fang YP

    2012-09-01

    Full Text Available Yi-Ping Fang,1 Pao-Chu Wu,2 Yaw-Bin Huang,3 Cherng-Chyi Tzeng,4 Yeh-Long Chen,4 Yu-Han Hung,2 Ming-Jun Tsai,5,6 Yi-Hung Tsai31Department of Biotechnology, Yuanpei University, Hsinchu, Taiwan; 2School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 3Graduate Institute of Clinical Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 4School of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan; 5Department of Neurology, China Medical University Hospital, Taichung, Taiwan; 6School of Medicine, Medical College, China Medical University, Taichung, TaiwanBackground: The synthetic potential chemotherapeutic agent 3-Chloro-4-[(4-methoxyphenylamino]furo[2,3-b]quinoline (PK-L4 is an analog of amsacrine. The half-life of PK-L4 is longer than that of amsacrine; however, PK-L4 is difficult to dissolve in aqueous media, which is problematic for administration by intravenous injection.Aims: To utilize solid lipid nanoparticles (SLNs modified with polyethylene glycol (PEG to improve the delivery of PK-L4 and investigate its biodistribution behavior after intravenous administration.Results: The particle size of the PK-L4-loaded SLNs was 47.3 nm and the size of the PEGylated form was smaller, at 28 nm. The entrapment efficiency (EE% of PK-L4 in SLNs with and without PEG showed a high capacity of approximately 100% encapsulation. Results also showed that the amount of PK-L4 released over a prolonged period from SLNs both with and without PEG was comparable to the non-formulated group, with 16.48% and 30.04%, respectively, of the drug being released, which fit a zero-order equation. The half-maximal inhibitory concentration values of PK-L4-loaded SLNs with and those without PEG were significantly reduced by 45%–64% in the human lung carcinoma cell line (A549, 99% in the human breast adenocarcinoma cell line with estrogen receptor (MCF7, and 95% in

  2. TP53 Codon 72 Polymorphism and P53 Protein Expression in Colorectal Cancer Specimens in Isfahan

    Directory of Open Access Journals (Sweden)

    Mehdi Nikbahkt Dastjerdi

    2011-02-01

    Full Text Available The TP53 tumor suppressor gene plays important roles in genomic stability. A common polymorphism at codon 72 of TP53 gene has been associated with increased risk for many human cancers. The p53 protein is expressed in colorectal cancer, but the reported prevalence of its expression varies widely. In the present study, the p53 protein expression in different genotypes of its codon 72 , was investigated. We undertook a case-control study on 250 controls and 250 paraffin block specimens of sporadic colorectal adenocarcinomas from the city of Isfahan. PCR amplification of TP53 codon 72 polymorphism: TP53 codon 72 genotypes were detected by PCR using specific primer pairs for amplifying the proline or the arginine Alleles. The PCR reaction was done separately for each of the two polymorphic variants. The amplified products were subjected to electrophoresis on 1% agarose gel in 1× TBE buffer and visualized on a transilluminator using ethidium bromide. Immunohistochemical Staining: We evaluated the expression patterns of p53 protein, as potential prognostic marker in colorectal cancer specimens by immunohistochemical staining. Statistical analyses: The χ2-test was used to assess the significance of any difference in the prevalence of TP53 codon 72 polymorphism between colorectal cancer patients and controls. The odds ratio and 95% CI (confidence intervals was used as a measure of the strength of the association. Statistical significance level was set to P≤0.05. In control samples, the genotype distribution for TP53 polymorphism showed 30.4%, 45.2% and 24.4% for the arginine/arginine, arginine/proline and proline/proline genotypes, respectively. Allelic frequencies corresponded to 0.663 for the arginine allele and 0.338 for the proline allele. In the cancer group 38.8% of the cases were arginine/arginine, 40.4% were arginine/proline and 20.8% were proline/proline. The corresponding frequencies were 0.590 for the arginine allele and 0.410 for the

  3. TP53 Arg72Pro polymorphism is associated with esophageal cancer risk: A meta-analysis

    Institute of Scientific and Technical Information of China (English)

    De-Ke Jiang; Lei Yao; Wen-Zhang Wang; Bo Peng; Wei-Hua Ren; Xian-Mei Yang; Long Yu

    2011-01-01

    AIM: To investigate the association between TP53 Ar-g72Pro polymorphism and esophageal cancer (EC) risk using meta-analysis.METHODS: All eligible studies published before March 1, 2010 were selected by searching PubMed using key-words “p53” or “TP53”, “polymorphism” or “variation”, “esophageal” and “cancer” or “carcinoma”. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were assessed for EC risk associated with TP53 Arg72Pro polymorphism using fixed- and random-effects models.RESULTS: Nine case-control studies involving 5545 subjects were included in this meta-analysis. Signifi-cantly reduced risk of EC was associated with TP53 genotypes for Arg/Arg + Arg/Pro vs Pro/Pro (OR = 0.73, 95% CI: 0.57-0.94, P = 0.014). Subgroup analy-ses according to the source of controls and the speci-mens used for determining TP53 Arg72Pro genotypes or sample size showed that significantly reduced risk was observed only in studies which have population-based controls (Arg/Arg vs Pro/Pro: OR = 0.56, 95% CI: 0.47-0.66, P < 0.001), and use white blood cells or normal tissue to assess TP53 genotypes of cases (Arg/Arg vs Pro/Pro: OR = 0.56, 95% CI: 0.47-0.65, P < 0.001) or include at least 200 subjects (Arg/Arg vs Pro/Pro: OR = 0.56, 95% CI: 0.47-0.65, P < 0.001). Analysis restricted to well-designed studies also sup-ported the significantly decreased risk of EC (Arg/Arg vs Pro/Pro: OR = 0.54, 95% CI: 0.46-0.64, P < 0.001). CONCLUSION: TP53 Arg72 carriers are significantly as-sociated with decreased EC risk. Nevertheless, more well-designed studies are needed to confirm our findings.

  4. Ameliorative effect of adenosine on hypoxia-reoxygenation injury in LLC-PK1, a porcine kidney cell line.

    Science.gov (United States)

    Yonehana, T; Gemba, M

    1999-06-01

    We studied the effects of adenosine on injury caused by hypoxia and reoxygenation in LLC-PK1 cells. Lactate dehydrogenase and gamma-glutamyltranspeptidase were released from cells exposed to hypoxia for 6 hr and then reoxygenation for 1 hr. The addition of adenosine at 100 microM to the medium before hypoxia began significantly decreased enzyme leakage into medium during both hypoxia and reoxygenation. The adenosine A1-receptor agonist, R(-)-N6-(2-phenylisopropyl)adenosine (R-PIA), at the concentration of 100 microM, did not affect enzyme release, but the adenosine A2-receptor agonist 2-p-[2-car-boxyethyl]phenethyl-amino-5'-N-ethylcarboxamido-adenosi ne hydrochloride (CGS 21680) at the concentration of 100 nM, suppressed the injury caused by hypoxia and reoxygenation. There were decreases in cAMP contents and ATP levels in LLC-PK1 cells injured by hypoxia and reoxygenation. Adenosine (100 microM) restored ATP levels in the cells during reoxygenation. With adenosine, the intracellular cAMP level was increased prominently during reoxygenation. These results suggest that adenosine protects LLC-PK1 cells from injury caused by hypoxia and reoxygenation by increasing the intracellular cAMP level via adenosine A2 receptor.

  5. Recombinant Treponema pallidum protein Tp0965 activates endothelial cells and increases the permeability of endothelial cell monolayer.

    Directory of Open Access Journals (Sweden)

    Rui-Li Zhang

    Full Text Available The recombinant Treponema pallidum protein Tp0965 (rTp0965, one of the many proteins derived from the genome of T. pallidum subsp. pallidum, shows strong immunogenicity and immunoreactivity. In this study, we investigated the effects of rTp0965 on the endothelial barrier. Treatment of human umbilical vein endothelial cells (HUVECs with rTp0965 resulted in increased levels of ICAM-1, E-selectin, and MCP-1 mRNA and protein expression. These increases contributed to the adhesion and chemataxis of monocytes (THP-1 cells to HUVECs preincubated with rTp0965. In addition, rTp0965 induced reorganization of F-actin and decreased expression of claudin-1 in HUVECs. Interestingly, inhibition of the RhoA/ROCK signal pathway protected against rTp0965-induced higher endothelial permeability as well as transendothelial migration of monocytes. These data indicate that Tp0965 protein may play an important role in the immunopathogenesis of syphilis.

  6. Mutational analysis of the activator of late transcription, Alt , in the lactococcal bacteriophage TP901-1

    DEFF Research Database (Denmark)

    Pedersen, Margit; Hammer, Karin

    2007-01-01

    An activator protein, Alt, synthesized during the early state of lytic infection is required for transcription of the late operon in the lactococcal phage TP901-1. In order to identify amino acid residues in the Alt protein required for activation of the TP901-1 late promoter, Plate, hydroxylamin...

  7. Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma

    DEFF Research Database (Denmark)

    Young, Ken H; Leroy, Karen; Møller, Michael Boe;

    2008-01-01

    The purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53 mutations were identified in 102 of 477 patients and the overall survival (OS) of pati...

  8. Heterologous expression of the Treponema pallidum laminin-binding adhesin Tp0751 in the culturable spirochete Treponema phagedenis.

    Science.gov (United States)

    Cameron, Caroline E; Kuroiwa, Janelle M Y; Yamada, Mitsunori; Francescutti, Teresa; Chi, Bo; Kuramitsu, Howard K

    2008-04-01

    Treponema pallidum subsp. pallidum, the causative agent of syphilis, is an unculturable, genetically intractable bacterium. Here we report the use of the shuttle vector pKMR4PEMCS for the expression of a previously identified T. pallidum laminin-binding adhesin, Tp0751, in the nonadherent, culturable spirochete Treponema phagedenis. Heterologous expression of Tp0751 in T. phagedenis was confirmed via reverse transcriptase PCR analysis with tp0751 gene-specific primers and immunofluorescence analysis with Tp0751-specific antibodies; the latter assay verified the expression of the laminin-binding adhesin on the treponemal surface. Expression of Tp0751 within T. phagedenis was functionally confirmed via laminin attachment assays, in which heterologous Tp0751 expression conferred upon T. phagedenis the capacity to attach to laminin. Further, specific inhibition of the attachment of T. phagedenis heterologously expressing Tp0751 to laminin was achieved by using purified antibodies raised against recombinant T. pallidum Tp0751. This is the first report of heterologous expression of a gene from an unculturable treponeme in T. phagedenis. This novel methodology will significantly advance the field of syphilis research by allowing targeted investigations of T. pallidum proteins purported to play a role in pathogenesis, and specifically host cell attachment, in the nonadherent spirochete T. phagedenis.

  9. TP53 mutation and human papilloma virus status of oral squamous cell carcinomas in young adult patients

    NARCIS (Netherlands)

    Braakhuis, B.J.M.; Rietbergen, M.M.; Buijze, M.; Snijders, P.J.F.; Bloemena, E.; Brakenhoff, R.H.; Leemans, C.R.

    2014-01-01

    Objective Little is known about the molecular carcinogenesis of oral squamous cell carcinoma (OSCC) in young adult patients. The aim of this study was to investigate the detailed TP53 mutation and human papilloma virus (HPV) status of OSCC in patients, younger than 45 years. Methods TP53 mutations w

  10. Human papillomavirus type 16 and TP53 mutation in oral cancer: matched analysis of the IARC multicenter study.

    NARCIS (Netherlands)

    Dai, M; Clifford, GM; Calvez, F le; Castellsague, X; Snijders, P.J.F.; Pawlita, M; Herrero, R; Hainaut, P; Franceschi, S

    2004-01-01

    TP53 mutations were analyzed in 35 human papillomavirus (HPV) type 16 DNA-positive cancers of the oral cavity and oropharynx and in 35 HPV DNA-negative cancers matched by subsite, country, sex, age, and tobacco and alcohol consumption. Wild-type TP53 was found more frequently in cancer specimens tha

  11. [Frequency, spectrum, and functional significance of TP53 mutations in patients with diffuse large B-cell lymphoma].

    Science.gov (United States)

    Voropaeva, E N; Pospelova, T I; Voevoda, M I; Maksimov, V N

    2017-01-01

    A comparative analysis of oncogene mutations shows that variations in their frequency, spectrum, and hot-spot locations depends on the type of tumor and the ethnic origin of the population studied. The current version of the IARC TP53 Mutation Database lacks information about the frequency and spectrum of TP53 mutations in patients with DLBCL in Russia. The aim of this study was to assess the frequency and functional significance of TP53 mutations in patients with DLBCL in Novosibirsk. The TP53 coding sequence and the adjacent intron regions were analyzed by direct sequencing in the tumor material from 74 patients with DLBCL. Mutations of the TP53 coding sequence were found in 18 (24.3%) patients. These data are consistent with the frequency of TP53  mutations observed in other studies. The spectrum of nucleotide substitutions found in DLBCL specimens corresponded to that described in the IARC TP53 Mutation Database. According to bioinformatic data and to reported experiments in vitro, most of the mutations detected result in the production of functionally inactive p53. Our results show that DLBCL progression is accompanied by the functional selection for mutations in TP53 exons 5-8.

  12. MGMT promoter hypermethylation is a frequent, early, and consistent event in astrocytoma progression, and not correlated with TP53 mutation

    NARCIS (Netherlands)

    F.H. Groenendijk (Floris); W. Taal (Walter); H.J. Dubbink (Erik Jan); C.R. Haarloo (Cathleen); M.C.M. Kouwenhoven (Mathilde); M.J. van den Bent (Martin); J.M. Kros (Johan); W.N.M. Dinjens (Winand)

    2011-01-01

    textabstractHypermethylation of the MGMT gene promoter and mutation of the TP53 tumor-suppressor gene are frequently present in diffuse astrocytomas. However, there is only anecdotal information about MGMT methylation status and TP53 mutations during progression of low-grade diffuse astrocytoma (AII

  13. Clinical Impact of TP53 Gene Mutations in Diffuse Large B-Cell Lymphoma (DLBCL)

    DEFF Research Database (Denmark)

    Young, Ken H; Patten, Nancy; Truong, Sim

    2009-01-01

    Mutations of the TP53 tumor suppressor gene are associated with a poor clinical outcome in DLBCL patients treated with CHOP. The impact of TP53 mutations on clinical outcome of DLBCL patients treated with Rituxan-CHOP has not been comprehensively analyzed. The purpose of this study was to analyze...

  14. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations

    DEFF Research Database (Denmark)

    Farooqui, Mohammed Z H; Valdez, Janet; Martyr, Sabrina

    2015-01-01

    BACKGROUND: Patients with chronic lymphocytic leukaemia (CLL) with TP53 aberrations respond poorly to first-line chemoimmunotherapy, resulting in early relapse and short survival. We investigated the safety and activity of ibrutinib in previously untreated and relapsed or refractory CLL with TP53...

  15. KRAS and TP53 mutations in bronchoscopy samples from former lung cancer patients.

    Science.gov (United States)

    Gao, Weimin; Jin, Jide; Yin, Jinling; Land, Stephanie; Gaither-Davis, Autumn; Christie, Neil; Luketich, James D; Siegfried, Jill M; Keohavong, Phouthone

    2017-02-01

    Mutations in the KRAS and TP53 genes have been found frequently in lung tumors and specimens from individuals at high risk for lung cancer and have been suggested as predictive markers for lung cancer. In order to assess the prognostic value of these two genes' mutations in lung cancer recurrence, we analyzed mutations in codon 12 of the KRAS gene and in hotspot codons of the TP53 gene in 176 bronchial biopsies obtained from 77 former lung cancer patients. Forty-seven patients (61.0%) showed mutations, including 35/77 (45.5%) in the KRAS gene and 25/77 (32.5%) in the TP53 gene, among them 13/77 (16.9%) had mutations in both genes. When grouped according to past or current smoking status, a higher proportion of current smokers showed mutations, in particular those in the TP53 gene (P = 0.07), compared with ex-smokers. These mutations were found in both abnormal lesions (8/20 or 40%) and histologically normal tissues (70/156 or 44.9%) (P = 0.812). They consisted primarily of G to A transition and G to T transversion in both the KRAS (41/56 or 73.2%) and TP53 (24/34 or 70.6%) genes, consistent with mutations found in lung tumors of smoking lung cancer patients. Overall, recurrence-free survival (RFS) among all subjects could be explained by age at diagnosis, tumor stage, tumor subtype, and smoking (P lung cancer patients. However, the presence of mutation of bronchial biopsies was not significantly associated with a shorter RFS time. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  16. Extremely high Tp53 mutation load in esophageal squamous cell carcinoma in Golestan Province, Iran.

    Directory of Open Access Journals (Sweden)

    Behnoush Abedi-Ardekani

    Full Text Available BACKGROUND: Golestan Province in northeastern Iran has one of the highest incidences of esophageal squamous cell carcinoma (ESCC in the world with rates over 50 per 100,000 person-years in both sexes. We have analyzed TP53 mutation patterns in tumors from this high-risk geographic area in search of clues to the mutagenic processes involved in causing ESCC. METHODOLOGY/PRINCIPAL FINDINGS: Biopsies of 119 confirmed ESCC tumor tissue from subjects enrolled in a case-control study conducted in Golestan Province were analyzed by direct sequencing of TP53 exons 2 through 11. Immunohistochemical staining for p53 was carried out using two monoclonal antibodies, DO7 and 1801. A total of 120 TP53 mutations were detected in 107/119 cases (89.9%, including 11 patients with double or triple mutations. The mutation pattern was heterogeneous with infrequent mutations at common TP53 "hotspots" but frequent transversions potentially attributable to environmental carcinogens forming bulky DNA adducts, including 40% at bases known as site of mutagenesis by polycyclic aromatic hydrocarbons (PAHs. Mutations showed different patterns according to the reported temperature of tea consumption, but no variation was observed in relation to ethnicity, tobacco or opium use, and alcoholic beverage consumption or urban versus rural residence. CONCLUSION/SIGNIFICANCE: ESCC tumors in people from Golestan Province show the highest rate of TP53 mutations ever reported in any cancer anywhere. The heterogeneous mutation pattern is highly suggestive of a causative role for multiple environmental carcinogens, including PAHs. The temperature and composition of tea may also influence mutagenesis.

  17. Evidence that TP_0144 of Treponema pallidum is a thiamine-binding protein.

    Science.gov (United States)

    Bian, Jiang; Tu, Youbin; Wang, Song-Mei; Wang, Xuan-Yi; Li, Chunhao

    2015-04-01

    Thiamine pyrophosphate (TPP), the biologically active form of thiamine (also known as vitamin B1), is an essential cofactor for several important enzymes involved in carbohydrate metabolism, and therefore, it is required for all living organisms. We recently found that a thiamine-binding protein (TDE_0143) is essential for the survival of Treponema denticola, an important bacterial pathogen that is associated with human periodontitis. In this report, we provide experimental evidence showing that TP_0144, a homolog of TDE_0143 from the syphilis spirochete Treponema pallidum, is a thiamine-binding protein that has biochemical features and functions that are similar to those of TDE_0143. First, structural modeling analysis reveal that both TDE_0143 and TP_0144 contain a conserved TPP-binding site and share similar structures to the thiamine-binding protein of Escherichia coli. Second, biochemical analysis shows that these two proteins bind to TPP with similar dissociation constant (Kd) values (TDE_0143, Kd of 36.50 nM; TP_0144, Kd of 32.62 nM). Finally, heterologous expression of TP_0144 in a ΔTDE_0143 strain, a previously constructed TDE_0143 mutant of T. denticola, fully restores its growth and TPP uptake when exogenous thiamine is limited. Collectively, these results indicate that TP_0144 is a thiamine-binding protein that is indispensable for T. pallidum to acquire exogenous thiamine, a key nutrient for bacterial survival. In addition, the studies shown in this report further underscore the feasibility of using T. denticola as a platform to study the biology and pathogenicity of T. pallidum and probably other uncultivable treponemal species as well.

  18. TP53 codon 72 polymorphism as a risk factor for cardiovascular disease in a Brazilian population

    Directory of Open Access Journals (Sweden)

    M.A.C. Smith

    2007-11-01

    Full Text Available TP53, a tumor suppressor gene, has a critical role in cell cycle, apoptosis and cell senescence and participates in many crucial physiological and pathological processes. Identification of TP53 polymorphism in older people and age-related diseases may provide an understanding of its physiology and pathophysiological role as well as risk factors for complex diseases. TP53 codon 72 (TP53:72 polymorphism was investigated in 383 individuals aged 66 to 97 years in a cohort from a Brazilian Elderly Longitudinal Study. We investigated allele frequency, genotype distribution and allele association with morbidities such as cardiovascular disease, type II diabetes, obesity, neoplasia, low cognitive level (dementia, and depression. We also determined the association of this polymorphism with serum lipid fractions and urea, creatinine, albumin, fasting glucose, and glycated hemoglobin levels. DNA was isolated from blood cells, amplified by PCR using sense 5'-TTGCCGTCCCAAGCAATGGATGA-3' and antisense 5'-TCTGGGAAGGGACAGAAGATGAC-3' primers and digested with the BstUI enzyme. This polymorphism is within exon 4 at nucleotide residue 347. Descriptive statistics, logistic regression analysis and Student t-test using the multiple comparison test were used. Allele frequencies, R (Arg = 0.69 and P (Pro = 0.31, were similar to other populations. Genotype distributions were within Hardy-Weinberg equilibrium. This polymorphism did not show significant association with any age-related disease or serum variables. However, R allele carriers showed lower HDL levels and a higher frequency of cardiovascular disease than P allele subjects. These findings may help to elucidate the physiopathological role of TP53:72 polymorphism in Brazilian elderly people.

  19. Discriminating among stellar population synthesis models of the TP-AGB phase in early quiescent galaxies

    Science.gov (United States)

    MacDougall, Mason; Newman, Andrew; Belli, Sirio; Ellis, Richard S.

    2017-01-01

    Galactic evolution at high redshifts is largely understood through stellar population synthesis (SPS) modeling of spectra and photometry integrated over all starlight of a galaxy. However, complex and poorly understood stellar phases like the unstable thermally-pulsating asymptotic giant branch (TP-AGB) phase make SPS modeling a difficult task. Recent models fail to agree on the TP-AGB contribution to the infrared luminosity, leading to significant discrepancy among the properties derived from modern SPS models when applied to early galaxies. Here we provide a thorough assessment of each of the most widely used SPS models by comparing their results and assessing their accuracy in modeling our unique dataset. We combine high-resolution spectroscopic observations from Keck/MOSFIRE with photometric data for 21 early quiescent galaxies with redshifts of z ~ 2. These galaxies are around the age of peak TP-AGB activity, between ~0.3 and 2 Gyr, and therefore provide an ideal test of the models. We find that models with a “light” TP-AGB contribution provide much better descriptions of our galaxies at ages of ~1 Gyr or less. This is true at high statistical significance and holds for models with or without dust reddening. However, contrary to previous studies, the model-dependent photometrically estimated ages are similar among the models, but they show only moderate agreement with the more model-independent spectroscopic ages derived from stellar absorption lines. The largest discrepancies are found for the Charlot & Bruzual (2007) models which show an artificial clustering of ages around 1 Gyr. The TP-AGB “light” models require more reddening, which can be independently tested by examining dust emission in the mid-infrared. The modeled fluxes are also mostly consistent with mid-infrared observations, with the exception of one model. Resolving these differences among the models will substantially strengthen our estimates of the properties of early quiescent

  20. PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights.

    Science.gov (United States)

    Ryan, Sinéad M; Frías, Jesús M; Wang, Xuexuan; Sayers, Claire T; Haddleton, David M; Brayden, David J

    2011-01-20

    Salmon calcitonin (sCT) was conjugated via cysteine-1 to novel comb-shaped end-functionalised (poly(PEG) methyl ether methacrylate) (sCT-P) polymers, to yield conjugates of total molecular weights (MW) inclusive of sCT: 6.5, 9.5, 23 and 40kDa. The conjugates were characterised by HPLC and their in vitro and in vivo bioactivity was measured by cAMP assay on human T47D cells and following intravenous (i.v.) injection to rats, respectively. Stability against endopeptidases, rat serum and liver homogenates was assessed. There were linear and exponential relationships between conjugate MW with potency and efficacy respectively, however the largest MW conjugate still retained 70% of E(max) and an EC(50) of 3.7nM. In vivo, while free sCT and the conjugates reduced serum [calcium] to a maximum of 15-30% over 240 min, the half-life (T(1/2)) was increased and the area under the curve (AUC) was extended in proportion to conjugate MW. Likewise, the polymer conferred protection on sCT against attack by trypsin, chymotrypsin, elastase, rat serum and liver homogenates, with the best protection afforded by sCT-P (40kDa). Mathematical modelling accurately predicted the MW relationships to in vitro efficacy, potency, in vivo PK and enzymatic stability. With a significant increase in T(1/2) for sCT, the 40kDa MW comb-shaped PEG conjugate of sCT may have potential as a long-acting injectable formulation.

  1. Welding Crack Analysis for TP304H Finned Tube Reheater%TP304H钢鳍片管再热器焊接裂纹分析

    Institute of Scientific and Technical Information of China (English)

    岳增武; 胡新芳; 王光东; 庄宗峰

    2004-01-01

    某厂循环流化床锅炉的高温再热器为TP304H钢鳍片管,现场组装焊接时,在鳍片与管子的角焊缝处出现多处裂纹.通过进行金相试验、断口分析及能谱微区成分分析,认为焊接热裂纹是造成开裂的主要原因.提出了提高焊接质量,防止焊接热裂纹的措施.

  2. Oxygen dependence of metabolic fluxes and energy generation of Saccharomyces cerevisiae CEN.PK113-1A

    Directory of Open Access Journals (Sweden)

    Wiebe Marilyn

    2008-07-01

    Full Text Available Abstract Background The yeast Saccharomyces cerevisiae is able to adjust to external oxygen availability by utilizing both respirative and fermentative metabolic modes. Adjusting the metabolic mode involves alteration of the intracellular metabolic fluxes that are determined by the cell's multilevel regulatory network. Oxygen is a major determinant of the physiology of S. cerevisiae but understanding of the oxygen dependence of intracellular flux distributions is still scarce. Results Metabolic flux distributions of S. cerevisiae CEN.PK113-1A growing in glucose-limited chemostat cultures at a dilution rate of 0.1 h-1 with 20.9%, 2.8%, 1.0%, 0.5% or 0.0% O2 in the inlet gas were quantified by 13C-MFA. Metabolic flux ratios from fractional [U-13C]glucose labelling experiments were used to solve the underdetermined MFA system of central carbon metabolism of S. cerevisiae. While ethanol production was observed already in 2.8% oxygen, only minor differences in the flux distribution were observed, compared to fully aerobic conditions. However, in 1.0% and 0.5% oxygen the respiratory rate was severely restricted, resulting in progressively reduced fluxes through the TCA cycle and the direction of major fluxes to the fermentative pathway. A redistribution of fluxes was observed in all branching points of central carbon metabolism. Yet only when oxygen provision was reduced to 0.5%, was the biomass yield exceeded by the yields of ethanol and CO2. Respirative ATP generation provided 59% of the ATP demand in fully aerobic conditions and still a substantial 25% in 0.5% oxygenation. An extensive redistribution of fluxes was observed in anaerobic conditions compared to all the aerobic conditions. Positive correlation between the transcriptional levels of metabolic enzymes and the corresponding fluxes in the different oxygenation conditions was found only in the respirative pathway. Conclusion 13C-constrained MFA enabled quantitative determination of

  3. Nanostructured lipid carriers as a novel oral delivery system for triptolide: induced changes in pharmacokinetics profile associated with reduced toxicity in male rats.

    Science.gov (United States)

    Zhang, Cong; Peng, Fan; Liu, Wei; Wan, Jiangling; Wan, Chunxi; Xu, Huibi; Lam, Christopher Waikei; Yang, Xiangliang

    2014-01-01

    After oral administration in rodents, triptolide (TP), a diterpenoid triepoxide compound, active as anti-inflammatory, immunosuppressive, anti-fertility, anti-cystogenesis, and anticancer agent, is rapidly absorbed into the blood circulation (from 5.0 to 19.5 minutes after dosing, depending on the rodent species) followed by a short elimination half-life (from about 20 minutes to less than 1 hour). Such significant and rapid fluctuations of TP in plasma likely contribute to its toxicity, which is characterized by injury to hepatic, renal, digestive, reproductive, and hematological systems. With the aim of prolonging drug release and improving its safety, TP-loaded nanostructured lipid carriers (TP-NLCs), composed of Compritol® 888 ATO (solid lipid) and Capryol™ 90 (liquid lipid), were developed using a microemulsion technique. The formulated TP-NLCs were also characterized and in vitro release was evaluated using the dialysis bag diffusion technique. In addition, the pharmacokinetics and toxicology profiles of TP-NLCs were compared to free TP and TP-loaded solid lipid nanoparticles (TP-SLNs; containing Compritol 888 ATO only). Results demonstrate that TP-NLCs had mean particle size of 231.8 nm, increased drug encapsulation with a 71.6% efficiency, and stable drug incorporation for over 1-month. TP-NLCs manifested a better in vitro sustained-release pattern compared to TP-SLNs. Furthermore, TP-NLCs prolonged mean residence time (MRT)0-t (Poral delivery system for a safer use of TP.

  4. Autophagy is induced through the ROS-TP53-DRAM1 pathway in response to mitochondrial protein synthesis inhibition.

    Science.gov (United States)

    Xie, Xiaolei; Le, Li; Fan, Yanxin; Lv, Lin; Zhang, Junjie

    2012-07-01

    Mitoribosome in mammalian cells is responsible for synthesis of 13 mtDNA-encoded proteins, which are integral parts of four mitochondrial respiratory chain complexes (I, III, IV and V). ERAL1 is a nuclear-encoded GTPase important for the formation of the 28S small mitoribosomal subunit. Here, we demonstrate that knockdown of ERAL1 by RNA interference inhibits mitochondrial protein synthesis and promotes reactive oxygen species (ROS) generation, leading to autophagic vacuolization in HeLa cells. Cells that lack ERAL1 expression showed a significant conversion of LC3-I to LC3-II and an enhanced accumulation of autophagic vacuoles carrying the LC3 marker, all of which were blocked by the autophagy inhibitor 3-MA as well as by the ROS scavenger NAC. Inhibition of mitochondrial protein synthesis either by ERAL1 siRNA or chloramphenicol (CAP), a specific inhibitor of mitoribosomes, induced autophagy in HTC-116 TP53 (+/+) cells, but not in HTC-116 TP53 (-/-) cells, indicating that tumor protein 53 (TP53) is essential for the autophagy induction. The ROS elevation resulting from mitochondrial protein synthesis inhibition induced TP53 expression at transcriptional levels by enhancing TP53 promoter activity, and increased TP53 protein stability by suppressing TP53 ubiquitination through MAPK14/p38 MAPK-mediated TP53 phosphorylation. Upregulation of TP53 and its downstream target gene DRAM1, but not CDKN1A/p21, was required for the autophagy induction in ERAL1 siRNA or CAP-treated cells. Altogether, these data indicate that autophagy is induced through the ROS-TP53-DRAM1 pathway in response to mitochondrial protein synthesis inhibition.

  5. Increased densities of binding sites for the peripheral-type benzodiazepine receptor ligand [3H]PK 11195 in congenital ornithine transcarbamylase-deficient sparse fur mouse.

    Science.gov (United States)

    Rao, V L; Qureshi, I A; Butterworth, R F

    1993-12-01

    Peripheral-type (mitochondrial) benzodiazepine receptors (PTBR) were studied in the brain and peripheral organs (kidney, liver, and testis) of normal male mice (CD-1/Y) and the congenitally hyperammonemic sparse fur (spf/Y) mouse. Radioligand binding assays were performed with [3H]PK 11195, a ligand with high selectivity and affinity for PTBR. Densities (maximal number of binding sites) of [3H]PK 11195 binding sites were greatest in kidney, followed by liver, testis, and brain. Densities of [3H]PK 11195 binding sites were significantly increased in all tissues of spf mice compared with control animals. In view of the localization of PTBR on the outer mitochondrial membrane, changes in PTBR in spf mouse tissues may modulate the altered mitochondrial function and oxidative metabolism, in brain and peripheral tissues, in congenital OTC deficiency. The positron emission tomography ligand 11C-PK 11195 could find an application in the assessment of end organ dysfunction in this disorder.

  6. 头颈部鳞癌中TP53基因的调控网络分析%TP53-related gene regulatory network analysis on head and neck squamous carcinoma

    Institute of Scientific and Technical Information of China (English)

    徐明义; 郑艳秋; 孙娟; 胡文良; 王亚平; 崔晓波; 李玲香

    2016-01-01

    Objective To find out the TP53-related mechanism underlying head and neck squamous cell carcinoma.Methods We used cbioportal to analyse the expression of TP53 and identify the co-expressed genes of TP53 in 279 samples from head and neck squamous cell carcinoma in TCGA database.We used String and DAVID database to establish the co-expression network of TP53 and analyze its func-tion.We used lncRNA2target and StarBase database to screen the microRNA,lncRNA and ceRNA that regulate TP53.Finally,Cytoscape soft-ware was used to establish TP53-related ceRNA network.Results In the 279 samples,77%samples were abnormal expression,and the sur-vival rate of patients with abnormal expression of TP53 was significantly lower than that of normal expression of TP53.Besides,we found 288 TP53-related co-expressed gene.(Spearman score and Pearson score>0.3)The functions of these genes were mainly transcription regulation, cell apoptosis,propagation and immune response.Gene regulatory network revealed that 43 microRNAs (i.g.,has-miR-186-5p and has-miR-202-3p),6 lncRNAs (e.g.,MEG1,TUG1 and MALAT1)and 56 ceRNAs (e.g.,PHC2,FZD4 and TUB)could regulate TP53.Conclusion We established TP53-related gene regulatory network and identified microRNA,lncRNA and ceRNA that regulate TP53.The data generated from this study could provide a new pointcut in research and treatment of head and neck squamous cell carcinoma.%目的:挖掘隐藏在头颈部鳞癌中抑癌基因TP53表达异常的机制。方法从TCGA数据库中选取279例头颈部鳞癌样本的测序数据,利用cbioportal获得TP53基因在头颈部鳞癌中的表达情况及其对患者生存的影响,并筛选样本中与TP53存在共表达关系的基因。利用String和DAVID数据库,建立TP53的共表达网络并分析网络功能,通过lncRNA2target和StarBase数据库,筛选出能够调控TP53的短链非编码RNA(microRNA),长链非编码RNA(lncRNA)和竞争性内源性RNA(ceRNA),利用Cyto-scape软件建立TP

  7. Distinct genetic difference between the Duffy binding protein (PkDBPαII) of Plasmodium knowlesi clinical isolates from North Borneo and Peninsular Malaysia.

    Science.gov (United States)

    Fong, Mun-Yik; Rashdi, Sarah A A; Yusof, Ruhani; Lau, Yee-Ling

    2015-02-21

    Plasmodium knowlesi is one of the monkey malaria parasites that can cause human malaria. The Duffy binding protein of P. knowlesi (PkDBPαII) is essential for the parasite's invasion into human and monkey erythrocytes. A previous study on P. knowlesi clinical isolates from Peninsular Malaysia reported high level of genetic diversity in the PkDBPαII. Furthermore, 36 amino acid haplotypes were identified and these haplotypes could be separated into allele group I and allele group II. In the present study, the PkDBPαII of clinical isolates from the Malaysian states of Sarawak and Sabah in North Borneo was investigated, and compared with the PkDBPαII of Peninsular Malaysia isolates. Blood samples from 28 knowlesi malaria patients were used. These samples were collected between 2011 and 2013 from hospitals in North Borneo. The PkDBPαII region of the isolates was amplified by PCR, cloned into Escherichia coli, and sequenced. The genetic diversity, natural selection and phylogenetics of PkDBPαII haplotypes were analysed using MEGA5 and DnaSP ver. 5.10.00 programmes. Forty-nine PkDBPαII sequences were obtained. Comparison at the nucleotide level against P. knowlesi strain H as reference sequence revealed 58 synonymous and 102 non-synonymous mutations. Analysis on these mutations showed that PkDBPαII was under purifying (negative) selection. At the amino acid level, 38 different PkDBPαII haplotypes were identified. Twelve of the 28 blood samples had mixed haplotype infections. Phylogenetic analysis revealed that all the haplotypes were in allele group I, but they formed a sub-group that was distinct from those of Peninsular Malaysia. Wright's FST fixation index indicated high genetic differentiation between the North Borneo and Peninsular Malaysia haplotypes. This study is the first to report the genetic diversity and natural selection of PkDBPαII of P. knowlesi from Borneo Island. The PkDBPαII haplotypes found in this study were distinct from those from

  8. Genetic diversity, haplotypes and allele groups of Duffy binding protein (PkDBPαII) of Plasmodium knowlesi clinical isolates from Peninsular Malaysia.

    Science.gov (United States)

    Fong, Mun-Yik; Lau, Yee-Ling; Chang, Phooi-Yee; Anthony, Claudia Nisha

    2014-04-03

    The monkey malaria parasite Plasmodium knowlesi is now recognized as the fifth species of Plasmodium that can cause human malaria. Like the region II of the Duffy binding protein of P. vivax (PvDBPII), the region II of the P. knowlesi Duffy binding protein (PkDBPαII) plays an essential role in the parasite's invasion into the host's erythrocyte. Numerous polymorphism studies have been carried out on PvDBPII, but none has been reported on PkDBPαII. In this study, the genetic diversity, haplotyes and allele groups of PkDBPαII of P. knowlesi clinical isolates from Peninsular Malaysia were investigated. Blood samples from 20 knowlesi malaria patients and 2 wild monkeys (Macaca fascicularis) were used. These samples were collected between 2010 and 2012. The PkDBPαII region of the isolates was amplified by PCR, cloned into Escherichia coli, and sequenced. The genetic diversity, natural selection and haplotypes of PkDBPαII were analysed using MEGA5 and DnaSP ver. 5.10.00 programmes. Fifty-three PkDBPαII sequences from human infections and 6 from monkeys were obtained. Comparison at the nucleotide level against P. knowlesi strain H as reference sequence showed 52 synonymous and 76 nonsynonymous mutations. Analysis on the rate of these mutations indicated that PkDBPαII was under purifying (negative) selection. At the amino acid level, 36 different PkDBPαII haplotypes were identified. Twelve of the 20 human and 1 monkey blood samples had mixed haplotype infections. These haplotypes were clustered into 2 distinct allele groups. The majority of the haplotypes clustered into the large dominant group. Our present study is the first to report the genetic diversity and natural selection of PkDBPαII. Hence, the haplotypes described in this report can be considered as novel. Although a high level of genetic diversity was observed, the PkDBPαII appeared to be under purifying selection. The distribution of the haplotypes was skewed, with one dominant major and one minor

  9. Imaging brain inflammation with [(11)C]PK11195 by PET and induction of the peripheral-type benzodiazepine receptor after transient focal ischemia in rats.

    Science.gov (United States)

    Rojas, Santiago; Martín, Abraham; Arranz, Maria J; Pareto, Deborah; Purroy, Jesús; Verdaguer, Esther; Llop, Jordi; Gómez, Vanessa; Gispert, Joan D; Millán, Olga; Chamorro, Angel; Planas, Anna M

    2007-12-01

    [(11)C]PK11195 is used in positron emission tomography (PET) studies for imaging brain inflammation in vivo as it binds to the peripheral-type benzodiazepine receptor (PBR) expressed by reactive glia and macrophages. However, features of the cellular reaction required to induce a positive [(11)C]PK11195 signal are not well characterized. We performed [(11)C]PK11195 PET and autoradiography in rats after transient focal cerebral ischemia. We determined [(3)H]PK11195 binding and PBR expression in brain tissue and examined the lesion with several markers. [(11)C]PK11195 standard uptake value increased at day 4 and grew further at day 7 within the ischemic core. Accordingly, ex vivo [(3)H]PK11195 binding increased at day 4, and increases further at day 7. The PET signal also augmented in peripheral regions, but to a lesser extent than in the core. Binding in the region surrounding infarction was supported by [(11)C]PK11195 autoradiography at day 7 showing that the radioactive signal extended beyond the infarcted core. Enhanced binding was preceded by increases in PBR mRNA expression in the ipsilateral hemisphere, and a 18-kDa band corresponding to PBR protein was detected. Peripheral-type benzodiazepine receptor immunohistochemistry showed subsets of ameboid microglia/macrophages within the infarcted core showing a distinctive strong PBR expression from day 4. These cells were often located surrounding microhemorrhages. Reactive astrocytes forming a rim surrounding infarction at day 7 also showed some PBR immunostaining. These results show cellular heterogeneity in the level of PBR expression, supporting that PBR is not a simple marker of inflammation, and that the extent of [(11)C]PK11195 binding depends on intrinsic features of the inflammatory cells.

  10. Optimizing intravenous fosfomycin dosing in combination with carbapenems for treatment of Pseudomonas aeruginosa infections in critically ill patients based on pharmacokinetic/pharmacodynamic (PK/PD) simulation

    OpenAIRE

    O. Asuphon; P. Montakantikul; J. Houngsaitong; Kiratisin, P.; P. Sonthisombat

    2016-01-01

    Objective: The purpose of the study was to determine the optimal dosing regimen of intravenous fosfomycin for the treatment of Pseudomonas aeruginosa (PA) based on PK/PD targets. Method: A total of 120 PA isolates were recovered from various clinical specimens at university hospital in Thailand. Minimum Inhibitory Concentrations (MICs) of all the isolates were determined by the E-test method. PK parameters were obtained from a published study. Monte Carlo simulation was performed to calcul...

  11. The origin of multiply sigmoid curves of pH-dependence. The partitioning of groups among titration pK values.

    Science.gov (United States)

    Dixon, H B; Clarke, S D; Smith, G A; Carne, T K

    1991-08-15

    An acid, HnA, with n ionizing groups is known to have the same titration curve as an equimolar mixture of n hypothetical monobasic acids, whose dissociation constants are known as the 'titration constants' of the real acid. We show that the pH-dependence of any property of HnA is also represented by the sum of one-site titration curves, characterized by these same titration constants. Since one such property is the degree of dissociation of one of the dissociating groups, a fraction of each group shows each of the various titration pK values, so that the group partitions among them. The n groups therefore share the same n titration pK values but differ in the fractions belonging to each. The one H+ ion per molecule that titrates with each pK is thus made up of the fractions, one from each group, that share this pK value. A group may possess a single pK value, in that it contributes virtually all of this pK and almost nothing to the others, only if either (1) in titrates in a different pH range from the other groups or (2) its affinity for H+ is unaffected by their ionization state.

  12. Fluorocycline TP-271 Is Potent against Complicated Community-Acquired Bacterial Pneumonia Pathogens

    Science.gov (United States)

    Fyfe, Corey; O’Brien, William; Hackel, Meredith; Minyard, Mary Beth; Waites, Ken B.; Dubois, Jacques; Murphy, Timothy M.; Slee, Andrew M.; Weiss, William J.; Sutcliffe, Joyce A.

    2017-01-01

    ABSTRACT TP-271 is a novel, fully synthetic fluorocycline antibiotic in clinical development for the treatment of respiratory infections caused by susceptible and multidrug-resistant pathogens. TP-271 was active in MIC assays against key community respiratory Gram-positive and Gram-negative pathogens, including Streptococcus pneumoniae (MIC90 = 0.03 µg/ml), methicillin-sensitive Staphylococcus aureus (MSSA; MIC90 = 0.25 µg/ml), methicillin-resistant S. aureus (MRSA; MIC90 = 0.12 µg/ml), Streptococcus pyogenes (MIC90 = 0.03 µg/ml), Haemophilus influenzae (MIC90 = 0.12 µg/ml), and Moraxella catarrhalis (MIC90 ≤0.016 µg/ml). TP-271 showed activity (MIC90 = 0.12 µg/ml) against community-acquired MRSA expressing Panton-Valentine leukocidin (PVL). MIC90 values against Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae were 0.004, 1, and 4 µg/ml, respectively. TP-271 was efficacious in neutropenic and immunocompetent animal pneumonia models, generally showing, compared to the burden at the start of dosing, ~2 to 5 log10 CFU reductions against MRSA, S. pneumoniae, and H. influenzae infections when given intravenously (i.v.) and ~1 to 4 log10 CFU reductions when given orally (p.o.). TP-271 was potent against key community-acquired bacterial pneumonia (CABP) pathogens and was minimally affected, or unaffected, by tetracycline-specific resistance mechanisms and fluoroquinolone or macrolide drug resistance phenotypes. IMPORTANCE Rising resistance rates for macrolides, fluoroquinolones, and β-lactams in the most common pathogens associated with community-acquired bacterial pneumonia (CABP) are of concern, especially for cases of moderate to severe infections in vulnerable populations such as the very young and the elderly. New antibiotics that are active against multidrug-resistant Streptococcus pneumoniae and Staphylococcus aureus are needed for use in the empirical treatment of the most severe forms of this disease. TP-271 is a promising

  13. Convergent evidence of the contribution of TP53 genetic variation (Pro72Arg) to metabolic activity and white matter volume in the frontal lobe in schizophrenia patients.

    Science.gov (United States)

    Molina, Vicente; Papiol, Sergi; Sanz, Javier; Rosa, Araceli; Arias, Bárbara; Fatjó-Vilas, Mar; Calama, Julia; Hernández, Ana I; Bécker, Joemir; Fañanás, Lourdes

    2011-05-01

    Abnormalities in white matter (WM) volumes and integrity in schizophrenia, together with post-mortem studies showing reduced expression of oligodendrocyte/myelination genes and apoptotic processes taking place in oligodendrocytes, suggest the interest of major regulators of apoptosis as candidate genes for some features related to myelin integrity in schizophrenia. Protein p53, encoded by TP53 gene, has a central role in the control of apoptosis and is involved in oligodendrocyte development. TP53 gene polymorphisms may account for variability in WM features, metabolic activity and biochemical markers of neuronal integrity and membrane turnover. Pro72Arg and Ins16bp polymorphisms at TP53 gene were analyzed in 20 DSM-IV schizophrenia patients. T1/T2-weighted sequences of these patients were acquired using a 1.5T Philips Gyroscan system. Scans were transformed into Talairach space and segmented into gray matter (GM), WM and cerebrospinal fluid (CSF) using Statistical Parametric Mapping under a ROI approach. Likewise dorsolateral prefrontal cortex (DLPFC) metabolic activity was measured using a procedure based on MRI/PET image fusion. In 13 of these patients proton magnetic resonance spectroscopy was used to examine N-acetylaspartate (NAA), creatine (Cr) and choline (Cho) levels in dorsolateral-medial prefrontal cortex (DLMPFC). MRI data were adjusted for age and brain volume using regression parameters from a healthy control group (n=45). Patients Pro/Arg heterozygous (Pro72Arg polymorphism) showed a generalized deficit in whole-brain WM that was especially prominent in frontal lobe and a lower metabolic activity in the DLPFC as compared to Pro/Pro homozygous. Pro/Arg subjects also showed decreased NAA/Cho and increased Cho/Cr ratios in right DLMPFC. TP53 genetic variability influences WM volumes in frontal lobes and it seems to modulate the metabolic activity in this region. Our results suggest that TP53 might influence aspects of myelin and white matter integrity

  14. Deep sequencing of the TP53 gene reveals a potential risk allele for non-small cell lung cancer and supports the negative prognostic value of TP53 variants.

    Science.gov (United States)

    Deben, Christophe; Van den Bossche, Jolien; Van Der Steen, Nele; Lardon, Filip; Wouters, An; de Beeck, Ken Op; Hermans, Christophe; Jacobs, Julie; Peeters, Marc; Van Camp, Guy; Rolfo, Christian; Deschoolmeester, Vanessa; Pauwels, Patrick

    2017-02-01

    The TP53 gene remains the most frequently altered gene in human cancer, of which variants are associated with cancer risk, therapy resistance, and poor prognosis in several tumor types. To determine the true prognostic value of TP53 variants in non-small cell lung cancer, this study conducted further research, particularly focusing on subtype and tumor stage. Therefore, we determined the TP53 status of 97 non-small cell lung cancer adenocarcinoma patients using next generation deep sequencing technology and defined the prognostic value of frequently occurring single nucleotide polymorphisms and mutations in the TP53 gene. Inactivating TP53 mutations acted as a predictor for both worse overall and progression-free survival in stage II-IV patients and patients treated with DNA-damaging (neo)adjuvant therapy. In stage I tumors, the Pro-allele of the TP53 R72P polymorphism acted as a predictor for worse overall survival. In addition, we detected the rare R213R (rs1800372, minor allele frequency: 0.0054) polymorphism in 7.2% of the patients and are the first to show the significant association with TP53 mutations in non-small cell lung cancer adenocarcinoma patients (p = 0.003). In conclusion, Our findings show an important role for TP53 variants as negative predictors for the outcome of non-small cell lung cancer adenocarcinoma patients, especially for TP53 inactivating mutations in advanced stage tumors treated with DNA-damaging agents, and provide the first evidence of the R213R G-allele as possible risk factor for non-small cell lung cancer.

  15. Patch recordings from the electrocytes of Electrophorus electricus. Na currents and PNa/PK variability

    Science.gov (United States)

    1991-01-01

    Sodium currents were recorded in cell-attached and inside-out patches from the innervated membrane of Electrophorus electrocytes. Electrocytes from Sachs and main electric organs were prepared as described by Pasquale et al. (1986. J. Membr. Biol. 93:195.). Maximal currents in the Sachs organ, measured with 1-2 microns diameter patch pipettes and at room temperature, were in the range of 20 to 300 pA (27 patches) and were obtained near +10 mV. This range of current corresponds to approximately 70 to 1,300 channels in a patch. Maximal current in main organ cells also occurred near +10 mV and were in the range of 100 to 400 pA. Delayed K current was observed in a few patches. The inactivation phase of the currents during maintained depolarizations appears to be a single-exponential relaxation. The time constant decreases from 1 ms near -55 mV to a minimum of 0.3 ms near 0 mV, and then gradually increases with stronger depolarization. The mean currents are half inactivated near -90 mV with an apparent voltage dependence of e-fold per 6 mV. No apparent differences were observed in the decay time course or steady-state inactivation of the currents in the same patch before and after excision. From ensemble fluctuation analysis the peak open probability was found to be approximately 0.5 at +25 mV and increased only gradually with larger depolarizations. The single channel conductances were approximately 20 pS with 200 mM Na outside and 200 mM K inside, and 40 pS in 400 mM solutions. Reversal potentials in the 200 Na parallel 200 K solutions ranged from +51 to +94 mV in multichannel patches, corresponding to selectivity ratios PNa/PK from 8 to 43. Large differences in reversal potentials were seen even among patches from the same cell. Several controls rule out obvious sources of error in the reversal potential measurements. It is concluded that there is heterogeneity in the selectivity properties of the Na channels. PMID:1650809

  16. Patch recordings from the electrocytes of Electrophorus electricus. Na currents and PNa/PK variability.

    Science.gov (United States)

    Shenkel, S; Sigworth, F J

    1991-05-01

    Sodium currents were recorded in cell-attached and inside-out patches from the innervated membrane of Electrophorus electrocytes. Electrocytes from Sachs and main electric organs were prepared as described by Pasquale et al. (1986. J. Membr. Biol. 93:195.). Maximal currents in the Sachs organ, measured with 1-2 microns diameter patch pipettes and at room temperature, were in the range of 20 to 300 pA (27 patches) and were obtained near +10 mV. This range of current corresponds to approximately 70 to 1,300 channels in a patch. Maximal current in main organ cells also occurred near +10 mV and were in the range of 100 to 400 pA. Delayed K current was observed in a few patches. The inactivation phase of the currents during maintained depolarizations appears to be a single-exponential relaxation. The time constant decreases from 1 ms near -55 mV to a minimum of 0.3 ms near 0 mV, and then gradually increases with stronger depolarization. The mean currents are half inactivated near -90 mV with an apparent voltage dependence of e-fold per 6 mV. No apparent differences were observed in the decay time course or steady-state inactivation of the currents in the same patch before and after excision. From ensemble fluctuation analysis the peak open probability was found to be approximately 0.5 at +25 mV and increased only gradually with larger depolarizations. The single channel conductances were approximately 20 pS with 200 mM Na outside and 200 mM K inside, and 40 pS in 400 mM solutions. Reversal potentials in the 200 Na parallel 200 K solutions ranged from +51 to +94 mV in multichannel patches, corresponding to selectivity ratios PNa/PK from 8 to 43. Large differences in reversal potentials were seen even among patches from the same cell. Several controls rule out obvious sources of error in the reversal potential measurements. It is concluded that there is heterogeneity in the selectivity properties of the Na channels.

  17. Clinical Impact of TP53 Gene Mutations in Diffuse Large B-Cell Lymphoma (DLBCL)

    DEFF Research Database (Denmark)

    Young, Ken H; Patten, Nancy; Truong, Sim

    2009-01-01

    survival=50 months) and 41% in patients with the DNA-binding domain mutations (median survival=49 months) compared to 52% for those with wt-TP53 (median survival=69 months). The complete remission rate was 51% in patients with any TP53 mutation and 44% in patients with the DNA-binding domain mutations...... decreased median OS (17 months) when compared to patients with Loop L2 (16% of all mutations) or loop-sheet-helix motifs (Loop L1-S10-H2, 20% of all mutations) with median OS of 49 and 50 months, respectively. In contrast to our previous CHOP series study, median survival was significantly improved...... of TP53 mutations, while TP53 deletion did not correlate with mutation or OS. In comparison to our previous series of patients treated only with CHOP, Rituxan-CHOP regimen improved OS in both wt-TP53 and TP53 mutated groups. The 5-year survival rate was 42% in patients with any TP53 mutation (median...

  18. TP53 mutation in patients with high-risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation.

    Science.gov (United States)

    Middeke, Jan M; Herold, Sylvia; Rücker-Braun, Elke; Berdel, Wolfgang E; Stelljes, Matthias; Kaufmann, Martin; Schäfer-Eckart, Kerstin; Baldus, Claudia D; Stuhlmann, Reingard; Ho, Anthony D; Einsele, Hermann; Rösler, Wolf; Serve, Hubert; Hänel, Mathias; Sohlbach, Kristina; Klesse, Christian; Mohr, Brigitte; Heidenreich, Falk; Stölzel, Friedrich; Röllig, Christoph; Platzbecker, Uwe; Ehninger, Gerhard; Bornhäuser, Martin; Thiede, Christian; Schetelig, Johannes

    2016-03-01

    Treatment success in patients with acute myeloid leukaemia (AML) is heterogeneous. Cytogenetic and molecular alterations are strong prognostic factors, which have been used to individualize treatment. Here, we studied the impact of TP53 mutations on the outcome of AML patients with adverse cytogenetic risk treated with allogeneic haematopoietic stem cell transplantation (HSCT). Samples of 97 patients with AML and adverse-risk cytogenetics who had received a HSCT within three randomized trials were analysed. Complete sequencing of the TP53 coding region was performed using next generation sequencing. The median age was 51 years. Overall, TP53 mutations were found in 40 patients (41%). With a median follow up of 67 months, the three-year probabilities of overall survival (OS) and event-free survival for patients with TP53 wild type were 33% [95% confidence interval (CI), 21% to 45%] and 24% (95% CI, 13% to 35%) compared to 10% (95% CI, 0% to 19%) and 8% (95% CI, 0% to 16%) (P = 0·002 and P = 0·007) for those with mutated TP53, respectively. In multivariate analysis, the TP53-mutation status had a negative impact on OS (Hazard Ratio = 1·7; P = 0·066). Mutational analysis of TP53 might be an important additional tool to predict outcome after HSCT in patients with adverse karyotype AML.

  19. TP53 alterations in pancreatic acinar cell carcinoma: new insights into the molecular pathology of this rare cancer.

    Science.gov (United States)

    La Rosa, Stefano; Bernasconi, Barbara; Frattini, Milo; Tibiletti, Maria Grazia; Molinari, Francesca; Furlan, Daniela; Sahnane, Nora; Vanoli, Alessandro; Albarello, Luca; Zhang, Lizhi; Notohara, Kenji; Casnedi, Selenia; Chenard, Marie-Pierre; Adsay, Volkan; Asioli, Sofia; Capella, Carlo; Sessa, Fausto

    2016-03-01

    The molecular alterations of pancreatic acinar cell carcinomas (ACCs) are poorly understood and have been reported as being different from those in ductal adenocarcinomas. Loss of TP53 gene function in the pathogenesis of ACCs is controversial since contradictory findings have been published. A comprehensive analysis of the different possible genetic and epigenetic mechanisms leading to TP53 alteration in ACC has never been reported and hence the role of TP53 in the pathogenesis and/or progression of ACC remains unclear. We investigated TP53 alterations in 54 tumor samples from 44 patients, including primary and metastatic ACC, using sequencing analysis, methylation-specific multiplex ligation probe amplification, fluorescence in situ hybridization, and immunohistochemistry. TP53 mutations were found in 13 % of primary ACCs and in 31 % of metastases. Primary ACCs and metastases showed the same mutational profile, with the exception of one case, characterized by a wild-type sequence in the primary carcinoma and a mutation in the corresponding metastasis. FISH analysis revealed deletion of the TP53 region in 53 % of primary ACCs and in 50 % of metastases. Promoter hypermethylation was found in one case. The molecular alterations correlated well with the immunohistochemical findings. A statistically significant association was found between the combination of mutation of one allele and loss of the other allele of TP53 and worse survival.

  20. Use of tilapia piscidin 3 (TP3) to protect against MRSA infection in mice with skin injuries.

    Science.gov (United States)

    Huang, Han-Ning; Chan, Yi-Lin; Hui, Cho-Fat; Wu, Jen-Leih; Wu, Chang-Jer; Chen, Jyh-Yih

    2015-05-30

    Antimicrobial peptides (AMPs), represent promising agents for new therapeutic approaches of infected wound treatment, on account of their antimicrobial and wound closure activities, and low potential for inducing resistance. However, therapeutic applications of these AMPs are limited by their toxicity and low stability in vivo. Previously, we reported that the 23 amino-acid designer peptide TP3 possessed antimicrobial activities. Here, we analyzed the wound closure activities of TP3 both and in vivo. TP3 at doses of up to 40 μg/ml did not affect the viability of baby hamster kidney cells. Furthermore, TP3 was found to be highly effective at combating peritonitis and wound infection caused by MRSA in mouse models, without inducing adverse behavioral effects or liver or kidney toxicity. TP3 treatment increased survival by 100% at 8 days after infection, and accelerated the progression of proliferation, remodeling, and maturation of infected wounds. Taken together, our results indicate that TP3 enhances the rate of survival of mice infected with the bacterial pathogen MRSA through both antimicrobial and immunomodulatory effects. Overall, these results suggest that TP3 may be suitable for development as a novel topical agent for treatment of infected wounds.

  1. Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acute myeloid leukemia treated with azacitidine.

    Science.gov (United States)

    Bally, Cecile; Adès, Lionel; Renneville, Aline; Sebert, Marie; Eclache, Virginie; Preudhomme, Claude; Mozziconacci, Marie-Joelle; de The, Hugues; Lehmann-Che, Jacqueline; Fenaux, Pierre

    2014-07-01

    TP53 mutations are found in 5-10% of MDS and AML, where they are generally associated with complex karyotype and an overall poor prognosis. However, the impact of TP53 mutations in MDS treated with azacitidine (AZA) remains unclear. We analyzed TP53 mutations in 62 patients with high risk MDS or AML treated with AZA. A TP53 mutation was found in 23 patients (37.1%), associated with complex karyotype in 18 (78.3%) of them. TP53 mutations had no significant impact on response or complete response to AZA (p=0.60 and p=0.26, respectively). By univariate analysis, OS was negatively influenced by the presence of TP53 mutation (median OS 12.4 months versus 23.7 months, pmutational status (HR 2.89 (95% confidence interval 1.38-6.04; p=0.005) retained statistical significance for OS. Results were similar when the analysis was restricted to MDS and CMML patients, excluding AML (HR=2.46 (95% confidence interval: 1.1-6.4); p=0.04)). Thus, TP53 mutations strongly correlated with poorer survival in higher risk MDS and AML treated with AZA.

  2. Different TP53 mutations are associated with specific chromosomal rearrangements, telomere length changes, and remodeling of the nuclear architecture of telomeres.

    Science.gov (United States)

    Samassekou, Oumar; Bastien, Nathalie; Lichtensztejn, Daniel; Yan, Ju; Mai, Sabine; Drouin, Régen

    2014-11-01

    TP53 mutations are the most common mutations in human cancers, and TP53-R175H and TP53-R273H are the most frequent. The impact of these mutations on genomic instability after tumor initiation is still uncovered. To gain insight into this, we studied the effects of three specific TP53 mutants (TP53-V143A, TP53-R175H, and TP53-R273H) on genomic instability using four isogenic lines of LoVo cells. Multicolor fluorescence in situ hybridization (FISH), three-dimensional (3D) quantitative FISH (Q-FISH) on interphase and Q-FISH on metaphases were used to investigate genomic instability. We found that LoVo cells expressing mutant TP53-R175H displayed the highest level of chromosomal instability among the LoVo cell lines. Furthermore, we observed that mutant TP53-R175H and TP53-V143A showed more alterations in their 3D nuclear architecture of telomeres than the mutant TP53-R273H and the wild type. Moreover, we noted an association between some chromosomal abnormalities and telomere elongation in the mutant TP53-R175H. Taken together, our results indicate that the mutation TP53-R175H is more likely to cause higher levels of genomic instability than the other TP53 mutations. We proposed that the type of TP53 mutations and the genetic background of a cancer cell are major determinants of the TP53-dependent genomic instability.

  3. Long term steam oxidation of TP 347H FG in power plants

    DEFF Research Database (Denmark)

    Hansson, Anette Nørgaard; Korcakova, Leona; Hald, John

    2005-01-01

    The long term oxidation behaviour of TP 347H FG at ultra supercritical steam conditions was assessed by exposing the steel in test superheater loops in a Danish coal-fired power plant. The steamside oxide layer was investigated with scanning electron microscopy and energy dispersive Xray diffract......The long term oxidation behaviour of TP 347H FG at ultra supercritical steam conditions was assessed by exposing the steel in test superheater loops in a Danish coal-fired power plant. The steamside oxide layer was investigated with scanning electron microscopy and energy dispersive Xray...... diffraction in order to reveal the effect of oxidation time and temperature on the microstructure. A double layered oxide formed during steam oxidation. The morphology of the inner Cr-containing layer was influenced by the oxidation temperature. At temperatures below 585 degrees C, it consisted of regions...

  4. Rhabdomyosarcoma-associated renal cell carcinoma: a link with constitutional Tp53 mutation.

    LENUS (Irish Health Repository)

    Curry, Sarah

    2012-02-01

    The 2004 World Health Organization classification includes the new entity "neuroblastoma-associated renal cell carcinoma." The pathogenetic link between these entities is unknown as yet. The patient reported herein developed renal cell carcinoma after anaplastic embryonal rhabdomyosarcoma, a previously unknown association. The 2nd malignancy developed very soon after the 1st one, prompting concern for inherent cancer predisposition rather than a therapy-induced 2nd malignancy. A variety of features raised suspicion for Tp53 mutation, and indeed a pathogenic germline Tp53 mutation was identified in this child, despite a negative family history for Li-Fraumeni syndrome. Consideration of underlying predisposition is advocated in the context of rapid evolution of 2nd childhood malignancy.

  5. Investigation of steam oxidation behaviour of TP347H FG Part 2: Exposure at 91 bar

    DEFF Research Database (Denmark)

    Jianmin, J; Montgomery, Melanie; Larsen, OH

    2005-01-01

    Tube specimens of TP347FG were exposed in a test superheater loop in a biomass plant in Denmark. The specimens were exposed to surface metal temperatures in the range of 455-568C, steam pressure of 91 bar and exposure duration of 3500 and 8700 hours. The oxide thickness and morphology was investi......Tube specimens of TP347FG were exposed in a test superheater loop in a biomass plant in Denmark. The specimens were exposed to surface metal temperatures in the range of 455-568C, steam pressure of 91 bar and exposure duration of 3500 and 8700 hours. The oxide thickness and morphology...... was investigated using light optical and scanning electron microscopy. The oxide present on the specimens is a duplex oxide with an inner chromium rich oxide and an outer iron rich oxide. The inner oxide consisted of a primary iron chromium nickel oxide in the original alloy grain and a chromium rich oxide...

  6. Hepatitis B and Hepatitis C Infection Biomarkers and TP53 Mutations in Hepatocellular Carcinomas from Colombia.

    Science.gov (United States)

    Navas, Maria-Cristina; Suarez, Iris; Carreño, Andrea; Uribe, Diego; Rios, Wilson Alfredo; Cortes-Mancera, Fabian; Martel, Ghyslaine; Vieco, Beatriz; Lozano, Diana; Jimenez, Carlos; Gouas, Doriane; Osorio, German; Hoyos, Sergio; Restrepo, Juan Carlos; Correa, Gonzalo; Jaramillo, Sergio; Lopez, Rocio; Bravo, Luis Eduardo; Arbelaez, Maria Patricia; Scoazec, Jean-Yves; Abedi-Ardekani, Behnoush; Santella, Regina M; Chemin, Isabelle; Hainaut, Pierre

    2011-01-01

    Hepatocellular Carcinoma (HCC) is a leading cause of cancer-related death worldwide. Globally, the most important HCC risk factors are Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV), chronic alcoholism, and dietary exposure to aflatoxins. We have described the epidemiological pattern of 202 HCC samples obtained from Colombian patients. Additionally we investigated HBV/HCV infections and TP53 mutations in 49 of these HCC cases. HBV biomarkers were detected in 58.1% of the cases; HBV genotypes F and D were characterized in three of the samples. The HCV biomarker was detected in 37% of the samples while HBV/HCV coinfection was found in 19.2%. Among TP53 mutations, 10.5% occur at the common aflatoxin mutation hotspot, codon 249. No data regarding chronic alcoholism was available from the cases. In conclusion, in this first study of HCC and biomarkers in a Colombian population, the main HCC risk factor was HBV infection.

  7. Single nucleotide polymorphisms in the TP53 region and susceptibility to invasive epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Schildkraut, Joellen M; Goode, Ellen L; Clyde, Merlise A;

    2009-01-01

    The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2......,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP......) in the TP53 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (OR), 95% probability intervals (PI), and Bayes factors (BF) for genotype associations...

  8. Phase III study of TAC and TP regimens as neoadjuvant chemotherapy in patients with triple-negative breast cancer

    Institute of Scientific and Technical Information of China (English)

    Hanguang Ruan; Juan Xiong; Meng Wu

    2014-01-01

    This study aimed to compare the eficacy and safety of neoadjuvant chemotherapy with TAC and TP regimens of triple negative breast cancer (TNBC).Methods: A total of 102 patients with TNBC were confirmed by histopathol-ogy. They were divided into TAC group (52 cases) and TP group (50 cases). Group TAC: Docetaxel 75 mg/m2 or paclitaxel (taxol liposome) 135 mg/m2 on d1, pirarubicin 40 mg/m2 or epirubicin 75 mg/m2 on d2, cyclophosphamide 600 mg/m2 on d1;Group TP: Docetaxel 75 mg/m2 or paclitaxel (taxol liposome) 135 mg/m2 on d1, cisplatin 30 mg/m2on d2-d4, with 21 days as a cycle. Al patients underwent operation after 2-4 cycles of chemotherapy. The short-term efects and toxic and adverse efects were evaluated. Results: In TAC group, 5 cases (9.6%) had pathological complete release (pCR), 35 cases (67.3%) partial release (PR), 9 cases (17.3%) stable disease (SD), and the response rate (RR) was 76.9%. In TP group, 4 cases (8%) had pCR, 32 cases (64%) PR, 5 cases (10%) SD, and RR was 72%. In 102 patients, 12 patients with tumor progression after 2 cycles of chemotherapy, included 3 cases in TAC group, 9 cases in TP group. In TAC group, 2 cases occurred atrial premature contraction; while 3 cases developed grade 2 renal injury in TP group. In TAC group, grade 3-4 hematologic toxicity and alo-pecia was significantly higher than that in TP group, but grade 3-4 gastrointestinal reaction rate in TP group was significantly higher than TAC group.Conclusion:TAC and TP regimens al had certain eficacy in the neoadjuvant chemotherapy for TNBC, and the toxicity reactions can be tolerated.

  9. ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells.

    Science.gov (United States)

    Kwok, Marwan; Davies, Nicholas; Agathanggelou, Angelo; Smith, Edward; Oldreive, Ceri; Petermann, Eva; Stewart, Grant; Brown, Jeff; Lau, Alan; Pratt, Guy; Parry, Helen; Taylor, Malcolm; Moss, Paul; Hillmen, Peter; Stankovic, Tatjana

    2016-02-04

    TP53 and ataxia telangiectasia mutated (ATM) defects are associated with genomic instability, clonal evolution, and chemoresistance in chronic lymphocytic leukemia (CLL). Currently, therapies capable of providing durable remissions in relapsed/refractory TP53- or ATM-defective CLL are lacking. Ataxia telangiectasia and Rad3-related (ATR) mediates response to replication stress, the absence of which leads to collapse of stalled replication forks into chromatid fragments that require resolution through the ATM/p53 pathway. Here, using AZD6738, a novel ATR kinase inhibitor, we investigated ATR inhibition as a synthetically lethal strategy to target CLL cells with TP53 or ATM defects. Irrespective of TP53 or ATM status, induction of CLL cell proliferation upregulated ATR protein, which then became activated in response to replication stress. In TP53- or ATM-defective CLL cells, inhibition of ATR signaling by AZD6738 led to an accumulation of unrepaired DNA damage, which was carried through into mitosis because of defective cell cycle checkpoints, resulting in cell death by mitotic catastrophe. Consequently, AZD6738 was selectively cytotoxic to both TP53- and ATM-defective CLL cell lines and primary cells. This was confirmed in vivo using primary xenograft models of TP53- or ATM-defective CLL, where treatment with AZD6738 resulted in decreased tumor load and reduction in the proportion of CLL cells with such defects. Moreover, AZD6738 sensitized TP53- or ATM-defective primary CLL cells to chemotherapy and ibrutinib. Our findings suggest that ATR is a promising therapeutic target for TP53- or ATM-defective CLL that warrants clinical investigation.

  10. Analysis of polymorphisms in codons 11, 72 and 248 of TP53 in Brazilian women with breast cancer.

    Science.gov (United States)

    Almeida, B C; Kleine, J P F O; Camargo-Kosugi, C M; Lisboa, M R; França, C N; França, J P; Silva, I D C G

    2016-02-22

    The association between TP53 gene polymorphisms and breast cancer (BC) in Brazilian women is a controversial topic. In this cross-sectional study, we evaluated the association between clinical pathological variables and three polymorphisms (TP53*11, TP53*72, and TP53*248) in BC patients and controls. Genomic DNA was extracted from the blood cells of 393 participants; the cancer-free control subjects were 26-72 years old (41 ± 11.03) and the BC patients were 28-80 years old (51 ± 10.70). We used standard polymerase chain reaction-restriction fragment length polymorphism and confirmed the results by genetic sequencing. In TP53*11, there was 100% homozygous Glu distribution in both groups. TP53*72 showed genotypic distribution: in the control group, there was 16.10% homozygous Pro, and 42.44% heterozygous and 41.46% homozygous Arg; in the BC group, there was 15.43% homozygous Pro, and 42.55% heterozygous and 42.02% homozygous Arg. The relative frequency of each allele was 0.37% for Pro and 0.63% for Arg in the control group, and 0.37% for Pro and 0.63% for Arg in the BC group. The nuclear grade (P = 0.0084) and adapted histological grade (P = 0.0265) were associated with TP53*72. The distribution of the codon 72 genotypes did not deviate from Hardy-Weinberg equilibrium in either group. In TP53*248, there was 100% homozygous Arg distribution in both groups. In codon 72, the Arg allele is the most prevalent in Brazilian women. TP53*72 may be associated with susceptibility to BC, although more studies are required to evaluate the profile of Brazilian women with BC.

  11. Identification of R2TP complex of Leishmania donovani and Plasmodium falciparum using genome wide in-silico analysis.

    Science.gov (United States)

    Ahmad, Moaz; Afrin, Farhat; Tuteja, Renu

    2013-11-01

    Recently discovered R2TP complex is an important multiprotein complex involved in multiple cellular process like snoRNP biogenesis, PIKK signaling, RNA polymerase II assembly and apoptosis. Within R2TP complex, Pih1 tightly interacts with Rvb1/Rvb2 and with Tah1 to form R2TP macromolecular complex. R2TP complex further interacts with Hsp90 to form R2TP-Hsp90 complex, which has been found critical in many cellular process. The genome wide screening of Leishmania donovani and Plasmodium falciparum led to the identification of RuvB like1, RuvB like 2, Pih1, and Tah1. Therefore, we speculate that this complex is also important for these parasites as in the yeast. The detailed analysis of crucial components of R2TP complex, Ld-RuvB like 1, and Ld-RuvB like 2, revealed the presence of characteristic motifs like DNA binding motif and ATPase motifs. Hsp90 is also reported from Leishmania donovani and Plasmodium falciparum suggesting that the R2TP complex further interacts with Hsp90 to form R2TP-Hsp90 complex. Recently it has been discovered that RuvB like proteins are overexpressed in many cancers and their ATPase activity is crucial for cancer cell proliferation and the human RuvBs have been proposed as suitable drug target for cancer. Similarly one of the Plasmodium falciparum RuvB like protein (PfRuvB3) has been found to be specific to the stage where nuclear division led multiplication of parasite take place. Considering all these it seems that the R2TP complex may be playing some critical role both in the cancer cell proliferation in human and rapid multiplication of the parasites Leishmania donovani and Plasmodium falciparum.

  12. TP53 gene polymorphisms at codons 11, 72, and 248 and association with endometriosis in a Brazilian population.

    Science.gov (United States)

    Camargo-Kosugi, C M; D'Amora, P; Kleine, J P F O; Carvalho, C V; Sato, H; Schor, E; Silva, I D C G

    2014-08-26

    We evaluated the association between TP53 gene polymorphisms and endometriosis in Brazilian women. Genomic DNA was extracted from swabs of buccal cells collected from hospital patients. TP53 gene polymorphisms were investigated at three codons: TP53 11 Glu/Gln or Lys (GAG->CAG or AAG), TP53 72 Arg/Pro (CCG->CCC), and TP53 248 Arg/Thr (CGG->TCG) using the polymerase chain reaction-restriction fragment length polymorphism method. TP53 11 presented the following genotypic distribution: the control group was 98.28% homozygous wild-type (Glu) and 1.72% homozygous variant (Gln/Lys), and the heterozygous genotype was not identified. The genotypic distribution in the endometriosis group was 96% homozygous wild-type (Glu) and 4% heterozygous (Glu-Gln/Lys); the homozygous variant genotype was not identified (P = 0.02). TP53 72 showed the following genotypic distribution: the control group was 29.75% homozygous wild-type (Arg), 47.11% heterozygous (Arg-Pro), and 23.14% homozygous variant (Pro). The genotypic distribution in the endometriosis group was 16.15% homozygous wild-type (Arg), 51.54% heterozygous (Arg-Pro), and 32.31% homozygous variant (Pro) (odds ratio = 2.26; 95% confidence interval = 1.19-4.03; P = 0.02). Only one patient had the homozygous TP53 248 genotype (Arg-Trp/Gln); all other patients were homozygous wild-type in both the control and endometriosis groups (P = 0.51; NS). We found that TP53 72 polymorphism may be associated with susceptibility to endometriosis; the presence of at least 1 polymorphic allele increased the chance of disease development by 2.26-fold. Hence, this genetic variant is a potential candidate marker for endometriosis.

  13. Non-Power-of-Two FFTs: Exploring the Flexibility of the Montium TP

    Directory of Open Access Journals (Sweden)

    Marcel D. van de Burgwal

    2009-01-01

    This paper presents the implementation of a class of non-power-of-two FFTs to discover the limitations and Flexibility of the Montium TP for less regular algorithms. A non-power-of-two FFT is less regular compared to a traditional power-of-two FFT. The results of the implementation show the processing time, accuracy, energy consumption and Flexibility of the implementation.

  14. Epigenetic modifications, chromatin distribution and TP53 transcription in a model of breast cancer progression.

    Science.gov (United States)

    Santos, Gilson C; da Silva, Ana P A; Feldman, Lucas; Ventura, Grasiella M; Vassetzky, Yegor; de Moura Gallo, Claudia V

    2015-04-01

    In the present paper we aimed to characterize epigenetic aspects and analyze TP53 transcription in the 21 T series, composed of breast cell lines: non-cancerous H16N2; Atypical Ductal Hyperplasia 21PT; Ductal Carcinoma in situ 21NT and Invasive Metastatic Carcinoma 21MT1. We detected a global genomic hypomethylation in 21NT and 21MT1. The histone modification markers analysis showed an important global decrease of the active chromatin mark H4Ac in 21MT1 relative to the other cell lines while the repressive mark H3K9Me3 were not significantly altered. The mRNA levels of DNA methylation and histone modification key enzymes are consistent with the observed genomic hypomethylation and histone hypoacetylation. The expression of DNMT3A/B increased at the initial stages of oncogenesis and the expression of DNMT1 and HAT1 decreased at the advanced stages of breast cancer. Using a confocal immunofluorescent assay, we observed that H4Ac was mostly located at the periphery and the repressive mark H3K9Me3, at the center of 21NT and 21MT1 cells nuclei. TP53 P1 promoter was found to be in an open chromatin state, with a relatively high enrichment of H4Ac and similar TP53 transcription levels in all 21 T cell lines. In conclusion, we observed epigenetic alterations (global genome hypomethylation, global hypoacetylation and accumulation of pericentric heterochromatin) in metastatic breast cancer cells of the 21 T series. These alterations may act at later stages of breast cancer progression and may not affect TP53 transcription at the P1 promoter.

  15. Prevalence of TP53 germ line mutations in young Pakistani breast cancer patients.

    Science.gov (United States)

    Rashid, Muhammad U; Gull, Sidra; Asghar, Kashif; Muhammad, Noor; Amin, Asim; Hamann, Ute

    2012-06-01

    Women from Pakistan and India are more often diagnosed with early-onset breast cancer than Caucasian women. Given that only 12% of Pakistani women diagnosed with breast cancer at or before 30 years of age have previously been shown to harbor germ line mutations in the breast cancer susceptibility genes BRCA1 and BRCA2, the genetic causes of the majority of early-onset cases are unexplained. Since germ line mutations in the tumor suppressor gene TP53 predispose women to early-onset breast cancer, we assessed the prevalence of TP53 mutations in 105 early-onset breast cancer patients from Pakistan, who had previously been found to be negative for BRCA1 and BRCA2 germ line mutations. The patient group included 67 women diagnosed with early-onset breast cancer at or before age 30 with no family history of breast or ovarian cancer (EO30NFH group) and 38 women diagnosed with breast cancer at or before age 40 with one or more first- or second-degree relatives with breast or ovarian cancer (EO40FH group). Mutation analysis of the complete TP53 coding region was performed using denaturing high-performance liquid chromatography analysis, followed by DNA sequencing of variant fragments. One deleterious mutation, c.499-500delCA in exon 5, was identified in the 105 breast cancer patients (1%). This mutation is novel in the germ line and has not been described in other populations. It was detected in a 28-year-old patient with no family history of breast or ovarian cancer. This mutation is rare as it was not detected in additional 157 recently recruited non-BRCA1 and non-BRCA2-associated early-onset breast cancer patients. Our findings show that TP53 mutations may account for a minimal portion of early-onset breast cancer in Pakistan.

  16. A New Generation of PARSEC-COLIBRI Stellar Isochrones Including the TP-AGB Phase

    Science.gov (United States)

    Marigo, Paola; Girardi, Léo; Bressan, Alessandro; Rosenfield, Philip; Aringer, Bernhard; Chen, Yang; Dussin, Marco; Nanni, Ambra; Pastorelli, Giada; Rodrigues, Thaíse S.; Trabucchi, Michele; Bladh, Sara; Dalcanton, Julianne; Groenewegen, Martin A. T.; Montalbán, Josefina; Wood, Peter R.

    2017-01-01

    We introduce a new generation of PARSEC–COLIBRI stellar isochrones that includes a detailed treatment of the thermally pulsing asymptotic giant branch (TP-AGB) phase, covering a wide range of initial metallicities (0.0001 < Zi < 0.06). Compared to previous releases, the main novelties and improvements are use of new TP-AGB tracks and related atmosphere models and spectra for M and C-type stars; inclusion of the surface H+He+CNO abundances in the isochrone tables, accounting for the effects of diffusion, dredge-up episodes and hot-bottom burning; inclusion of complete thermal pulse cycles, with a complete description of the in-cycle changes in the stellar parameters; new pulsation models to describe the long-period variability in the fundamental and first-overtone modes; and new dust models that follow the growth of the grains during the AGB evolution, in combination with radiative transfer calculations for the reprocessing of the photospheric emission. Overall, these improvements are expected to lead to a more consistent and detailed description of properties of TP-AGB stars expected in resolved stellar populations, especially in regard to their mean photometric properties from optical to mid-infrared wavelengths. We illustrate the expected numbers of TP-AGB stars of different types in stellar populations covering a wide range of ages and initial metallicities, providing further details on the “C-star island” that appears at intermediate values of age and metallicity, and about the AGB-boosting effect that occurs at ages close to 1.6-Gyr for populations of all metallicities. The isochrones are available through a new dedicated web server.

  17. The role of EP and TP receptors in the response to prostaglandin E2 in the aorta of WKY and spontaneously hypertensive rats

    DEFF Research Database (Denmark)

    Tang, Eva Hc; Jensen, Boye; Skøtt, Ole;

    2007-01-01

    -dependent relaxations in WKY but not in aortas of the SHR. High concentrations of PGE(2) evoked contractions predominately through the activation of thromboxane-prostanoid (TP) receptors in the WKY, but involves the dual activation EP and TP receptors in the SHR. SQ29,548, BAYu3405 and Terutroban (TP receptor...

  18. TP53 alterations in primary and secondary Sézary syndrome: A diagnostic tool for the assessment of malignancy in patients with erythroderma.

    Science.gov (United States)

    Gros, Audrey; Laharanne, Elodie; Vergier, Marie; Prochazkova-Carlotti, Martina; Pham-Ledard, Anne; Bandres, Thomas; Poglio, Sandrine; Berhouet, Sabine; Vergier, Béatrice; Vial, Jean-Philippe; Chevret, Edith; Beylot-Barry, Marie; Merlio, Jean-Philippe

    2017-01-01

    Recent massive parallel sequencing data have evidenced the genetic diversity and complexity of Sézary syndrome mutational landscape with TP53 alterations being the most prevalent genetic abnormality. We analyzed a cohort of 35 patients with SS and a control group of 8 patients with chronic inflammatory dermatoses. TP53 status was analyzed at different clinical stages especially in 9 patients with a past-history of mycosis fungoides (MF), coined secondary SS. TP53 mutations were only detected in 10 patients with either primary or secondary SS (29%) corresponding to point mutations, small insertions and deletions which were unique in each case. Interestingly, TP53 mutations were both detected in sequential unselected blood mononuclear cells and in skin specimens. Cytogenetic analysis of blood specimens of 32 patients with SS showed a TP53 deletion in 27 cases (84%). Altogether 29 out of 35 cases exhibited TP53 mutation and/or deletion (83%). No difference in prognosis was observed according to TP53 status while patients with secondary SS had a worse prognosis than patients with primary SS. Interestingly, patients with TP53 alterations displayed a younger age and the presence of TP53 alteration at initial diagnosis stage supports a pivotal oncogenic role for TP53 mutation in SS as well as in erythrodermic MF making TP53 assessment an ancillary method for the diagnosis of patients with erythroderma as patients with inflammatory dermatoses did not display TP53 alteration.

  19. TP53结构功能及活性调节的最新研究进展

    Institute of Scientific and Technical Information of China (English)

    李虹; 姚开泰

    2001-01-01

    TP53是一种广谱肿瘤抑制基因,其产物为多功能的转录调节因子,可以发挥调节细胞生长、细胞凋亡和DNA修复的作用.对TP53的结构与功能的研究一直是TP53研究的热点和重点内容.本文阐述了有关该蛋白结构功能及活性调节的最新研究进展.

  20. Human tumor cells segregate into radiosensitivity groups that associate with ATM and TP53 status

    Energy Technology Data Exchange (ETDEWEB)

    Williams, Jerry R.; Yonggang Zhang; Russell, James [Radiobiology Laboratory, Johns Hopkins Oncology Center. Baltimore, MD (United States); Koch, Cameron [Dept. of Radiation Oncology, Univ. of Pennsylvania, Philadelphia, PA (United States); Little, John B. [John B. Little Center, Harvard School of Public Health. Boston, MA (United States)

    2007-07-15

    We seek to determine whether cellular radiosensitivity in nineteen human colorectal tumor cell lines and three human glioblastoma tumor cell lines segregate into statistically distinct groups and whether such groups correlate with gene expression. We measure clonogenic survival in 22 cell lines that vary in radiosensitivity and in expression of selected genes: ATM, TP53, CDKN1A, 14-3-3{sigma}, Ki-ras and DNA mismatch repair genes. We describe and compare radiosensitivity in these cell lines by one-parameter or two parameter analysis. Radiosensitivity varies among and between colorectal tumor cell lines and glioblastoma cell lines. When compared directly using survival, or using two-parameter analysis of radiosensitivity, cell lines distribute into four statistically-significant radiosensitivity groups. These groups associate strongly with the status of two genes, ATM and TP53, but do not associate with CDKN1A, 14-3-3{sigma}, Ki-ras and DNA mismatch repair genes. Intrinsic cellular radiosensitivity of 22 colorectal and glioblastoma cell lines fall into four radiosensitivity groups that associate with expression of ATM and TP53. These analyses suggest multiple mechanisms underlay intrinsic cellular radiosensitivity.

  1. ESTADO DEL ARTE MPLS-TP CONMUTACIÓN MULTIPROTOCOLO MEDIANTE ETIQUETAS - PERFIL DE TRANSPORTE

    Directory of Open Access Journals (Sweden)

    Lois Albert Espinel García

    2013-09-01

    Full Text Available La creciente demanda en servicios de telecomunicaciones genera la necesidad de desarrollar diferentes modelos de red. En el año 2008, la UIT-T une sinergias con la IETF para desarrollar un protocolo llamado MPLS-TP cuya arquitectura representa el resultado la agregación de la eficiencia en el transporte de paquetes de IP/MPLS con la fiabilidad en el transporte de SONET/SDH. Este trabajo presenta un estado del arte de MPLS-TP donde se plasman los estudios actuales y avances relacionados con ésta tecnología: modelos de arquitectura óptica, modelos de protección en OAM. Además se presenta la estructura, funcionamiento y características que hacen de MPLS-TP una opción para las redes de transporte de siguiente generación. El material de apoyo para el desarrollo de este artículo ha sido obtenido de la base documental de recursos electrónicos con contenido científico de apoyo a la investigación de la Universidad Distrital Francisco José de Caldas.

  2. TP53 and MDM2 gene polymorphisms and risk of hepatocellular carcinoma among Italian patients

    Directory of Open Access Journals (Sweden)

    Buonaguro Franco M

    2011-08-01

    Full Text Available Abstract Background Single-nucleotide polymorphisms within TP53 gene (codon 72 exon 4, rs1042522, encoding either arginine or proline and MDM2 promoter (SNP309; rs2279744, have been independently associated with increased risk of several cancer types. Few studies have analysed the role of these polymorphisms in the development of hepatocellular carcinoma. Methods Genotype distribution of TP53 codon 72 and MDM2 SNP309 in 61 viral hepatitis-related hepatocellular carcinoma cases and 122 blood samples (healthy controls from Italian subjects were determined by PCR and restriction fragment length polymorphism (RFLP. Results Frequencies of TP53 codon 72 alleles were not significantly different between cases and controls. A significant increase of MDM2 SNP309 G/G and T/G genotypes were observed among hepatocellular carcinoma cases (Odds Ratio, OR = 3.56, 95% Confidence Limits, 95% CI = 1.3-9.7; and OR = 2.82, 95% CI = 1.3-6.4, respectively. Conclusions These results highlight a significant role of MDM2 SNP309 G allele as a susceptibility gene for the development of viral hepatitis-related hepatocellular carcinoma among Italian subjects.

  3. TP53 polymorphisms are involved in inverse colorectal cancer comorbidity in Chinese schizophrenia patients

    Institute of Scientific and Technical Information of China (English)

    Sun Liming; Huang Guoxin; Zhao Leyong; Chen Xiaofen; Chen Wenjiao

    2015-01-01

    The inverse cancer comorbidity in schizophrenia patients may be related to the genetic factors ,involving the regu‐lation of apoptosis .The tumour suppressor gene TP53 ,involved in neural apoptosis ,is one of the potential candidate genes associat‐ed with schizophrenia which might reduce colorectal cancer risk .We recruited 270 schizophrenia patients and 312 colorectal cancer patients without schizophrenia .To examine the genetic association between schizophrenia and colorectal cancer ,we analysed eight SNPs (rs12951053 ,rs1625895 ,rs2909430 ,rs9895829 ,rs1042522 ,rs8079544 ,rs8064946 ,rs17806770) covering 14 .35 kb in the re‐gion of TP53 .We observed that one of the eight genetic polymorphisms showed statistically significant differences between the colo‐rectal cancer subjects and the schizophrenia subjects (rs12951053 ,P=0 .000 1 ,OR 1 .70 ,95% CI 1 .30-2 .23) .In addition ,the hap‐lotype of A‐G (rs12951053‐rs8064946) ,giving a global P=0 .001 8 ,was the most significant .Our data indicate that the polymor‐phisms of rs12951053 in TP53 confer reduced susceptibility to colorectal cancer and suggest a potential protective mechanism a‐gainst colorectal cancer in the schizophrenia patients of Han Chinese origin .

  4. KRAS, BRAF, and TP53 deep sequencing for colorectal carcinoma patient diagnostics.

    Science.gov (United States)

    Rechsteiner, Markus; von Teichman, Adriana; Rüschoff, Jan H; Fankhauser, Niklaus; Pestalozzi, Bernhard; Schraml, Peter; Weber, Achim; Wild, Peter; Zimmermann, Dieter; Moch, Holger

    2013-05-01

    In colorectal carcinoma, KRAS (alias Ki-ras) and BRAF mutations have emerged as predictors of resistance to anti-epidermal growth factor receptor antibody treatment and worse patient outcome, respectively. In this study, we aimed to establish a high-throughput deep sequencing workflow according to 454 pyrosequencing technology to cope with the increasing demand for sequence information at medical institutions. A cohort of 81 patients with known KRAS mutation status detected by Sanger sequencing was chosen for deep sequencing. The workflow allowed us to analyze seven amplicons (one BRAF, two KRAS, and four TP53 exons) of nine patients in parallel in one deep sequencing run. Target amplification and variant calling showed reproducible results with input DNA derived from FFPE tissue that ranged from 0.4 to 50 ng with the use of different targets and multiplex identifiers. Equimolar pooling of each amplicon in a deep sequencing run was necessary to counterbalance differences in patient tissue quality. Five BRAF and 49 TP53 mutations with functional consequences were detected. The lowest mutation frequency detected in a patient tumor population was 5% in TP53 exon 5. This low-frequency mutation was successfully verified in a second PCR and deep sequencing run. In summary, our workflow allows us to process 315 targets a week and provides the quality, flexibility, and speed needed to be integrated as standard procedure for mutational analysis in diagnostics.

  5. Molecular Characterization of TP53 Gene in Human Populations Exposed to Low-Dose Ionizing Radiation

    Directory of Open Access Journals (Sweden)

    Igor Brasil-Costa

    2013-01-01

    Full Text Available Ionizing radiation, such as that emitted by uranium, may cause mutations and consequently lead to neoplasia in human cells. The TP53 gene acts to maintain genomic integrity and constitutes an important biomarker of susceptibility. The present study investigated the main alterations observed in exons 4, 5, 6, 7, and 8 of the TP53 gene and adjacent introns in Amazonian populations exposed to radioactivity. Samples were collected from 163 individuals. Occurrence of the following alterations was observed: (i a missense exchange in exon 4 (Arg72Pro; (ii 2 synonymous exchanges, 1 in exon 5 (His179His, and another in exon 6 (Arg213Arg; (iii 4 intronic exchanges, 3 in intron 7 (C → T at position 13.436; C → T at position 13.491; T → G at position 13.511 and 1 in intron 8 (T → G at position 13.958. Alteration of codon 72 was found to be an important risk factor for cancer development (P=0.024; OR=6.48; CI: 1.29–32.64 when adjusted for age and smoking. Thus, TP53 gene may be an important biomarker for carcinogenesis susceptibility in human populations exposed to ionizing radiation.

  6. Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12.

    Science.gov (United States)

    Mäkinen, Netta; Aavikko, Mervi; Heikkinen, Tuomas; Taipale, Minna; Taipale, Jussi; Koivisto-Korander, Riitta; Bützow, Ralf; Vahteristo, Pia

    2016-02-01

    Uterine leiomyosarcomas (ULMSs) are aggressive smooth muscle tumors associated with poor clinical outcome. Despite previous cytogenetic and molecular studies, their molecular background has remained elusive. To examine somatic variation in ULMS, we performed exome sequencing on 19 tumors. Altogether, 43 genes were mutated in at least two ULMSs. Most frequently mutated genes included tumor protein P53 (TP53; 6/19; 33%), alpha thalassemia/mental retardation syndrome X-linked (ATRX; 5/19; 26%), and mediator complex subunit 12 (MED12; 4/19; 21%). Unlike ATRX mutations, both TP53 and MED12 alterations have repeatedly been associated with ULMSs. All the observed ATRX alterations were either nonsense or frameshift mutations. ATRX protein levels were reliably analyzed by immunohistochemistry in altogether 44 ULMSs, and the majority of tumors (23/44; 52%) showed clearly reduced expression. Loss of ATRX expression has been associated with alternative lengthening of telomeres (ALT), and thus the telomere length was analyzed with telomere-specific fluorescence in situ hybridization. The ALT phenotype was confirmed in all ULMSs showing diminished ATRX expression. Exome data also revealed one nonsense mutation in death-domain associated protein (DAXX), another gene previously associated with ALT, and the tumor showed ALT positivity. In conclusion, exome sequencing revealed that TP53, ATRX, and MED12 are frequently mutated in ULMSs. ALT phenotype was commonly seen in tumors, indicating that ATR inhibitors, which were recently suggested as possible new drugs for ATRX-deficient tumors, could provide a potential novel therapeutic option for ULMS.

  7. TP 53基因在特定血液病和淋巴瘤中的研究进展%Dysfunction of the TP53 in some lymphoid malignancies and blood cancer

    Institute of Scientific and Technical Information of China (English)

    濮晓红; 叶庆

    2014-01-01

    TP53 is a tumor suppressor gene for gene network, tumor suppressor p53 protein ( cellular tumor antigen p53) , is“the guardian of the genome,” preserves genome stability under cellular stress, and is involved in various processes of development, differentiation, aging and disease. Dysfunction of TP53 with wild-type coding sequence can result deregulated gene expression, stability and activity of p53. Mutation and dysfunction of TP53 gene is important in the pathogensis of many human cancers. Besides, the status of TP53 is an independent prognostic factor in most blood cancer and lymphoma types. We review the significance of TP53 dysfunction and discuss the role of TP53 associated with lymphomagenesis and blood cancer.%TP53基因是重要的抑癌基因之一,其编码的蛋白---肿瘤抑制蛋白p53能够使许多基因保持其稳定性,并调节细胞的生长、分化、衰老,避免疾病产生,被称为“基因守护者”。当TP53基因缺失、突变和调节紊乱时,将直接影响p53蛋白的功能和活性,从而导致很多肿瘤的发生;除此之外TP53的基因状态也成为判断淋巴瘤和血液病预后的重要指标。本文通过综述TP53基因缺失和突变在不同血液病和淋巴瘤中的意义,使人们对TP53基因与血液肿瘤和淋巴瘤的关系有更清晰的认识。

  8. Changes in the response of MCF-7 cells to ionizing radiation after the combination of ATM and DNA-PK inhibition.

    Science.gov (United States)

    Ćmielová, Jana; Havelek, Radim; Vávrová, Jiřina; Řezáčová, Martina

    2015-05-01

    The aim of the present study is to evaluate the role of ATM (KU55933) and DNA-PK (NU7441) inhibitors in the repair of double-strand breaks and downstream signaling of DNA damage introduced by ionizing radiation. The irradiation of MCF-7 cells alone increased the proportion of cells in the G1 phase in comparison with mock-treated cells. After ATM inhibitor pretreatment, the cells were more accumulated in the G2 phase, whereas DNA-PK inhibitor application increased the percentage of cells in the G1 phase. ATM and DNA-PK inhibitor application alone increased the sensitivity of MCF-7 cells to ionizing radiation; however, combining both inhibitors together resulted in a further enhancement of cell death. Unexpectedly, combining both inhibitors decreased the percentage of senescent cells and increased G2 cell cycle arrest 3 days after treatment. After irradiation, the p21 protein was increased and Chk1 and Chk2 were activated. These proteins were not increased in cells pretreated with the ATM inhibitor prior to ionizing radiation exposure, albeit DNA-PK inhibitor application did not affect the amount of proteins detected. Formation of γH2AX was found to be ATM and DNA-PK dependent, application of the ATM inhibitor suppressed incidence of γH2AX, whereas DNA-PK caused persistence of γH2AX. Our results suggest that the further investigation of the ATM inhibitor in combination with the DNA-PK inhibitor as sensitizers preventing cell senescence and promoting cell death in breast carcinoma MCF-7 cells is warranted.

  9. Lesions inflammatory activity quantification in multiple sclerosis using [{sup 11}C]-(R)-PK11195 PET brain images; Quantificacao da atividade inflamatoria em lesoes na esclerose multipla usando imagens PET cerebrais com [{sup 11}C]-(R)-PK11195

    Energy Technology Data Exchange (ETDEWEB)

    Schuck, Phelipi N.; Narciso, Lucas D.L.; Dartora, Caroline M.; Silva, Ana M. Marques da, E-mail: phelipi.schuck@acad.pucrs.br [Pontificia Universidade Catolica do Rio Grande do Sul (PUC-RS), Porto Alegre, RS (Brazil). Nucleo de Pesquisa em Imagens Medicas

    2016-07-01

    The criteria for multiple sclerosis (MS) diagnosis include the presence of lesions in brain regions called black holes (BH), characterized by low signal on magnetic resonance imaging T1-weighted. Studies suggest that lesions in MS, if there is an inflammatory process, can be detected in PET imaging with [{sup 11}C]- (R)-PK11195. The aim of this study is to investigate the uptake of [{sup 11}C]-(R)-PK11195 in BH in PET images, searching for inflammation activity in lesions and neighborhoods. Semiquantitative methods of SUV and uptake normalization were applied to PET images, in different time intervals, acquired from 8 MS patients and 5 healthy controls. Higher uptake was identified in BH and its edges, when compared with health controls white matter, when the SUV method is applied (p < 0,01, 40 to 60 min). When uptake normalization method is applied, smaller uptake in black holes and its your edges is observed, when compared with white matter apparently healthy (p < 0,01, 0 to 60 min). (author)

  10. TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer.

    Science.gov (United States)

    Fagerholm, Rainer; Khan, Sofia; Schmidt, Marjanka K; García-Closas, Montserrat; Heikkilä, Päivi; Saarela, Jani; Beesley, Jonathan; Jamshidi, Maral; Aittomäki, Kristiina; Liu, Jianjun; Ali, H Raza; Andrulis, Irene L; Beckmann, Matthias W; Behrens, Sabine; Blows, Fiona M; Brenner, Hermann; Chang-Claude, Jenny; Couch, Fergus J; Czene, Kamila; Fasching, Peter A; Figueroa, Jonine; Floris, Giuseppe; Glendon, Gord; Guo, Qi; Hall, Per; Hallberg, Emily; Hamann, Ute; Holleczek, Bernd; Hooning, Maartje J; Hopper, John L; Jager, Agnes; Kabisch, Maria; Keeman, Renske; Kosma, Veli-Matti; Lambrechts, Diether; Lindblom, Annika; Mannermaa, Arto; Margolin, Sara; Provenzano, Elena; Shah, Mitul; Southey, Melissa C; Dennis, Joe; Lush, Michael; Michailidou, Kyriaki; Wang, Qin; Bolla, Manjeet K; Dunning, Alison M; Easton, Douglas F; Pharoah, Paul D P; Chenevix-Trench, Georgia; Blomqvist, Carl; Nevanlinna, Heli

    2017-02-05

    TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes.In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 × 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 × 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines.If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer.

  11. Cryo-EM Imaging of DNA-PK DNA Damage Repair Complexes

    Energy Technology Data Exchange (ETDEWEB)

    Phoebe L. Stewart

    2005-06-27

    Exposure to low levels of ionizing radiation causes DNA double-strand breaks (DSBs) that must be repaired for cell survival. Higher eukaryotes respond to DSBs by arresting the cell cycle, presumably to repair the DNA lesions before cell division. In mammalian cells, the nonhomologous end-joining DSB repair pathway is mediated by the 470 kDa DNA-dependent protein kinase catalytic subunit (DNA-PKcs) together with the DNA-binding factors Ku70 and Ku80. Mouse knock-out models of these three proteins are all exquisitely sensitive to low doses of ionizing radiation. In the presence of DNA ends, Ku binds to the DNA and then recruits DNA-PKcs. After formation of the complex, the kinase activity associated with DNA-PKcs becomes activated. This kinase activity has been shown to be essential for repairing DNA DSBs in vivo since expression of a kinase-dead form of DNA-PKcs in a mammalian cell line that lacks DNA-PKcs fails to complement the radiosensitive phenotype. The immense size of DNA-PKcs suggests that it may also serve as a docking site for other DNA repair proteins. Since the assembly of the DNA-PK complex onto DNA is a prerequisite for DSB repair, it is critical to obtain structural information on the complex. Cryo-electron microscopy (cryo-EM) and single particle reconstruction methods provide a powerful way to image large macromolecular assemblies at near atomic (10-15 ?) resolution. We have already used cryo-EM methods to examine the structure of the isolated DNA-PKcs protein. This structure reveals numerous cavities throughout the protein that may allow passage of single or double-stranded DNA. Pseudo two-fold symmetry was found for the monomeric protein, suggesting that DNA-PKcs may interact with two DNA ends or two Ku heterodimers simultaneously. Here we propose to study the structure of the cross-linked DNA-PKcs/Ku/DNA complex. Difference imaging with our published DNA-PKcs structure will enable us to elucidate the architecture of the complex. A second

  12. Lung tumor KRAS and TP53 mutations in nonsmokers reflect exposure to PAH-rich coal combustion emissions

    Energy Technology Data Exchange (ETDEWEB)

    De Marini, D.M.; Landi, S.; Tian, D.F.; Hanley, N.M.; Li, X.M.; Hu, F.D.; Roop, B.C.; Mass, M.J.; Keohavong, P.; Gao, W.M.; Olivier, M.; Hainaut, P.; Mumford, J.L. [US EPA, Research Triangle Park, NC (United States). Environmental Carcinogenesis Division

    2001-09-15

    The TP53 and codon 12 KRAS mutations in lung tumors from 24 nonsmokers whose tumors were associated with exposure to smoky coal were determined. Among any tumors studied previously, these showed the highest percentage of mutations that (a) were G to T transversions at either KRAS (86%) or TP53 (76%), (b) clustered at the G-rich codons 153-158 of TP53 (33%), and (c) had 100% of the guanines of the G to T transversions on the nontranscribed strand. This mutation spectrum is consistent with an exposure to polycyclic aromatic hydrocarbons, which are the primary component of the smoky coal emissions. These results show that mutations in the TP53 and KRAS genes can reflect a specific environmental exposure.

  13. TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence.

    Science.gov (United States)

    Skinner, Heath D; Sandulache, Vlad C; Ow, Thomas J; Meyn, Raymond E; Yordy, John S; Beadle, Beth M; Fitzgerald, Alison L; Giri, Uma; Ang, K Kian; Myers, Jeffrey N

    2012-01-01

    Mortality of patients with head and neck squamous cell carcinoma (HNSCC) is primarily driven by tumor cell radioresistance leading to locoregional recurrence (LRR). In this study, we use a classification of TP53 mutation (disruptive vs. nondisruptive) and examine impact on clinical outcomes and radiation sensitivity. Seventy-four patients with HNSCC treated with surgery and postoperative radiation and 38 HNSCC cell lines were assembled; for each, TP53 was sequenced and the in vitro radioresistance measured using clonogenic assays. p53 protein expression was inhibited using short hairpin RNA (shRNA) and overexpressed using a retrovirus. Radiation-induced apoptosis, mitotic cell death, senescence, and reactive oxygen species (ROS) assays were carried out. The effect of the drug metformin on overcoming mutant p53-associated radiation resistance was examined in vitro as well as in vivo, using an orthotopic xenograft model. Mutant TP53 alone was not predictive of LRR; however, disruptive TP53 mutation strongly predicted LRR (P = 0.03). Cell lines with disruptive mutations were significantly more radioresistant (P disruptive TP53 mutations significantly decreased radiation-induced senescence, as measured by SA-β-gal staining, p21 expression, and release of ROS. The mitochondrial agent metformin potentiated the effects of radiation in the presence of a disruptive TP53 mutation partially via senescence. Examination of our patient cohort showed that LRR was decreased in patients taking metformin. Disruptive TP53 mutations in HNSCC tumors predicts for LRR, because of increased radioresistance via the inhibition of senescence. Metformin can serve as a radiosensitizer for HNSCC with disruptive TP53, presaging the possibility of personalizing HNSCC treatment. © 2011 AACR.

  14. Evidence for an association of TP53 codon 72 polymorphism with sporadic colorectal cancer risk in Isfahan

    Directory of Open Access Journals (Sweden)

    Mehdi Nikbakht Dastjerdi

    2008-12-01

    Full Text Available

    • BACKGROUND: A common polymorphism at codon 72 of TP53 gene has been associated with increased risk for many human cancers. We studied this TP53 polymorphism in colorectal adenocarcinomas in small population selected from Isfahan city.
    • METHODS: Samples: We undertook a case-control study on 180 controls and 180 paraffin block specimens of sporadic colorectal adenocarcinomas. PCR amplification of TP53 codon 72 polymorphism: TP53 codon 72 genotypes were detected by PCR using specific primer pairs for amplifying the Proline or the Arginine alleles.
    • STATISTICAL ANALYSES: The 42-test was used to assess the significance of any difference in the prevalence of TP53 codon 72 polymorphism between colorectal cancer patients and controls.
    • RESULTS: In control samples, the genotype distribution for TP53 polymorphism showed 28.3%, 48.9% and 22.8% for the Arginine/Arginine, Arginine/Proline and Proline/Proline genotypes, respectively. In the cancer group 40% of the cases were Arginine/Arginine, 42.2% were Arginine/Proline and 17.8% were Proline/Proline. A significant difference between cases and controls was found for the Arginine/Arginine genotype compared with (grouped Arginine/Proline and Proline/Proline genotypes (Odds Ratio = 1.686 (1.085-2.620, P = 0.02.
    • CONCLUSIONS: TP53 codon 72 polymorphism may be a genetic predisposing factor for colorectal adenocarcinomas in Isfahan city.
    • KEYWORDS: Colorectal adenocarcinoma, TP53, Arginine, Proline, Polymorphism.

  15. Impact of TP53 Mutations on Outcome in EGFR-Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors.

    Science.gov (United States)

    Canale, Matteo; Petracci, Elisabetta; Delmonte, Angelo; Chiadini, Elisa; Dazzi, Claudio; Papi, Maximilian; Capelli, Laura; Casanova, Claudia; De Luigi, Nicoletta; Mariotti, Marita; Gamboni, Alessandro; Chiari, Rita; Bennati, Chiara; Calistri, Daniele; Ludovini, Vienna; Crinò, Lucio; Amadori, Dino; Ulivi, Paola

    2016-10-25

    Purpose: To analyze the impact of TP53 mutations on response to first-line tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non-small cell lung cancer (NSCLC).Experimental Design: 136 EGFR-mutated NSCLC patients receiving first-line TKIs were analyzed. TP53 mutations were evaluated in 123 patients in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).Results:TP53 mutations were observed in 37 (30.1%), 10 (27.0%), 6 (16.2%), 9 (24.3%), and 12 (32.4%) patients in exons 5, 6, 7, and 8, respectively. DCR was 70% in TP53-mutated patients compared with 88% in TP53-wild type (wt) patients [relative risk, RR, of disease progression: 3.17 (95% CI, 1.21-8.48), P = 0.019]. In particular, a 42% DCR was observed in patients with TP53 exon 8 mutation versus 87% in exon 8 wt patients [RR of disease progression 9.6 (2.71-36.63), P TP53 exon 8 mutations compared with others (4.2 vs. 12.5, P = 0.058, and 16.2 vs. 32.3, P = 0.114, respectively); these differences became significant in the subgroup with EGFR exon 19 deletion (4.2 vs. 16.8, P TP53 mutations, especially exon 8 mutations, reduce responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, mainly those carrying exon 19 deletions. Clin Cancer Res; 1-8. ©2016 AACR.

  16. Expression and Prognostic Significance of EP300, TP53 and BAX in Clear Cell Renal Cell Carcinoma.

    Science.gov (United States)

    Godlewski, Janusz; Krazinski, Bartlomiej E; Kowalczyk, Anna E; Kiewisz, Jolanta; Kiezun, Jacek; Kwiatkowski, Przemyslaw; Sliwińska-Jewsiewicka, Agnieszka; Wierzbicki, Piotr W; Kmieć, Zbigniew

    2017-06-01

    Histone acetyltransferase E1A-binding protein p300 (EP300), tumor protein p53 (TP53) and B-cell lymphoma-2-associated X protein (BAX) contribute to the regulation of the cell cycle and apoptosis, cellular processes that are often impaired in cancer cells. The aim of this study was to determine the expression levels of EP300, TP53 and BAX genes and their respective proteins in clear cell renal cell carcinoma (ccRCC) and evaluate the value of these factors as prognostic factors. EP300, TP53 and BAX expression at the transcript and protein levels were determined by quantitative polymerase-chain reaction (QPCR) and immunohistochemistry (IHC) in paired tumor and kidney specimens from 31 patients with ccRCC. Levels of EP300, TP53 and BAX transcripts were found increased in tumor tissues. Immunoreactivity for TP53 was elevated in cancer cells when compared to unchanged kidney, while EP300 and BAX immunoexpression in ccRCC did not differ from that of normal renal tissue. Immunoreactivity for TP53 was positively associated with larger tumor size. In contrast, stronger BAX immunoexpression correlated with smaller tumor diameters. The average immunoreactivity for BAX was higher in localized, kidney-confined tumor than in advanced/recurrent tumors. None of the analyzed transcripts or proteins correlated with the overall survival of patients. Although TP53 and BAX immunoreactivity levels were associated with some clinicopathological parameters of the patients, the expression of EP300, TP53 and BAX did not reveal any prognostic significance in ccRCC. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  17. Population PK/PD model of homocysteine concentrations after high-dose methotrexate treatment in patients with acute lymphoblastic leukemia.

    Directory of Open Access Journals (Sweden)

    Hauke Rühs

    Full Text Available Elevated homocysteine concentrations have been associated with methotrexate-induced neurotoxicity. Based on methotrexate and homocysteine plasma concentrations of 494 children with acute lymphoblastic leukemia treated with high-dose methotrexate in the TOTAL XV study, a pharmacokinetic/pharmacodynamic (PK/PD model was built with NONMEM. Several compartment and indirect response models were investigated. The pharmacokinetic disposition of methotrexate was best described by a two-compartment model. Homocysteine concentrations were included by an indirect response model where methotrexate inhibition of the homocysteine elimination rate was described by an E(max model. The homocysteine baseline level was found to be age-dependent. Simulations revealed that folinate rescue therapy does not affect peak concentrations of homocysteine but leads to a modestly reduced homocysteine exposure. In conclusion, our PK/PD model describes the increase of methotrexate-induced HCY concentrations with satisfactory precision and can be applied to assess the effect of folinate regimens on the HCY concentration-time course.

  18. Quantitative autoradiographic determination of binding sites for a peripheral benzodiazepine ligand ((/sup 3/H)PK 11195) in human iris

    Energy Technology Data Exchange (ETDEWEB)

    Valtier, D.; Malgouris, C.; Uzan, A.

    1987-01-01

    Specific binding sites of peripheral-type benzodiazepines were investigated in human iris/ciliary body (8 eyes). Examination of color-coded prints and densitometric quantification of autoradiograms were performed on slides (20 ..mu..m) labelled with (/sup 3/H)PK 11195 (1 nM) at 25 deg C. Nonspecific binding was determined with PK 11211 (5 ..mu..M) or Ro 5-4864 (5 ..mu..M). Binding sites were present on all the slides, with equivalent density in the 3 regions of the preparation (ciliary body, iris and pupil margin). The numbers of binding sites in ciliary body, iris, and pupil margin, respectively were: 42.7 +- 0.2, 30.1 +- 0.5 and 37.4 +- 0.4 femtomol/mg protein. Labelling on the pupil margin seemed to coincide with the iris sphincter muscle. The presence of peripheral benzodiazepine binding sites in iris muscular tissue, and particularly in the pupil margin, suggests that the iris preparation may be a valuable tool to detect putative physiological effects of peripheral benzodiazepines on muscular motility.

  19. Microglia activation in multiple sclerosis black holes predicts outcome in progressive patients: an in vivo [(11)C](R)-PK11195-PET pilot study.

    Science.gov (United States)

    Giannetti, Paolo; Politis, Marios; Su, Paul; Turkheimer, Federico; Malik, Omar; Keihaninejad, Shiva; Wu, Kit; Reynolds, Richard; Nicholas, Richard; Piccini, Paola

    2014-05-01

    The pathophysiological correlates and the contribution to persisting disability of hypointense T1-weighted MRI lesions, black holes (BH), in multiple sclerosis (MS) are still unclear. In order to study the in vivo functional correlates of this MRI finding, we used 11C-PK11195 PET (PK-PET) to investigate changes in microglial activity. Ten relapsing and 9 progressive MS subjects had a PK-PET scan and a MRI scan alongside a full clinical assessment, including the expanded disability status scale (EDSS) for evaluation of disability. We studied the PK binding potential of the specifically bound radioligand relative to the non-displaceable radioligand in tissue (BPND) in T1 BHs. Out of a total of 1242 BHs identified, 947 were PK enhancing. The PKBPND was correlated with the EDSS (r=0.818; pholes" representing loss of axons and myelin, but display inflammatory activity in the form of activated microglia. The significant association between PKBPND, neurological impairment and outcome in progressive subjects supports a role for activated microglia in disability progression.

  20. Tissue-specific alterations of binding sites for peripheral-type benzodiazepine receptor ligand [3H]PK11195 in rats following portacaval anastomosis.

    Science.gov (United States)

    Rao, V L; Audet, R; Therrien, G; Butterworth, R F

    1994-05-01

    Kinetics of binding of [3H]PK11195, an antagonist ligand with high selectivity for the peripheral-type (mitochondrial) benzodiazepine receptor (PTBR), was studied in homogenates of cerebral cortex, kidney, heart, and testis of portacaval shunted rats and sham-operated controls. Portacaval anastomosis resulted in a significant two- to threefold increase in the number of [3H]PK11195 binding sites in cerebral cortex and kidney. A reduction in the number of [3H]PK11195 binding sites was observed in testis preparations, while the number of binding sites in the heart remained unaltered. These differences in the response of PTBRs to portacaval anastomosis, in different organs suggest that the physiological function of these receptors and the factors regulating them are modulated by distinct mechanisms. The finding of increased densities of [3H]PK11195 binding sites in brain and kidney following portacaval anastomosis parallels the cellular hypertrophy in these tissues and, together with previous observations of similar increases of these binding sites in brain and kidney in congenital hyperammonemia, suggest a pathophysiologic role for ammonia in these changes. In contrast, the significant loss of [3H]PK11195 binding sites in testicular preparations following portacaval anastomosis together with the known effects of steroid hormones on these sites suggests a role for PTBRs in the pathogenesis of testicular atrophy in chronic liver disease.

  1. PkMADS1 is a novel MADS box gene regulating adventitious shoot induction and vegetative shoot development in Paulownia kawakamii.

    Science.gov (United States)

    Prakash, A Pavan; Kumar, Prakash P

    2002-01-01

    Direct regeneration of shoot buds in vitro is an important technique in plant genetic manipulation. We describe the isolation and functional characterization of a novel MADS box cDNA (PkMADS1) from Paulownia kawakamii leaf explants undergoing adventitious shoot regeneration. mRNA gel blot analysis confirmed the expression of PkMADS1 in the shoot-forming cultures, but no signal was observed in the callus-forming cultures. PkMADS1 transcripts were also detected in shoot apices, but not in root apices, initial leaf explants or the flower. In situ hybridization revealed that its expression was restricted to developing shoot primordia in the excised leaf cultures, suggesting a role for this gene in adventitious shoot formation. Transgenic Paulownia plants over-expressing the PkMADS1 gene showed some changes in phenotype, such as axillary shoot formation. In the antisense transformants, shoots were stunted and had altered phyllotaxy, and, in some lines, the shoot apical meristem appeared to have been used up early during shoot development. Leaf explants from the antisense transgenic plants showed a tenfold decrease in shoot regeneration compared with explants from sense transformants or wild-type. Our results show that PkMADS1 is a regulator of shoot morphogenesis.

  2. Protective effect of a protein kinase inhibitor on cellular injury induced by cephaloridine in the porcine kidney cell line LLC-PK(1).

    Science.gov (United States)

    Kawai, Yoshiko; Kohda, Yuka; Kodawara, Takaaki; Gemba, Munekazu

    2005-08-01

    We investigated the effects of a protein kinase C inhibitor and a tyrosine kinase inhibitor on the cellular injury induced by cephaloridine in an established renal epithelial cell line, LLC-PK(1). Cephaloridine increased the leakage of lactate dehydrogenase (LDH) from LLC-PK(1) cells into the medium and also caused an increase in the level of lipid peroxide (index of oxidative stress) in the cells. Treatment of the cells with a hydroxyl radical scavenger, dimethylthiourea (DMTU), inhibited the increases in LDH leakage and lipid peroxidation in LLC-PK(1) cells exposed to cephaloridine. A protein kinase C inhibitor, H-7, and tyrosine kinase inhibitors, genistein and lavendustinA, inhibited the increases in LDH leakage and lipid peroxidation in LLC-PK(1) cells exposed to cephaloridine. These results suggest that a signaling pathway which involves protein kinase C and tyrosine kinase plays a role in the generation of reactive oxygen species in LLC-PK(1) cells damaged by cephaloridine.

  3. Absence of tumor suppressor tumor protein 53-induced nuclear protein 1 (TP53INP1) sensitizes mouse thymocytes and embryonic fibroblasts to redox-driven apoptosis.

    Science.gov (United States)

    N'guessan, Prudence; Pouyet, Laurent; Gosset, Gaëlle; Hamlaoui, Sonia; Seillier, Marion; Cano, Carla E; Seux, Mylène; Stocker, Pierre; Culcasi, Marcel; Iovanna, Juan L; Dusetti, Nelson J; Pietri, Sylvia; Carrier, Alice

    2011-09-15

    The p53-transcriptional target TP53INP1 is a potent stress-response protein promoting p53 activity. We previously showed that ectopic overexpression of TP53INP1 facilitates cell cycle arrest as well as cell death. Here we report a study investigating cell death in mice deficient for TP53INP1. Surprisingly, we found enhanced stress-induced apoptosis in TP53INP1-deficient cells. This observation is underpinned in different cell types in vivo (thymocytes) and in vitro (thymocytes and MEFs), following different types of injury inducing either p53-dependent or -independent cell death. Nevertheless, absence of TP53INP1 is unable to overcome impaired cell death of p53-deficient thymocytes. Stress-induced ROS production is enhanced in the absence of TP53INP1, and antioxidant NAC complementation abolishes increased sensitivity to apoptosis of TP53INP1-deficient cells. Furthermore, antioxidant defenses are defective in TP53INP1-deficient mice in correlation with ROS dysregulation. Finally, we show that autophagy is reduced in TP53INP1-deficient cells both at the basal level and upon stress. Altogether, these data show that impaired ROS regulation in TP53INP1-deficient cells is responsible for their sensitivity to induced apoptosis. In addition, they suggest that this sensitivity could rely on a defect of autophagy. Therefore, these data emphasize the role of TP53INP1 in protection against cell injury.

  4. FGFR4 polymorphism, TP53 mutation, and their combinations are prognostic factors for oral squamous cell carcinoma.

    Science.gov (United States)

    Tanuma, Jun-Ichi; Izumo, Toshiyuki; Hirano, Masato; Oyazato, Yoshitaka; Hori, Fumiya; Umemura, Eri; Shisa, Hayase; Hiai, Hiroshi; Kitano, Motoo

    2010-03-01

    The genotype of the fibroblast growth factor receptor 4 (FGFR4) gene and TP53 mutation have been reported as prognostic factors for cancers of the head and neck, bladder, breast and colon. To determine whether they are applicable for oral squamous cell carcinoma (OSCC), we investigated these two genes in OSCC samples from 150 patients who had undergone radical surgery and in 100 cancer-free individuals. In OSCC, the FGFR4 Gly388Arg polymorphism and the presence or absence of mutation in TP53 did not show a significant association with the clinicopathological features of the tumors at surgery. However, the FGFR4 Arg388 allele, as well as mutations in TP53, was found to be closely associated with poor prognosis. Moreover, these two parameters synergistically affected the survival of OSCC patients. During 60 months of observation after radical surgery, a majority of patients with homozygous Arg388 FGFR4 plus mutated TP53 died of cancer, whereas >90% patients carrying homozygous Gly388 FGFR4 plus wild-type TP53 survived. Therefore, the FGFR4 Gly388Arg polymorphism and TP53 mutations, as well as their combinations, are excellent predictors of the prognosis for OSCC patients.

  5. TP53通路分子遗传学改变与肝细胞癌

    Institute of Scientific and Technical Information of China (English)

    王岩(综述); 黄坚(审校)

    2013-01-01

    肝细胞癌是一种常见的恶性肿瘤,TP53突变在其发病机制中有重要作用。在我国大陆地区,约有50% HCC患者携带TP53突变,最常见的是黄曲霉毒素导致的R249S突变。MDM2和p14ARF是TP53通路的两个重要调节因子,近来研究显示MDM2扩增和p14ARF纯合性缺失/启动子甲基化也参与了HCC的发生发展过程。目前,有越来越多关于TP53通路改变在HCC早期诊断、预后和治疗中应用的研究,但还需要更多的研究证实。本文重点介绍了TP53通路分子遗传学改变(包括TP53突变、MDM2扩增和p14ARF纯合性缺失/启动子甲基化)与肝细胞癌发生的关系。

  6. KRAS and TP53 mutations in inflammatory bowel disease-associated colorectal cancer: a meta-analysis.

    Science.gov (United States)

    Du, Lijun; Kim, John J; Shen, Jinhua; Chen, Binrui; Dai, Ning

    2017-01-07

    Although KRAS and TP53 mutations are common in both inflammatory bowel disease-associated colorectal cancer (IBD-CRC) and sporadic colorectal cancer (S-CRC), molecular events leading to carcinogenesis may be different. Previous studies comparing the frequency of KRAS and TP53 mutations in IBD-CRC and S-CRC were inconsistent. We performed a meta-analysis to compare the presence of KRAS and TP53 mutations among patients with IBD-CRC, S-CRC, and IBD without dysplasia. A total of 19 publications (482 patients with IBD-CRC, 4,222 with S-CRC, 281 with IBD without dysplasia) met the study inclusion criteria. KRAS mutation was less frequent (RR=0.71, 95%CI 0.56-0.90; P=0.004) while TP53 mutation was more common (RR=1.24, 95%CI 1.10-1.39; PTP53 (RR=2.15, 95%CI 1.07-4.31 P=0.03) mutations were more prevalent in patients with IBD-CRC compared to IBD without dysplasia. In conclusion, IBD-CRC and S-CRC appear to have biologically different molecular pathways. TP53 appears to be more important than KRAS in IBD-CRC compared to S-CRC. Our findings suggest possible roles of TP53 and KRAS as biomarkers for cancer and dysplasia screening among patients with IBD and may also provide targeted therapy in patients with IBD-CRC.

  7. TP53-dependent chromosome instability is associated with transient reductions in telomere length in immortal telomerase-positive cell lines

    Science.gov (United States)

    Schwartz, J. L.; Jordan, R.; Liber, H.; Murnane, J. P.; Evans, H. H.

    2001-01-01

    Telomere shortening in telomerase-negative somatic cells leads to the activation of the TP53 protein and the elimination of potentially unstable cells. We examined the effect of TP53 gene expression on both telomere metabolism and chromosome stability in immortal, telomerase-positive cell lines. Telomere length, telomerase activity, and chromosome instability were measured in multiple clones isolated from three related human B-lymphoblast cell lines that vary in TP53 expression; TK6 cells express wild-type TP53, WTK1 cells overexpress a mutant form of TP53, and NH32 cells express no TP53 protein. Clonal variations in both telomere length and chromosome stability were observed, and shorter telomeres were associated with higher levels of chromosome instability. The shortest telomeres were found in WTK1- and NH32-derived cells, and these cells had 5- to 10-fold higher levels of chromosome instability. The primary marker of instability was the presence of dicentric chromosomes. Aneuploidy and other stable chromosome alterations were also found in clones showing high levels of dicentrics. Polyploidy was found only in WTK1-derived cells. Both telomere length and chromosome instability fluctuated in the different cell populations with time in culture, presumably as unstable cells and cells with short telomeres were eliminated from the growing population. Our results suggest that transient reductions in telomere lengths may be common in immortal cell lines and that these alterations in telomere metabolism can have a profound effect on chromosome stability. Copyright 2000 Wiley-Liss, Inc.

  8. Evaluation of the Determine Syphilis TP assay for the detection of antibodies against Treponema pallidum for the serodiagnosis of syphilis.

    Science.gov (United States)

    Zhuang, Y-H; Tian, Y; Chen, Y; Tang, J; Wang, J-Q; Li, P; Li, Q; Jiang, Y-Q

    2012-06-01

    Currently, infectious syphilis has been resurgent in China and has become a significant public health problem. The rapid expansion of syphilis screening programs is urgently required. In the present study, the performance of the Determine Syphilis TP assay (Determine TP assay) for the detection of antibodies against Treponema pallidum (T. pallidum) for syphilis serodiagnosis was evaluated. In total, 300 serum samples were tested for the presence of treponemal-specific antibodies using the Treponema pallidum particle agglutination (TPPA) assay, the Determine TP assay, and the InTec immunochromatography assay (InTec assay). The Determine TP assay detected 99, 11, and 5 positive results, whereas the InTec assay detected 97, 3, and 3 positive samples from group I (100 TPPA-positive sera), group II (13 TPPA 1:80 +/- sera), and group III (187 TPPA-negative sera), respectively. The sensitivity, specificity, and the rate concordant with TPPA for the Determine TP assay were 97.35, 98.91, and 97.33%, respectively. In comparison to the TPPA, the Determine TP assay is simple to perform and time-saving, making it a favorable alternative for the detection of T. pallidum-specific antibodies where other T. pallidum-specific confirmatory tests are not available. In addition, this rapid treponemal test promotes prompt treatment for syphilis by providing early laboratory diagnosis.

  9. Correlation of TP53 Overexpression and Clinical Parameters with Five-Year Survival in Oral Squamous Cell Carcinoma Patients.

    Science.gov (United States)

    Ali, Syed A; Khan, Hamza A; Irfan, Omar; Samad, Adeel; Mirza, Yumna; Awan, Muhammad S

    2017-06-27

    Introduction TP53 mutation and overexpression have been correlated with poor survival in many cancers including oral squamous cell carcinoma (OSCC). We aim to understand the role of TP53 overexpression in OSCC in our population and correlate it with five-year survival to test its viability as a prognostic marker for OSCC patients. Materials and methods Patients with biopsy proven OSCC at Aga Khan University Hospital from January 2000 to January 2008 were recruited. Immunohistochemistry was used to establish TP53 status and the results were published. Following up on these patients, five-year data were collected and correlated with TP53 status and other clinicopathologic parameters. Results Overexpression of TP53 was not significantly associated with five-year survival (hazard ratio [HR]: 1.543; 95% CI: 0.911-2.612; p = 0.107). Conclusion Although we had proven statistical relevance when correlated with overall survival in our previous study, we were unable to extend the same relevance to TP53 overexpression when it comes to five-year survival.

  10. 基于L2TP VPN加密技术的水文虚拟网应用研究%Application research of hydrologic virtual network based on L2TP VPN encryptin technology

    Institute of Scientific and Technical Information of China (English)

    李庆金; 万鹏; 周建伟

    2012-01-01

    With the development and popularization of the network and 3 G wireless network technologies, special network technology constituted by 3G or GSM has become more mature using the 3G or GSM. The use of VPN network communication becomes more and more urgent. To constitute wide area network in a relatively remote and distributed hydrological station building, not only cost largely but also is a difficult work. By means of internet, via L2TP VPN encryption technology in construction of hydrologic virtual network, can not only solve the hydrological station network in real time flood forecast, but also realize the internal resource sharing, and internal office automation system access of the dispersed sites in the absence of special internal network. After nearly a year of the production run, Shandong hydrology, water level station reporting effectiveness greatly increased, the error rate was almost zero, gained apparent benefit.%随着网络的普及和3G等无线网络等技术的不断发展,通过3G或GSM构建专用网的技术也日渐成熟.利用专用虚拟网进行网络通讯的需求越来越迫切.在相对偏远且分散的水文站点间,构建专用广域网,不仅耗资大,而且实施困难.借助于互联网,通过L2TP VPN加密技术构建水文虚拟网,既解决了水文站点的实时网络报汛问题,还实现了内部资源的共享,实现了分散站点在没有专用内部网络情况下对内部办公自动化系统的访问.经过近一年的生产运行,山东各水文、水位站点的报汛时效性得以大幅提高,差错率几近零的水平,取得了明显的效益.

  11. A functionally significant SNP in TP53 and breast cancer risk in African-American women.

    Science.gov (United States)

    Murphy, Maureen E; Liu, Song; Yao, Song; Huo, Dezheng; Liu, Qin; Dolfi, Sonia C; Hirshfield, Kim M; Hong, Chi-Chen; Hu, Qiang; Olshan, Andrew F; Ogundiran, Temidayo O; Adebamowo, Clement; Domchek, Susan M; Nathanson, Katherine L; Nemesure, Barbara; Ambs, Stefan; Blot, William J; Feng, Ye; John, Esther M; Bernstein, Leslie; Zheng, Wei; Hu, Jennifer J; Ziegler, Regina G; Nyante, Sarah; Ingles, Sue A; Press, Michael F; Deming, Sandra L; Rodriguez-Gil, Jorge L; Haiman, Christopher A; Olopade, Olufunmilayo I; Lunetta, Kathryn L; Palmer, Julie R; Ambrosone, Christine B

    2017-01-01

    A coding region polymorphism exists in the TP53 gene (Pro47Ser; rs1800371) in individuals of African descent, which reduces p53 tumor suppressor function in a mouse model. It has been unclear whether this functionally significant polymorphism alters cancer risk in humans. This analysis included 6907 women with breast cancer and 7644 controls from the AMBER, ROOT, and AABC consortia. We used multivariable logistic regression to estimate associations between the TP53 Pro47Ser allele and overall breast cancer risk. Because polymorphisms in TP53 tend to be associated with cancer risk in pre-menopausal women, we also limited our analyses to this population in the AMBER and ROOT consortia, where menopausal status was known, and conducted a fixed effects meta-analysis. In an analysis of all women in the AMBER, ROOT, and AABC consortia, we found no evidence for association of the Pro47Ser variant with breast cancer risk. However, when we restricted our analysis to only pre-menopausal women from the AMBER and ROOT consortia, there was a per allele odds ratio of 1.72 (95% confidence interval 1.08-2.76; p-value = 0.023). Although the Pro47Ser variant was not associated with overall breast cancer risk, it may increase risk among pre-menopausal women of African ancestry. Following up on more studies in human populations may better elucidate the role of this variant in breast cancer etiology. However, because of the low frequency of the polymorphism in women of African ancestry, its impact at a population level may be minimal.

  12. Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12.

    Directory of Open Access Journals (Sweden)

    Netta Mäkinen

    2016-02-01

    Full Text Available Uterine leiomyosarcomas (ULMSs are aggressive smooth muscle tumors associated with poor clinical outcome. Despite previous cytogenetic and molecular studies, their molecular background has remained elusive. To examine somatic variation in ULMS, we performed exome sequencing on 19 tumors. Altogether, 43 genes were mutated in at least two ULMSs. Most frequently mutated genes included tumor protein P53 (TP53; 6/19; 33%, alpha thalassemia/mental retardation syndrome X-linked (ATRX; 5/19; 26%, and mediator complex subunit 12 (MED12; 4/19; 21%. Unlike ATRX mutations, both TP53 and MED12 alterations have repeatedly been associated with ULMSs. All the observed ATRX alterations were either nonsense or frameshift mutations. ATRX protein levels were reliably analyzed by immunohistochemistry in altogether 44 ULMSs, and the majority of tumors (23/44; 52% showed clearly reduced expression. Loss of ATRX expression has been associated with alternative lengthening of telomeres (ALT, and thus the telomere length was analyzed with telomere-specific fluorescence in situ hybridization. The ALT phenotype was confirmed in all ULMSs showing diminished ATRX expression. Exome data also revealed one nonsense mutation in death-domain associated protein (DAXX, another gene previously associated with ALT, and the tumor showed ALT positivity. In conclusion, exome sequencing revealed that TP53, ATRX, and MED12 are frequently mutated in ULMSs. ALT phenotype was commonly seen in tumors, indicating that ATR inhibitors, which were recently suggested as possible new drugs for ATRX-deficient tumors, could provide a potential novel therapeutic option for ULMS.

  13. SCPS-TP, TCP, and Rate-Based Protocol Evaluation. Revised

    Science.gov (United States)

    Tran, Diepchi T.; Lawas-Grodek, Frances J.; Dimond, Robert P.; Ivancic, William D.

    2005-01-01

    Tests were performed at Glenn Research Center to compare the performance of the Space Communications Protocol Standard Transport Protocol (SCPS TP, otherwise known as "TCP Tranquility") relative to other variants of TCP and to determine the implementation maturity level of these protocols, particularly for higher speeds. The testing was performed over reasonably high data rates of up to 100 Mbps with delays that are characteristic of near-planetary environments. The tests were run for a fixed packet size, but for variously errored environments. This report documents the testing performed to date.

  14. Flight test report Focke Wulf Piaggio P149D-TP 2015

    CSIR Research Space (South Africa)

    Barker, D

    2015-09-01

    Full Text Available stream_source_info Barker_2015.pdf.txt stream_content_type text/plain stream_size 12410 Content-Encoding UTF-8 stream_name Barker_2015.pdf.txt Content-Type text/plain; charset=UTF-8 Flight Test Report Focke Wulf... Piaggio P149D-TP IASSA 2015 Des Barker Flight Test Society of South Africa Scope • Executive Summary of Flight Test Programme: – Background – Objectives of Test Programme – Scope of Modifications – Flight Test Team – Conditions...

  15. CT Image Reconstruction from Sparse Projections Using Adaptive TpV Regularization

    Directory of Open Access Journals (Sweden)

    Hongliang Qi

    2015-01-01

    Full Text Available Radiation dose reduction without losing CT image quality has been an increasing concern. Reducing the number of X-ray projections to reconstruct CT images, which is also called sparse-projection reconstruction, can potentially avoid excessive dose delivered to patients in CT examination. To overcome the disadvantages of total variation (TV minimization method, in this work we introduce a novel adaptive TpV regularization into sparse-projection image reconstruction and use FISTA technique to accelerate iterative convergence. The numerical experiments demonstrate that the proposed method suppresses noise and artifacts more efficiently, and preserves structure information better than other existing reconstruction methods.

  16. TP53 Polymorphisms allow for genetic sub-grouping of the canine transmissible venereal tumor

    Science.gov (United States)

    Sánchez-Servín, Abel; Córdova-Alarcon, Emilio; Fajardo, Raúl

    2009-01-01

    The canine transmissible venereal tumor (CTVT) is found mainly in dogs' sexual organs. Currently, it is widely accepted that all samples of CTVT show similar histopathological characteristics and share common genetic alterations. Despite the common genetic origin of CTVT, mutations in the P53 gene have been reported. In this study, we proposed that tumor samples can be genetically grouped using this gene. The presence of different subgroups of CTVT was determined in Mexican dogs using the TP53 gene sequence in CTVT samples. Four new polymorphisms were found and therefore, the CTVT samples were classified in five subgroups. PMID:19934603

  17. A phenylalanine ammonia-lyase ortholog (PkPAL1) from Picrorhiza kurrooa Royle ex. Benth: molecular cloning, promoter analysis and response to biotic and abiotic elicitors.

    Science.gov (United States)

    Bhat, Wajid Waheed; Razdan, Sumeer; Rana, Satiander; Dhar, Niha; Wani, Tariq Ahmad; Qazi, Parvaiz; Vishwakarma, Ram; Lattoo, Surrinder K

    2014-09-01

    Picrorhiza kurrooa Royle ex Benth. is a highly reputed medicinal herb utilised in the preparation of a number of herbal drug formulations, principally due to the presence of novel monoterpene iridoid glycosides kenned as picrosides. Phenylalanine ammonia-lyase catalyses an important rate-limiting step in phenylpropanoid pathway and supplies precursors like cinnamic acid, vanillic acid, ferulic acid, etc., to a variety of secondary metabolites including picrosides. The imperilled status of P. kurrooa coupled with lack of information regarding biogenesis of picrosides necessitates deciphering the biosynthetic pathway for picrosides. In the present study, a PAL gene, designated PkPAL1 was isolated from P. kurrooa. The cDNA is 2312 bp in length, consisting of an ORF of 2142 bp encoding for a 713 amino acid protein having a predicted molecular weight of 77.66 kDa and an isoelectric point of pH 6.82. qRT-PCR analysis of various tissues of P. kurrooa showed that PkPAL1 transcript levels were highest in the leaves, consistent with picroside accumulation pattern. Using Genome walking, a 718 bp promoter region was also isolated resulting in identification of distinct cis-regulatory elements including TGA-element, TGACG-motif, CGTCA-motif, etc. qRT-PCR indicated up-regulation of PkPAL1 by methyl jasmonate, salicylic acid, 2,4-dicholorophenoxy acetic acid and UV-B elicitations that corroborated positively with the identified cis-elements within the promoter region. Moreover, altitude was found to have a positive effect on the PkPAL1 transcript levels, driving the expression of PkPAL1 abundantly. Based on docking analysis, we identified eight residues as potentially essential for substrate binding in PkPAL1.

  18. {sup 18}F-GE-180: a novel TSPO radiotracer compared to {sup 11}C-R-PK11195 in a preclinical model of stroke

    Energy Technology Data Exchange (ETDEWEB)

    Boutin, Herve; Gerhard, Alexander [University of Manchester, Faculty of Medical and Human Sciences, Manchester (United Kingdom); University of Manchester, Wolfson Molecular Imaging Centre, Manchester (United Kingdom); Murray, Katie [University of Manchester, Faculty of Life Sciences, Manchester (United Kingdom); Pradillo, Jesus [University of Manchester, Faculty of Life Sciences, Manchester (United Kingdom); Universidad Complutense/Politecnica de Madrid, Madrid (Spain); Maroy, Renaud [SHFJ - CEA Orsay, Orsay (France); Smigova, Alison [University of Manchester, Wolfson Molecular Imaging Centre, Manchester (United Kingdom); Jones, Paul A.; Trigg, William [GE Healthcare Ltd., Amersham (United Kingdom)

    2014-10-29

    Neuroinflammation plays a critical role in various neuropathological conditions, and hence there is renewed interest in the translocator protein (TSPO) as a biomarker of microglial activation and macrophage infiltration in the brain. This is reflected in the large amount of research conducted seeking to replace the prototypical PET radiotracer {sup 11}C-R-PK11195 with a TSPO ligand with higher performance. Here we report the in vivo preclinical investigation of the novel TSPO tracer {sup 18}F-GE-180 in a rat model of stroke. Focal cerebral ischaemia was induced in Wistar rats by 60-min occlusion of the middle cerebral artery (MCAO). Brain damage was assessed 24 h after MCAO by T2 MRI. Rats were scanned with {sup 11}C-R-PK11195 and {sup 18}F-GE-180 5 or 6 days after MCAO. Specificity of binding was confirmed by injection of unlabelled R-PK11195 or GE-180 20 min after injection of {sup 18}F-GE-180. In vivo data were confirmed by ex vivo immunohistochemistry for microglial (CD11b) and astrocytic biomarkers (GFAP). {sup 18}F-GE-180 uptake was 24 % higher in the core of the ischaemic lesion and 18 % lower in the contralateral healthy tissue than that of {sup 11}C-R-PK11195 uptake (1.5 ± 0.2-fold higher signal to noise ratio). We confirmed this finding using the simplified reference tissue model (BP{sub ND} = 3.5 ± 0.4 and 2.4 ± 0.5 for {sup 18}F-GE-180 and {sup 11}C-R-PK11195, respectively, with R{sub 1} = 1). Injection of unlabelled R-PK11195 or GE-180 20 min after injection of {sup 18}F-GE-180 significantly displaced {sup 18}F-GE-180 (69 ± 5 % and 63 ± 4 %, respectively). Specificity of the binding was also confirmed by in vitro autoradiography, and the location and presence of activated microglia and infiltrated macrophages were confirmed by immunohistochemistry. The in vivo binding characteristics of {sup 18}F-GE-180 demonstrate a better signal to noise ratio than {sup 11}C-R-PK11195 due to both a better signal in the lesion and lower nonspecific binding in

  19. Overexpression of RBBP6, alone or combined with mutant TP53, is predictive of poor prognosis in colon cancer.

    Directory of Open Access Journals (Sweden)

    Jian Chen

    Full Text Available Retinoblastoma binding protein 6 (RBBP6 plays an important role in chaperone-mediated ubiquitination and interacts with TP53 in carcinogenesis. However, the clinicopathologic significance of RBBP6 expression in colon cancer is unknown; in particular, the prognostic value of RBBP6 combined with TP53 expression has not been explored. Therefore, quantitative real-time PCR and western blot analyses were performed to detect RBBP6 expression in colon cancer tissues. RBBP6 and TP53 expression were assessed by immunohistochemistry in a tissue microarray format, in which the primary colon cancer tissue was paired with noncancerous tissue. Tissue specimens were obtained from 203 patients. We found that RBBP6 was overexpressed in colon tumorous tissues and was significantly associated with clinical stage, depth of tumor invasion, lymph node metastasis (LNM, distant metastasis, and histologic grade. Further studies revealed that a corresponding correlation between RBBP6 overexpression and mutant TP53 was evident in colon cancer (r = 0.450; P<0.001. RBBP6 expression was an independent prognostic factor for overall survival (OS and disease free survival (DFS. Interestingly, patients with tumors that had both RBBP6 overexpression and mutant TP53 protein accumulation relapsed and died within a significantly short period after surgery (P<0.001. Multivariate analysis showed that patients with LNM and patients with both RBBP6- and TP53-positive tumors had extremely poor OS (HR 6.75; 95% CI 2.63-17.35; P<0.001 and DFS (HR 8.08; 95% CI 2.80-23.30; P<0.001. These clinical findings indicate that the assessment of both RBBP6 and mutant TP53 expression will be helpful in predicting colon cancer prognosis.

  20. Ultra-deep sequencing detects ovarian cancer cells in peritoneal fluid and reveals somatic TP53 mutations in noncancerous tissues.

    Science.gov (United States)

    Krimmel, Jeffrey D; Schmitt, Michael W; Harrell, Maria I; Agnew, Kathy J; Kennedy, Scott R; Emond, Mary J; Loeb, Lawrence A; Swisher, Elizabeth M; Risques, Rosa Ana

    2016-05-24

    Current sequencing methods are error-prone, which precludes the identification of low frequency mutations for early cancer detection. Duplex sequencing is a sequencing technology that decreases errors by scoring mutations present only in both strands of DNA. Our aim was to determine whether duplex sequencing could detect extremely rare cancer cells present in peritoneal fluid from women with high-grade serous ovarian carcinomas (HGSOCs). These aggressive cancers are typically diagnosed at a late stage and are characterized by TP53 mutations and peritoneal dissemination. We used duplex sequencing to analyze TP53 mutations in 17 peritoneal fluid samples from women with HGSOC and 20 from women without cancer. The tumor TP53 mutation was detected in 94% (16/17) of peritoneal fluid samples from women with HGSOC (frequency as low as 1 mutant per 24,736 normal genomes). Additionally, we detected extremely low frequency TP53 mutations (median mutant fraction 1/13,139) in peritoneal fluid from nearly all patients with and without cancer (35/37). These mutations were mostly deleterious, clustered in hotspots, increased with age, and were more abundant in women with cancer than in controls. The total burden of TP53 mutations in peritoneal fluid distinguished cancers from controls with 82% sensitivity (14/17) and 90% specificity (18/20). Age-associated, low frequency TP53 mutations were also found in 100% of peripheral blood samples from 15 women with and without ovarian cancer (none with hematologic disorder). Our results demonstrate the ability of duplex sequencing to detect rare cancer cells and provide evidence of widespread, low frequency, age-associated somatic TP53 mutation in noncancerous tissue.

  1. High prevalence of TP53 mutations is associated with poor survival and an EMT signature in gliosarcoma patients

    Science.gov (United States)

    Cho, Sung-Yup; Park, Changho; Na, Deukchae; Han, Jee Yun; Lee, Jieun; Park, Ok-Kyoung; Zhang, Chengsheng; Sung, Chang Ohk; Moon, Hyo Eun; Kim, Yona; Kim, Jeong Hoon; Kim, Jong Jae; Khang, Shin Kwang; Nam, Do-Hyun; Choi, Jung Won; Suh, Yeon-Lim; Kim, Dong Gyu; Park, Sung Hye; Youn, Hyewon; Yun, Kyuson; Kim, Jong-Il; Lee, Charles; Paek, Sun Ha; Park, Hansoo

    2017-01-01

    Gliosarcoma (GS) is a rare variant (2%) of glioblastoma (GBM) that poses clinical genomic challenges because of its poor prognosis and limited genomic information. To gain a comprehensive view of the genomic alterations in GS and to understand the molecular etiology of GS, we applied whole-exome sequencing analyses for 28 GS cases (6 blood-matched fresh-frozen tissues for the discovery set, 22 formalin-fixed paraffin-embedded tissues for the validation set) and copy-number variation microarrays for 5 blood-matched fresh-frozen tissues. TP53 mutations were more prevalent in the GS cases (20/28, 70%) compared to the GBM cases (29/90, 32%), and the GS patients with TP53 mutations showed a significantly shorter survival (multivariate Cox analysis, hazard ratio=23.9, 95% confidence interval, 2.87–199.63, P=0.003). A pathway analysis showed recurrent alterations in MAPK signaling (EGFR, RASGRF2 and TP53), phosphatidylinositol/calcium signaling (CACNA1s, PLCs and ITPRs) and focal adhesion/tight junction (PTEN and PAK3) pathways. Genomic profiling of the matched recurrent GS cases detected the occurrence of TP53 mutations in two recurrent GS cases, which suggests that TP53 mutations play a role in treatment resistance. Functionally, we found that TP53 mutations are associated with the epithelial–mesenchymal transition (EMT) process of sarcomatous components of GS. We provide the first comprehensive genome-wide genetic alternation profiling of GS, which suggests novel prognostic subgroups in GS patients based on their TP53 mutation status and provides new insight in the pathogenesis and targeted treatment of GS. PMID:28408749

  2. TP53 mutation does not confer a poor outcome in adult patients with acute lymphoblastic leukemia who are treated with frontline hyper-CVAD-based regimens.

    Science.gov (United States)

    Kanagal-Shamanna, Rashmi; Jain, Preetesh; Takahashi, Koichi; Short, Nicholas J; Tang, Guilin; Issa, Ghayas C; Ravandi, Farhad; Garcia-Manero, Guillermo; Yin, Cameron C; Luthra, Rajyalakshmi; Patel, Keyur P; Khoury, Joseph D; Montalban-Bravo, Guillermo; Sasaki, Koji; Kadia, Tapan M; Borthakur, Gautam; Konopleva, Marina; Jain, Nitin; Garris, Rebecca; Pierce, Sherry; Wierda, William; Estrov, Zeev; Cortes, Jorge; O'Brien, Susan; Kantarjian, Hagop M; Jabbour, Elias

    2017-10-01

    Tumor protein 53 (TP53) mutations are uncommon in adult patients with acute lymphoblastic leukemia (ALL) and predict a poor outcome. TP53 mutation analysis was performed in 164 newly diagnosed adult patients with ALL using a combination of targeted amplicon-based next-generation sequencing and Sanger sequencing. TP53 mutations were detected in 25 patients (15%), with a median allelic frequency of 42.2% (range, 5.6%-93.8%). The majority of mutations were single-nucleotide variants of missense type and involved the DNA-binding domain. TP53-mutated (TP53(mut) ) ALL was found to be significantly associated with older age, lower median white blood cell and platelet counts, lower frequency of Philadelphia chromosome and a higher frequency of low hypodiploid karyotype compared with ALL with wild-type TP53 (TP53(wt) ). To evaluate the prognostic effect of TP53 mutations, the authors selected 146 patients with B-cell immunophenotype ALL (24 with TP53(mut) and 122 with TP53(wt) ) who were uniformly treated with frontline hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD)-based regimens; >90% of these individuals also received a monoclonal antibody. Over a median follow-up duration of 15 months, there was no significant difference in the median overall survival, event-free survival, and duration of complete remission noted between patients with TP53(mut) ALL and those with TP53(wt) ALL. Hyper-CVAD-based regimens appear to negate the poor prognostic impact of TP53 mutations in patients with adult B-cell immunophenotype ALL. Cancer 2017;123:3717-24. © 2017 American Cancer Society. © 2017 American Cancer Society.

  3. Molecular Mapping of Two Novel Stripe Rust Resistant Genes YrTp1 and YrTp2 in A-3 Derived from Triticum aestivum × Thinopyrum ponticum

    Institute of Scientific and Technical Information of China (English)

    YIN Xue-gui; SHANG Xun-wu; PANG Bin-shuang; SONG Jian-rong; CAO Shi-qin; LI Jin-chang; ZHANG Xue-yong

    2006-01-01

    Loss of variety resistance to stripe rust (Puccinia striiformis Westend f. sp. tritici) is an important factor causing massive periodical epidemic of rust in wheat production. Creation and development of new races of rust pathogen have led to serious crisis of resistance loss in widely planted varieties. This has quickened the search for new resistance resources.Molecular marker could facilitate the identification of the location of novel genes. A line A-3 with high resistance(immune) to currently epidemic yellow rust races (CY29, 31, 32) was screened out in offspring of Triticum aestivum ×Thinopyrum ponticum. Segregation in F2 and BC1 populations indicated that the resistance was controlled by two independent genes: one dominant and one recessive. SSR markers were employed to map the two resistant genes in the F2 and BC1 populations. A marker WMC477-167bp located on 2BS was linked to the dominant gene with genetic distance of 0.4 cM. Another marker WMC364-208bp located on 7BS was linked to the recessive-resistant gene with genetic distance of 5.8 cM. The two genes identified in this paper might be two novel stripe rust resistant genes, which were temporarily designated as YrTpl and YrTp2, respectively. The tightly linking markers facilitate transfer of the two resistant genes into the new varieties to control epidemic of yellow rust.

  4. PkANN - II. A non-linear matter power spectrum interpolator developed using artificial neural networks

    CERN Document Server

    Agarwal, Shankar; Feldman, Hume A; Lahav, Ofer; Thomas, Shaun A

    2013-01-01

    In this paper we introduce PkANN, a freely available software package for interpolating the non-linear matter power spectrum, constructed using Artificial Neural Networks (ANNs). Previously, using Halofit to calculate matter power spectrum, we demonstrated that ANNs can make extremely quick and accurate predictions of the power spectrum. Now, using a suite of 6380 N-body simulations spanning 580 cosmologies, we train ANNs to predict the power spectrum over the cosmological parameter space spanning $3\\sigma$ confidence level (CL) around the concordance cosmology. When presented with a set of cosmological parameters ($\\Omega_{\\rm m} h^2, \\Omega_{\\rm b} h^2, n_s, w, \\sigma_8, \\sum m_\

  5. Comparison of the anti-inflammatory actions of flunixin and ketoprofen in horses applying PK/PD modelling.

    Science.gov (United States)

    Landoni, M F; Lees, P

    1995-07-01

    A comparative study in horses of the pharmacokinetics (PK) and pharmacodynamics (PD) of 2 extensively used nonsteroidal anti-inflammatory drugs (NSAIDs), flunixin (FXN) and ketoprofen (KTP), was carried out applying PK/PD modelling. To evaluate the anti-inflammatory properties of these drugs a model of acute inflammation, comprising surgically implanted subcutaneous tissue cages stimulated by intracaveal injection of carrageenan, was used. FXN elimination half-life (T1/2 beta) in plasma was 3.37 +/- 1.09 h. However, in exudate a much longer T1/2 beta was obtained (15.99 +/- 3.80 h). Apparent volume of distribution (Vdarea) for FXN was 0.317 +/- 0.126 l/kg and body clearance (ClB) was 0.058 +/- 0.004 l/kg/h. KTP displayed enantioselective pharmacokinetics, the S(+) enantiomer being predominant in plasma, exudate and transudate. T1/2 beta values for R(-) and S(+)KTP were, respectively, 1.09 +/- 0.19 h and 1.51 +/- 0.45 h (plasma) and 19.73 +/- 2.72 h and 22.64 +/- 4.34 h (exudate), respectively. R(-)KTP was cleared more rapidly than the S(+) enantiomer. ClB values were 0.277 +/- 0.035 l/kg/h and 0.202 +/- 0.022 l/kg/h, respectively. FXN and KTP pharmacodynamics was evaluated by determining their inhibitory effects on serum thromboxane (Tx)B2, exudate prostaglandin (PG)E2, leukotriene (LT)B4 and beta-glucuronidase (beta-glu) and intradermal bradykinin-induced swelling. Both drugs produced marked inhibition of serum TxB2 synthesis for up to 24 h, with no significant differences between the drugs. FXN was a more potent inhibitor of exudate PGE2, the EC50 for FXN being lower (P < 0.01) than that for KTP (0.019 +/- 0.010 microgram/ml and 0.057 +/- 0.009 microgram/ml, respectively). Neither drug had any effect on exudate LTB4 concentration. Differences between the 2 drugs were observed for the inhibition of beta-glu, the Emax for KTP being higher (P < 0.01) than for FXN. However, no differences were observed in other PD parameters. Both FXN and KTP inhibited bradykinin

  6. Investigation on steam oxidation behaviour of TP347H FG Part I Exposure at 256 bar

    DEFF Research Database (Denmark)

    Jianmin, J; Montgomery, Melanie; Larsen, OH

    2005-01-01

    The stainless steel TP347H FG is a candidate material for the final stage tubing of superheater and reheater sections of ultra supercritical boilers operated at steam temperatures up to 620C in the mild corrosion environments of coal-firing. A series of field tests has been conducted with the afo......The stainless steel TP347H FG is a candidate material for the final stage tubing of superheater and reheater sections of ultra supercritical boilers operated at steam temperatures up to 620C in the mild corrosion environments of coal-firing. A series of field tests has been conducted...... with the aforementioned steel in coal-fired boilers and this paper focuses on the steam oxidation behaviour for specimens tested at various metal temperatures for exposure times of 7700, 23000 and 30000 hours as investigated by light optical and scanning electron microscopy. The oxide present on the specimens is a duplex......, where the larger the metal grain size, the thicker the oxidation scale. This gave the appearance of uneven inner oxides with a varying pit thickness. Comparison of the pit thickness measurement and oxide composition reveals that the oxidation rate is fast during the initial oxidation stage...

  7. Occurrence of Neuroblastoma among TP53 p.R337H Carriers.

    Science.gov (United States)

    Seidinger, Ana Luiza; Fortes, Fernanda Paschoal; Mastellaro, Maria José; Cardinalli, Izilda Aparecida; Zambaldi, Lilian Girotto; Aguiar, Simone Santos; Yunes, José Andrés

    2015-01-01

    The high incidence of adrenocortical tumors and choroid plexus carcinoma in children from South and Southeastern regions of Brazil is associated with the germline p.R337H mutation of TP53 gene. The concomitant occurrence of neuroblastoma and adrenocortical tumors in pediatric patients harboring the p.R337H mutation at our institution prompted us to investigate the putative association between p.R337H and pediatric neuroblastoma. Genomic DNA samples from 83 neuroblastoma patients referred to a single institution during the period of 2000-2014 were screened for the p.R337H mutation. Available samples from carriers were investigated for both nuclear p53 accumulation and loss of heterozigosity in tumor. Clinical data were obtained from medical records in order to assess the impact of 337H allele on manifestation of the disease. Seven out 83 neuroblastoma patients (8.4%) were carriers of the TP53 p.R337H mutation in our cohort. Immunohistochemical analysis of p.R337H-positive tumors revealed nuclear p53 accumulation. Loss of heterozigosity was not found among available samples. The presence of 337H allele was associated with increased proportion of stage I tumors. Our data indicate that in addition to adrenocortical tumors, choroid plexus carcinoma, breast cancer and osteosarcoma, genetic counseling and clinical surveillance should consider neuroblastoma as a potential neoplasia affecting p.R337H carriers.

  8. Screening for TP53 mutations in osteosarcomas using constant denaturant gel electrophoresis (CDGE).

    Science.gov (United States)

    Smith-Sørensen, B; Gebhardt, M C; Kloen, P; McIntyre, J; Aguilar, F; Cerutti, P; Børresen, A L

    1993-01-01

    We have previously developed conditions to screen for TP53 point mutations inside the conserved domains II-V of the gene by using constant denaturant gel electrophoresis (CDGE). The present study reports conditions for screening more of the codons in the frequently mutated region exon 5-8 and for detecting mutations in sequences encoding functional domains in the N- and C-terminal part of the protein. The ability of the CDGE technique to detect mutations was studied using controls with known sequence deviations. The resolution power of the technique to separate different types of mutations was tested by using seven different single base pair mutants all residing in a stretch of four base pairs. All mutants were separated from the wild type. The established CDGE screening strategy was then used to look for mutations in DNA from 28 osteosarcomas. Six (21.5%) of the samples were shown to have a TP53 mutation, and the exact characterization was performed by direct sequencing. All of these were within the frequently reported mutated region exon 5-8.

  9. TP-Space RRT – Kinematic Path Planning of Non-Holonomic Any-Shape Vehicles

    Directory of Open Access Journals (Sweden)

    Jose Luis Blanco

    2015-05-01

    Full Text Available The autonomous navigation of vehicles typically combines two kinds of methods: a path is first planned, and then the robot is driven by a local obstacle-avoidance controller. The present work, which focuses on path planning, proposes an extension to the well-known rapidly-exploring random tree (RRT algorithm to allow its integration with a trajectory parameter-space (TP-space as an efficient method to detect collision-free, kinematically-feasible paths for arbitrarily-shaped vehicles. In contrast to original RRT, this proposal generates navigation trees, with poses as nodes, whose edges are all kinematically-feasible paths, suitable to being accurately followed by vehicles driven by pure reactive algorithms. Initial experiments demonstrate the suitability of the method with an Ackermann-steering vehicle model whose severe kinematic constraints cannot be obviated. An important result that sets this work apart from previous research is the finding that employing several families of potential trajectories to expand the tree, which can be done efficiently under the TP-space formalism, improves the optimality of the planned trajectories. A reference C++ implementation has been released as open-source.

  10. CS 30322-023: an ultra metal-poor TP-AGB star?

    CERN Document Server

    Masseron, T; Famaey, B; Goriely, S; Plez, B; Siess, L; Beers, T C; Primas, F; Jorissen, A

    2006-01-01

    With [Fe/H] = -3.5, CS 30322-023 is the most metal-poor star to exhibit a clear s-process signature and the most metal-poor ``lead star'' known. CS 30322-023 is also remarkable in having the lowest surface gravity (log g <= -0.3) among the metal-poor stars studied to date. The available evidence indicates that this star is presently a thermally-pulsing asymptotic giant branch (TP-AGB) star, with no strong indication of binarity thus far (although a signal of period 192 d is clearly present in the radial-velocity data, this is likely due to pulsation of the stellar envelope). We show that low-mass TP-AGB stars are not expected to be exceedingly rare in a magnitude-limited sample such as the HK survey, because their high luminosities make it possible to sample them over a very large volume. The strong N overabundance and the low 12C/13C ratio (4) in this star is typical of the operation of the CN cycle. Coupled with a Na overabundance and the absence of a strong C overabundance, this pattern seems to imply t...

  11. Hepatitis B and Hepatitis C Infection Biomarkers and TP53 Mutations in Hepatocellular Carcinomas from Colombia

    Directory of Open Access Journals (Sweden)

    Maria-Cristina Navas

    2011-01-01

    Full Text Available Hepatocellular Carcinoma (HCC is a leading cause of cancer-related death worldwide. Globally, the most important HCC risk factors are Hepatitis B Virus (HBV and/or Hepatitis C Virus (HCV, chronic alcoholism, and dietary exposure to aflatoxins. We have described the epidemiological pattern of 202 HCC samples obtained from Colombian patients. Additionally we investigated HBV/HCV infections and TP53 mutations in 49 of these HCC cases. HBV biomarkers were detected in 58.1% of the cases; HBV genotypes F and D were characterized in three of the samples. The HCV biomarker was detected in 37% of the samples while HBV/HCV coinfection was found in 19.2%. Among TP53 mutations, 10.5% occur at the common aflatoxin mutation hotspot, codon 249. No data regarding chronic alcoholism was available from the cases. In conclusion, in this first study of HCC and biomarkers in a Colombian population, the main HCC risk factor was HBV infection.

  12. A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.

    Science.gov (United States)

    Stacey, Simon N; Sulem, Patrick; Jonasdottir, Aslaug; Masson, Gisli; Gudmundsson, Julius; Gudbjartsson, Daniel F; Magnusson, Olafur T; Gudjonsson, Sigurjon A; Sigurgeirsson, Bardur; Thorisdottir, Kristin; Ragnarsson, Rafn; Benediktsdottir, Kristrun R; Nexø, Bjørn A; Tjønneland, Anne; Overvad, Kim; Rudnai, Peter; Gurzau, Eugene; Koppova, Kvetoslava; Hemminki, Kari; Corredera, Cristina; Fuentelsaz, Victoria; Grasa, Pilar; Navarrete, Sebastian; Fuertes, Fernando; García-Prats, Maria D; Sanambrosio, Enrique; Panadero, Angeles; De Juan, Ana; Garcia, Almudena; Rivera, Fernando; Planelles, Dolores; Soriano, Virtudes; Requena, Celia; Aben, Katja K; van Rossum, Michelle M; Cremers, Ruben G H M; van Oort, Inge M; van Spronsen, Dick-Johan; Schalken, Jack A; Peters, Wilbert H M; Helfand, Brian T; Donovan, Jenny L; Hamdy, Freddie C; Badescu, Daniel; Codreanu, Ovidiu; Jinga, Mariana; Csiki, Irma E; Constantinescu, Vali; Badea, Paula; Mates, Ioan N; Dinu, Daniela E; Constantin, Adrian; Mates, Dana; Kristjansdottir, Sjofn; Agnarsson, Bjarni A; Jonsson, Eirikur; Barkardottir, Rosa B; Einarsson, Gudmundur V; Sigurdsson, Fridbjorn; Moller, Pall H; Stefansson, Tryggvi; Valdimarsson, Trausti; Johannsson, Oskar T; Sigurdsson, Helgi; Jonsson, Thorvaldur; Jonasson, Jon G; Tryggvadottir, Laufey; Rice, Terri; Hansen, Helen M; Xiao, Yuanyuan; Lachance, Daniel H; O Neill, Brian Patrick; Kosel, Matthew L; Decker, Paul A; Thorleifsson, Gudmar; Johannsdottir, Hrefna; Helgadottir, Hafdis T; Sigurdsson, Asgeir; Steinthorsdottir, Valgerdur; Lindblom, Annika; Sandler, Robert S; Keku, Temitope O; Banasik, Karina; Jørgensen, Torben; Witte, Daniel R; Hansen, Torben; Pedersen, Oluf; Jinga, Viorel; Neal, David E; Catalona, William J; Wrensch, Margaret; Wiencke, John; Jenkins, Robert B; Nagore, Eduardo; Vogel, Ulla; Kiemeney, Lambertus A; Kumar, Rajiv; Mayordomo, José I; Olafsson, Jon H; Kong, Augustine; Thorsteinsdottir, Unnur; Rafnar, Thorunn; Stefansson, Kari

    2011-09-25

    To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).

  13. TP0326, a Treponema pallidum β-barrel assembly machinery A (BamA) orthologue and rare outer membrane protein.

    Science.gov (United States)

    Desrosiers, Daniel C; Anand, Arvind; Luthra, Amit; Dunham-Ems, Star M; LeDoyt, Morgan; Cummings, Michael A D; Eshghi, Azad; Cameron, Caroline E; Cruz, Adriana R; Salazar, Juan C; Caimano, Melissa J; Radolf, Justin D

    2011-06-01

    Definitive identification of Treponema pallidum rare outer membrane proteins (OMPs) has long eluded researchers. TP0326, the sole protein in T. pallidum with sequence homology to a Gram-negative OMP, belongs to the BamA family of proteins essential for OM biogenesis. Structural modelling predicted that five polypeptide transport-associated (POTRA) domains comprise the N-terminus of TP0326, while the C-terminus forms an 18-stranded amphipathic β-barrel. Circular dichroism, heat modifiability by SDS-PAGE, Triton X-114 phase partitioning and liposome incorporation supported these topological predictions and confirmed that the β-barrel is responsible for the native protein's amphiphilicity. Expression analyses revealed that native TP0326 is expressed at low abundance, while a protease-surface accessibility assay confirmed surface exposure. Size-exclusion chromatography and blue native polyacrylamide gel electrophoresis revealed a modular Bam complex in T. pallidum larger than that of Escherichia coli. Non-orthologous ancillary factors and self-association of TP0326 via its β-barrel may both contribute to the Bam complex. T. pallidum-infected rabbits mount a vigorous antibody response to both POTRA and β-barrel portions of TP0326, whereas humans with secondary syphilis respond predominantly to POTRA. The syphilis spirochaete appears to have devised a stratagem for harnessing the Bam pathway while satisfying its need to limit surface antigenicity.

  14. TP-ellipsis with a polarity particle in multiple-complementizer contexts in Spanish: on topical remnants and focal licensors

    Directory of Open Access Journals (Sweden)

    Julio Villa-García

    2016-12-01

    Full Text Available This paper investigates TP-ellipsis in Spanish in the context of multiple-complementizer clauses (i.e., … que XP que ellipsis licensor ellipsis site. The paper argues for a standard ΣP-account of TP ellipsis, with the polarity/focal item (e.g., también/tampoco/sí/no crucially involved in the licensing of ellipsis. It is argued that the XP-que sequence is hosted in TopicP. The XP is a contrastive topic functioning as the remnant of TP-ellipsis and que is an instance of recomplementation que –a topic marker. The ellipsis licensor, for its part, sits in a CP-related projection that follows TopicP. Given the parallelism drawn here between the items that can partake in the licensing of TP-ellipsis and run-of-the-mill focused phrases, the paper puts forth the claim that ΣP and FocusP should be conflated. Similarly, I explore the relationship established between TopicP (the remnant and ΣP/FocusP (the ellipsis licensor in the process of TP ellipsis as well as offer an account of the inability of jussive/optative que to survive ellipsis, unlike recomplementation que.

  15. Defects in mitophagy promote redox-driven metabolic syndrome in the absence of TP53INP1.

    Science.gov (United States)

    Seillier, Marion; Pouyet, Laurent; N'Guessan, Prudence; Nollet, Marie; Capo, Florence; Guillaumond, Fabienne; Peyta, Laure; Dumas, Jean-François; Varrault, Annie; Bertrand, Gyslaine; Bonnafous, Stéphanie; Tran, Albert; Meur, Gargi; Marchetti, Piero; Ravier, Magalie A; Dalle, Stéphane; Gual, Philippe; Muller, Dany; Rutter, Guy A; Servais, Stéphane; Iovanna, Juan L; Carrier, Alice

    2015-03-30

    The metabolic syndrome covers metabolic abnormalities including obesity and type 2 diabetes (T2D). T2D is characterized by insulin resistance resulting from both environmental and genetic factors. A genome-wide association study (GWAS) published in 2010 identified TP53INP1 as a new T2D susceptibility locus, but a pathological mechanism was not identified. In this work, we show that mice lacking TP53INP1 are prone to redox-driven obesity and insulin resistance. Furthermore, we demonstrate that the reactive oxygen species increase in TP53INP1-deficient cells results from accumulation of defective mitochondria associated with impaired PINK/PARKIN mitophagy. This chronic oxidative stress also favors accumulation of lipid droplets. Taken together, our data provide evidence that the GWAS-identified TP53INP1 gene prevents metabolic syndrome, through a mechanism involving prevention of oxidative stress by mitochondrial homeostasis regulation. In conclusion, this study highlights TP53INP1 as a molecular regulator of redox-driven metabolic syndrome and provides a new preclinical mouse model for metabolic syndrome clinical research.

  16. 中国乳腺癌高风险人群中TP53基因胚系突变的研究%Germline mutations of TP53 gene among Chinese families with high risk for breast cancer

    Institute of Scientific and Technical Information of China (English)

    杨晓晨; 胡震; 吴炅; 柳光宇; 狄根红; 陈灿铭; 侯意枫; 黄晓燕; 刘哲斌

    2015-01-01

    Objective To evaluate the role of germline mutations of TP53 gene among a Chinese population with high risk for breast cancer.Methods A total of 81 BRCA-negative breast cancer probands from cancer families were analyzed using targeted capture and next-generation sequencing.Candidate mutations were verified with Sanger sequencing.Co-segregation analyses were carried out to explore the likely pathogenicity of the mutation.Results Of the 81 BRCA-negative patients, 3 exonic mutations in the TP53 gene were identified in 3 breast cancer patients.Of these, 2 mutations were previously reported and 1 was novel.One family with TP53 mutation has met the criteria for Li-Fraumeni syndrome (LFS) and accounted for 9.1% of all families who fulfilled the diagnostic criteria for LFS.Two of the carriers were diagnosed with breast cancer under the age of 30, and have accounted for 11.8% (2/17) of all very young (≤30 years) breast cancer patients in our study.Conclusion The TP53 germline mutation is more common in Chinese population with a high risk for breast cancer than previously thought.TP53 gene mutation screening should be considered particularly for patients with a family history of LFS and very young age of onset.%目的 研究中国乳腺癌高风险人群中TP53基因胚系突变的情况.方法 应用目标区域捕获和大规模平行测序的方法,对81个来自肿瘤高风险家系、BRCA1/2突变阴性的乳腺癌先证者基因组DNA进行TP53基因的突变检测.挑选候选突变进行Sanger测序验证及共分离研究.结果 在81例BRCA1/2突变阴性的乳腺癌先证者中,分别在3例乳腺癌先证者中发现3个位于TP53外显子区的突变.其中两个为已知突变,一个为新发现的突变.1例TP53突变携带者的家族史符合Li-Fraumeni综合征的标准,占所有符合Li-Fraumeni综合征标准家系的9.1%(1/11).2例TP53突变携带者诊断乳腺癌时的年龄小于30岁,占所有非常年轻乳腺癌患者(≤30岁)的11.8%(2

  17. 兔豆状囊尾蚴TpRS1基因的克隆及其序列分析%Cloning and Sequence Analysis of TpRS1 Gene from Cysticercus pisiformis

    Institute of Scientific and Technical Information of China (English)

    韩乐乐; 李作磊; 苟惠天; 孙晓林

    2014-01-01

    旨在研究兔豆状囊尾蚴TpRS1的功能,根据GenBank中猪带绦虫RS1 cDNA序列设计引物,以豆状囊尾蚴总RNA为模板,利用RT-PCR技术首次克隆到兔豆状囊尾蚴TpRS1的完整开放阅读框序列,并利用生物信息学软件对该基因及其编码蛋白的基本理化性质、疏水性、信号肽、二级结构和抗原位点等方面进行了预测和分析。结果表明,兔豆状囊尾蚴TpRS1的cDNA序列为275 bp的基因片段,该序列含有一个由258个核苷酸组成的开放阅读框,编码85个氨基酸。其编码蛋白疏水性,分子质量为9.6 kD,理论等电点为9.07。TpRS1二级结构中α螺旋占70.59%,β折叠占5.88%,其余23.53%为无规卷曲,TpRS1没有信号肽序列,同源性分析表明与其他带科绦虫的一致性在72%以上,系统进化分析表明与泡状带绦虫处于同一进化分支。%To study the function of TpRS1 gene from Cysticercus pisiformis, the open reading frame(ORF)cDNA sequence of TpRS1 gene was cloned by RT-PCR from C. pisiformis total RNA with primers derived from Taenia solium RS1 gene sequence in the GenBank database. Biochemical properties, secondary structure, signal, hydrophobicity and antigenicity in TpRS1 protein were predicted by bioinformatics tools. The results indicated that TpRS1 cDNA sequence contained an ORF of 258 nucleotides and the deduced protein consisted of 85 amino acids with the theoretical molecular weight of 9.6 kD and isoelectric point of 9.07. Analysis of secondary structure revealed 70.59%and 5.88%ofα-helix andβ-strands, respectively, and others were loop. The signal peptide sequence of TpRS1 were not identified. TpRS1 protein sequence showed more than 72%identity with other Taenia spp.. Phylogenetic analysis indicated that TpRS1 located in the same clade with Taenia hydatigena.

  18. Human Treponema pallidum 11q/j isolate belongs to subsp. endemicum but contains two loci with a sequence in TP0548 and TP0488 similar to subsp. pertenue and subsp. pallidum, respectively.

    Directory of Open Access Journals (Sweden)

    Lenka Mikalová

    2017-03-01

    Full Text Available Treponema pallidum subsp. endemicum (TEN is the causative agent of endemic syphilis (bejel. An unusual human TEN 11q/j isolate was obtained from a syphilis-like primary genital lesion from a patient that returned to France from Pakistan.The TEN 11q/j isolate was characterized using nested PCR followed by Sanger sequencing and/or direct Illumina sequencing. Altogether, 44 chromosomal regions were analyzed. Overall, the 11q/j isolate clustered with TEN strains Bosnia A and Iraq B as expected from previous TEN classification of the 11q/j isolate. However, the 11q/j sequence in a 505 bp-long region at the TP0488 locus was similar to Treponema pallidum subsp. pallidum (TPA strains, but not to TEN Bosnia A and Iraq B sequences, suggesting a recombination event at this locus. Similarly, the 11q/j sequence in a 613 bp-long region at the TP0548 locus was similar to Treponema pallidum subsp. pertenue (TPE strains, but not to TEN sequences.A detailed analysis of two recombinant loci found in the 11q/j clinical isolate revealed that the recombination event occurred just once, in the TP0488, with the donor sequence originating from a TPA strain. Since TEN Bosnia A and Iraq B were found to contain TPA-like sequences at the TP0548 locus, the recombination at TP0548 took place in a treponeme that was an ancestor to both TEN Bosnia A and Iraq B. The sequence of 11q/j isolate in TP0548 represents an ancestral TEN sequence that is similar to yaws-causing treponemes. In addition to the importance of the 11q/j isolate for reconstruction of the TEN phylogeny, this case emphasizes the possible role of TEN strains in development of syphilis-like lesions.

  19. Evaluation of TP53 Pro72Arg and MDM2 SNP285-SNP309 polymorphisms in an Italian cohort of LFS suggestive patients lacking identifiable TP53 germline mutations.

    Science.gov (United States)

    Ponti, Francesca; Corsini, Serena; Gnoli, Maria; Pedrini, Elena; Mordenti, Marina; Sangiorgi, Luca

    2016-10-01

    Li-Fraumeni syndrome (LFS) is a rare genetic cancer predisposition disease, partly determined by the presence of a TP53 germline mutation; lacking thereof, in presence of a typical LFS phenotype, defines a wide group of 'LFS Suggestive' patients. Alternative LFS susceptibility genes have been investigated without promising results, thus suggesting other genetic determinants involvement in cancer predisposition. Hence, this study explores the single and combined effects of cancer risk, age of onset and cancer type of three single nucleotide polymorphisms (SNPs)-TP53 Pro72Arg, MDM2 SNP285 and SNP309-already described as modifiers on TP53 mutation carriers but not properly investigated in LFS Suggestive patients. This case-control study examines 34 Italian LFS Suggestive lacking of germline TP53 mutations and 95 tumour-free subjects. A significant prevalence of homozygous MDM2 SNP309 G in the LFS Suggestive group (p TP53 positive families. Conversely its anticipating role on tumour onset has not been confirmed, as in our results it was associated with the SNP309 T allele. A strong combined outcome with a 'dosage' effect has also been reported for TP53 P72 and MDM2 SNP309 G allele on cancer susceptibility (p < 0.0005). Whereas the MDM2 SNP285 C allele neutralizing effect on MDM2 SNP309 G variant is not evident in our population. Although it needs further evaluations, obtained results strengthen the role of MDM2 SNP309 as a genetic factor in hereditary predisposition to cancer, so improving LFS Suggestive patients management.

  20. Human Treponema pallidum 11q/j isolate belongs to subsp. endemicum but contains two loci with a sequence in TP0548 and TP0488 similar to subsp. pertenue and subsp. pallidum, respectively.

    Science.gov (United States)

    Mikalová, Lenka; Strouhal, Michal; Oppelt, Jan; Grange, Philippe Alain; Janier, Michel; Benhaddou, Nadjet; Dupin, Nicolas; Šmajs, David

    2017-03-01

    Treponema pallidum subsp. endemicum (TEN) is the causative agent of endemic syphilis (bejel). An unusual human TEN 11q/j isolate was obtained from a syphilis-like primary genital lesion from a patient that returned to France from Pakistan. The TEN 11q/j isolate was characterized using nested PCR followed by Sanger sequencing and/or direct Illumina sequencing. Altogether, 44 chromosomal regions were analyzed. Overall, the 11q/j isolate clustered with TEN strains Bosnia A and Iraq B as expected from previous TEN classification of the 11q/j isolate. However, the 11q/j sequence in a 505 bp-long region at the TP0488 locus was similar to Treponema pallidum subsp. pallidum (TPA) strains, but not to TEN Bosnia A and Iraq B sequences, suggesting a recombination event at this locus. Similarly, the 11q/j sequence in a 613 bp-long region at the TP0548 locus was similar to Treponema pallidum subsp. pertenue (TPE) strains, but not to TEN sequences. A detailed analysis of two recombinant loci found in the 11q/j clinical isolate revealed that the recombination event occurred just once, in the TP0488, with the donor sequence originating from a TPA strain. Since TEN Bosnia A and Iraq B were found to contain TPA-like sequences at the TP0548 locus, the recombination at TP0548 took place in a treponeme that was an ancestor to both TEN Bosnia A and Iraq B. The sequence of 11q/j isolate in TP0548 represents an ancestral TEN sequence that is similar to yaws-causing treponemes. In addition to the importance of the 11q/j isolate for reconstruction of the TEN phylogeny, this case emphasizes the possible role of TEN strains in development of syphilis-like lesions.

  1. 室早 TpR 指数与特发性流出道室早症状的关系%Relationship between TpR index and symptoms of idiopathic outflow tract premature ventricu-lar contraction

    Institute of Scientific and Technical Information of China (English)

    张奇; 赵春梅; 王德国; 杨琴; 李小荣; 张凤祥; 曹克将

    2016-01-01

    Objective To analyze the relationship between arrhythmic symptoms of the patients with outflow tract premature ventricular contraction (PVC)and characteristics of surface electrocardi-ogram(ECG),and to explore its clinical significance.Methods According to the existence of PVC-related arrhythmic symptoms,97 outflow tract PVC patients were divided into two group:symptomatic group(60 cases)and asymptomatic group(37 cases).The examination of echocardio-graphy and standard 1 2 lead surface ECG were performed on all the patients.The measured parame-ters included PVC burden,the width of PVC complex,coupling interval,index of PVC coupling in-terval(PVC coupling interval ÷sinus RR cycle ×1 00%),TpR interval of PVC(the duration from si-nus T peak before PVC to the starting point of PVC)and TpR index of PVC(TpR interval of PVC ÷sinus TpR interval ×1 00%).The relationship between the above measured parameters and arrhyth-mic symptoms was analyzed.Results In the symptomatic group,the index of PVC coupling inter-val,TpR interval of PVC and TpR index of PVC were significantly higher than those in the asympto-matic group(P <0.05).However,there was no statistically significant difference of PVC burden, origin of PVC or other ECG parameters between the two groups.Spearman correlation analysis showed that PVC-related symptoms were significantly positively correlated with the index of PVC coupling interval(r =0.324,P <0.05),TpR interval of PVC(r =0.272,P <0.05)and TpR in-dex of PVC(r =0.457,P <0.05).Conclusion PVC-related symptoms are associated with higher index of PVC coupling interval and TpR index for patients with outflow tract PVC.Those symptoms are related to the delayed emergence of PVC,which is helpful in the control of PVC clinically.%目的:分析流出道室早(premature ventricular contraction,PVC)患者心律失常症状与体表心电图特征的关系及其临床意义。方法将97例流出道室早患者根据有无心律失常症

  2. Research on the correlationship with the expression of MYC, PTEN, TP53 and esophageal carcinoma in Kazakh%MYC、PTEN和TP53表达与哈萨克族食管癌相关性研究

    Institute of Scientific and Technical Information of China (English)

    郭琼; 沙亚哈提·别尔克哈之; 李惠武

    2014-01-01

    [目的]检测MYC、PTEN、TP53在哈萨克族食管癌组织和远端无癌组织的表达,分析与临床病理因素的关系,探讨它们在哈萨克族食管癌发生发展中可能存在的关系.[方法] Trizol一步法获取组织标本总RNA,逆转录为cDNA,运用半定量RT-PCR技术检测食管癌组织、远端无癌组织中三个基因mRNA表达量及阳性表达率.[结果]①MYC mRNA表达量在食管癌组织中高于远端无癌组织(P <0.01);PTEN、TP53 mRNA表达量在远端无癌组织中高于癌组织(P <0.01,P<0.05);②MYC阳性表达率在食管癌组织中高于远端无癌组织(P<0.01);PTEN、TP53阳性表达率在远端无癌组织中高于癌组织(P <0.01,P<0.05));③MYC表达与分化程度(P<0.05)、TNM分期(P<0.05)、淋巴结转移(P<0.01)和侵犯深度(P<0.05)有关;PTEN表达与分化程度有关(P <0.05);TP53的表达与上述指标无关;④MYC和PTEN、TP53表达呈负相关(r=-0.494;r=-0.428);PTEN、TP53表达呈正相关(r=0.531).[结论]哈萨克族食管癌组织中MYC表达上调,PTEN、TP53低表达或不表达.上述结果说明MYC参与哈萨克族食管癌的发生和发展,PTEN、TP53则是阻止食管组织发生癌变的保护性基因.

  3. Identification of a novel TP53 germline mutation in one child with adrenocortical carcinoma%肾上腺皮质癌患儿TP53基因的一个新生殖系突变

    Institute of Scientific and Technical Information of China (English)

    司锘; 孙淼; 卢超霞; 刘彦山; 齐展; 杨威; 赵秀丽; 张学

    2009-01-01

    Objective To detect the germline TP53 gene mutation in a child with pediatric adrenocortical carcinoma (ADCC) in order to provide genetic diagnosis and counseling. Methods Genomic DNA was extracted from peripheral blood from a girl with ADCC and her parents. All TP53 exons and their flanking intronic sequences were PCR-amplified and subjected to automatic DNA sequencing. Results Direct sequencing of PCR products revealed a heterozygous G insertion between nucleotide 522 and 523 (c.522-523insG) in TP53 exon 5. This novel mutation is predicted to result in a frame shift at codon 175, producing a new reading frame ending in a stop at position 6 (p.R175AfsX6). The same heterozygous mutation was also found in her father, but not in her mother. Conclusion A novel germline mutation in the TP53 gene has been identified in one case with pediatric ADCC.%目的 研究1例肾上腺皮质癌患儿TP53基因突变情况,为该病的基因诊断与遗传咨询提供依据.方法 提取1例肾上腺皮质癌患儿及父母外周血基因组DNA,针对TP53基因设计特异性引物,采用聚合酶链式反应(PCR)扩增基因的全部编码及侧翼序列,对扩增产物进行直接测序.结果 PCR结合DNA测序发现患者TP53基因第5外显子存在异常:第522与523位核苷酸间插入一个鸟嘌呤(c.522-523insG),导致P53蛋白DNA结合域第175位密码子由精氨酸(R)变为丙氨酸(A),并从突变位置起发生移码,产生移码突变(p.R175AfsX6).患者父亲带有相同的突变,而母亲未发现此突变.结论 TP53基因p.R175AfsX6生殖系突变是导致该例患者肾上腺皮质癌的特异突变.

  4. Rotameric transformations in the photochemistry of TpM(CO)2(η(3)-C3H4R), where Tp = tris(pyrazolyl)borate, M = Mo or W, and R = H or Me.

    Science.gov (United States)

    Thornley, Wyatt A; Bitterwolf, Thomas E

    2015-05-01

    Low energy photolysis of TpM(CO)2(η(3)-C3H4R), where Tp = tris(pyrazolyl)borate, M = Mo or W, and R = 2-H or 2-Me in PVC matrices at 85 K results in exo/gauche isomerism of the allyl ligand. This transformation comes in contrast to the behaviour observed in cyclopentadienyl analogues which undergo exo/endo isomerism. DFT computations reveal an η(3) → η(1)* → η(3) mechanism for the allyl rotameric interconversion where the η(1)*-allyl intermediate is generated upon MLCT excitation.

  5. Feline and canine coronaviruses are released from the basolateral side of polarized epithelial LLC-PK1 cells expressing the recombinant feline aminopeptidase-N cDNA

    NARCIS (Netherlands)

    Rossen, J W; Kouame, J; Goedheer, A J; Vennema, H; Rottier, P J

    2001-01-01

    In this study feline (FECV and FIPV) and canine (CCoV) coronavirus entry into and release from polarized porcine epithelial LLC-PK1 cells, stably expressing the recombinant feline aminopeptidase-N cDNA, were investigated. Virus entry appeared to occur preferentially through the apical membrane, simi

  6. The distribution of radioactivity in brains of rats given (N-methyl- sup 11 C)PK 11195 in vivo after induction of a cortical ischaemic lesion

    Energy Technology Data Exchange (ETDEWEB)

    Cremer, J.E.; Hume, S.P.; Cullen, B.M.; Myers, R.; Manjil, L.G.; Turton, D.R.; Luthra, S.K.; Bateman, D.M.; Pike, V.W. (Hammersmith Hospital, London (United Kingdom). M.R.C. Cyclotron Unit)

    1992-02-01

    PK 11195 is a selective ligand for the peripheral-type benzodiazepine bindings site (PTBBS). There are few sites in normal brain but their number increases in association with tissue necrosis. The time-course of appearance of PTBBS around a focally induced ischaemic lesion in frontal cortex of rat brain was established by autoradiography using (N-methyl-{sup 3} H )PK 11195. Using this information and the same experimental model of ischaemia, the distribution of radioactivity after injection of carbon-11 labelled PK 11195 was studied. The purpose was to synthesize (N-methyl-{sup 11}C)PK 11195 and to test its suitability as a tracer for depicting the presence of PTBB in ischaemic lesions. The time-profiles of distribution of radioactivity in brain regions after intravenous injection of tracer and the ratio of radioactivity in lesioned compared with unlesioned cortex were determined. Data for the temporal (days after lesion induction) and for the regional retention of radioactivity were consistent with independent evidence (autoradiographic and immunohistochemical) for the occurence of increased numbers of PTBBS, predominantly in association with macrophages, in areas undergoing necrosis. (Author).

  7. Assessment of neuroinflammation and microglial activation in Alzheimer's disease with radiolabelled PK11195 and single photon emission computed tomography - A Pilot Study

    NARCIS (Netherlands)

    Versijpt, JJ; Dumont, F; Van Laere, KJ; Decoo, D; Santens, P; Audenaert, K; Achten, E; Slegers, G; Dierckx, RA; Korf, J

    2003-01-01

    Objectives: Inflammation contributes to degeneration in Alzheimer's disease (AD), not simply as a secondary phenomenon, but primarily as a significant source of pathology. [I-123]iodo-PK11195 is a single photon emission computed tomography (SPECT) ligand for the peripheral benzodiazepine receptor, t

  8. Search for K-p→π0π0π0Λ from threshold to pK-=750 MeV/c

    Science.gov (United States)

    Borgh, M.; Prakhov, S.; Nefkens, B. M.; Allgower, C. E.; Bekrenev, V.; Briscoe, W. J.; Clajus, M.; Comfort, J. R.; Craig, K.; Grosnick, D.; Isenhower, D.; Knecht, N.; Koetke, D.; Koulbardis, A.; Kozlenko, N.; Kruglov, S.; Lolos, G.; Lopatin, I.; Manley, D. M.; Manweiler, R.; Marušić, A.; McDonald, S.; Olmsted, J.; Papandreou, Z.; Peaslee, D.; Phaisangittisakul, N.; Price, J. W.; Ramirez, A. F.; Sadler, M.; Shafi, A.; Spinka, H.; Stanislaus, T. D.; Starostin, A.; Staudenmaier, H. M.; Supek, I.; Tippens, W. B.

    2003-07-01

    The results of a search for K-p→π0π0π0Λ (where the 3π0’s are not from η-meson decay) are presented. The data were obtained with the Crystal Ball spectrometer at eight beam momenta from 514 to 750 MeV/c. For the six beam momenta below pK-=714 MeV/c, no signal was found; the 90% C.L. upper limit obtained for the K-p→3π0Λ total cross section σt varies between 2 and 7 μb. This small upper limit is indicative that spontaneous π0 emission is insignificant, since the K-p→π0π0π0Λ threshold is at pK-=397 MeV/c. A signal was observed only at pK-=750 MeV/c, with σt=25±7 μb. These results can be explained only if triple π0 production goes predominantly by hyperon resonance deexcitation, K-p→Σ*→π0Λ*. There are several candidates for the Σ* but only one for the Λ*, namely, the Λ(1520)3/2-, as the threshold for K-p→π0Λ(1520) is at pK-=704 MeV/c.

  9. What We Stand "For", Not "Against": Presenting Our Teacher Education Colleagues with the Case for Social Foundations in PK-12 Teacher Preparation Programs

    Science.gov (United States)

    Hartlep, Nicholas D.; Porfilio, Bradley J.; Otto, Stacy; O'Brien, Kathleen

    2015-01-01

    Social Foundations of Education (SFE) courses play a critical role in preparing professional, effective PK-12 teachers, yet, for reasons argued in this article and elsewhere, such courses remain under attack. In this article, by arguing what SFE "stands for" as opposed to what it "stands against," the authors intend to…

  10. Pharmacokinetic analysis of [11C]PBR28 in the rat model of herpes encephalitis: comparison with (R)-[11C]PK11195 for pre-clinical imaging

    NARCIS (Netherlands)

    Kopschina Feltes, Paula; Parente, Andrea; Vállez Garcia, David; Sijbesma, Jurgen; Moriguchi Jeckel, Cristina; Dierckx, Rudi; de Vries, Erik; Doorduin, Janine

    2015-01-01

    Aim: [11C]PBR28 is a second generation translocator protein (TSPO) ligand with supposedly better imaging characteristics than the most commonly used tracer [11C]PK11195. Surprisingly, only limited studies have evaluated the pharmacokinetic and binding profile of [11C]PBR28 in neuroinflammatory model

  11. Pharmacokinetic analysis of 11C-PBR28 in the rat model of herpes encephalitis (HSE): comparison with (R)-11C-PK11195

    NARCIS (Netherlands)

    Parente, Andrea; Kopschina Feltes, Paula; Vállez Garcia, David; Sijbesma, Jurgen; Moriguchi Jeckel, Cristina M; Dierckx, Rudi; de Vries, Erik F; Doorduin, Janine

    2016-01-01

    11C-PBR28 is a second generation TSPO tracer with supposedly superior characteristics than the most commonly used tracer for neuroinflammation, (R)-11C-PK11195. Despite its use in clinical research, no studies on the imaging properties and pharmacokinetic analysis of 11C-PBR28 in rodent models of ne

  12. Evaluation of FlaB1, FlaB2, FlaB3, and Tp0463 of Treponema pallidum for serodiagnosis of syphilis.

    Science.gov (United States)

    Jiang, Chuanhao; Xiao, Jinhong; Xie, Yafeng; Xiao, Yongjian; Wang, Chuan; Kuang, Xingxing; Xu, Man; Li, Ranhui; Zeng, Tiebing; Liu, Shuanquan; Yu, Jian; Zhao, Feijun; Wu, Yimou

    2016-02-01

    Syphilis is a multistage disease caused by the invasive spirochete Treponema pallidum subsp. pallidum, and accurate diagnosis is important for the prevention and treatment of syphilis. Here, to identify appropriate diagnostic antigens for serodiagnosis of syphilis, 6 recombinant proteins were expressed in Escherichia coli and purified, including flagellins (FlaB1 [Tp0868], FlaB2 [Tp0792], and FlaB3 [Tp0870]), Tp0463, Tp0751, and Tp1038. The sensitivities were determined by screening sera from individuals with primary (n=82), secondary (n=115), latent (n=105), and congenital (n=65) syphilis. The specificities were determined by screening sera from uninfected controls (n=30) and potentially cross-reactive infections including Lyme disease (n=30), leptospirosis (n=5), and hepatitis B (n=30). Our data showed that FlaB1, FlaB2, FlaB3, Tp0463, and Tp1038 exhibited higher overall sensitivities and specificities for detecting IgG antibody, with 95.4% and 98.9%, 92.6% and 95.8%, 95.1% and 95.8%, 92.6% and 97.9%, and 95.9% and 98.9%, respectively. In contrast, Tp0751 demonstrated only an overall sensitivity of 39.2%. For comparison, the sensitivity and specificity of Architect Syphilis TP were determined to be 98.1% and 93.7%, respectively. In addition, FlaB1, FlaB2, FlaB3, and Tp0463 demonstrated excellent performance for detecting IgM antibody in primary and congenital syphilis, with sensitivities of 76.8% and 83.1%, 72.0% and 87.7%, 74.4% and 89.2%, and 64.6% and 75.3%, respectively. These results indicate that FlaB1, FlaB2, FlaB3, and Tp0463 could be as novel diagnostic candidates for serodiagnosis of syphilis.

  13. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome.

    Science.gov (United States)

    Rücker, Frank G; Schlenk, Richard F; Bullinger, Lars; Kayser, Sabine; Teleanu, Veronica; Kett, Helena; Habdank, Marianne; Kugler, Carla-Maria; Holzmann, Karlheinz; Gaidzik, Verena I; Paschka, Peter; Held, Gerhard; von Lilienfeld-Toal, Marie; Lübbert, Michael; Fröhling, Stefan; Zenz, Thorsten; Krauter, Jürgen; Schlegelberger, Brigitte; Ganser, Arnold; Lichter, Peter; Döhner, Konstanze; Döhner, Hartmut

    2012-03-01

    To assess the frequency of TP53 alterations and their correlation with other genetic changes and outcome in acute myeloid leukemia with complex karyotype (CK-AML), we performed integrative analysis using TP53 mutational screening and array-based genomic profiling in 234 CK-AMLs. TP53 mutations were found in 141 of 234 (60%) and TP53 losses were identified in 94 of 234 (40%) CK-AMLs; in total, 164 of 234 (70%) cases had TP53 alterations. TP53-altered CK-AML were characterized by a higher degree of genomic complexity (aberrations per case, 14.30 vs 6.16; P number alterations, such as -5/5q-, -7/7q-, -16/16q-, -18/18q-, +1/+1p, and +11/+11q/amp11q13∼25; among CK-AMLs, TP53-altered more frequently exhibited a monosomal karyotype (MK). Patients with TP53 alterations were older and had significantly lower complete remission rates, inferior event-free, relapse-free, and overall survival. In multivariable analysis for overall survival, TP53 alterations, white blood cell counts, and age were the only significant factors. In conclusion, TP53 is the most frequently known altered gene in CK-AML. TP53 alterations are associated with older age, genomic complexity, specific DNA copy number alterations, MK, and dismal outcome. In multivariable analysis, TP53 alteration is the most important prognostic factor in CK-AML, outweighing all other variables, including the MK category.

  14. Steam oxidation of TP 347H FG. Laboratory exposures versus service conditions at the power plant

    Energy Technology Data Exchange (ETDEWEB)

    Hansson, Anette N. [DONG Energy A/S, Copenhagen (Denmark); Montgomery, Melanie [DONG Energy A/S, Copenhagen (Denmark); Technical Univ. of Denmark, Lyngby (Denmark). Dept. of Mechanical Engineering; Vattenfall Heat Nordic, Copenhagen (Denmark)

    2010-07-01

    TP347H FG is often used as final superheater tubing at Danish Power Plants. The oxidation behaviour of TP347H FG in steam was investigated both in laboratory conditions and field conditions. Short time exposures (336 hours) were performed in the laboratory at 500, 600 and 700 C in gasses with 8 or 46% H{sub 2}O and varying oxygen partial pressures. The shortest exposure time at the power plant was 7720 h, the temperature varied between 500 and 650 C. Surprisingly, thicker oxide layers formed within the laboratory facility at 600 and 700 C than during the long time exposures at the power plant. This could not be explained by spallation. Double-layered oxides developed during oxidation. The outer layer consist of Fe-oxides and the inner oxide contained Fe and the remaining alloy elements. Investigations with scanning electron microscopy (SEM) revealed that the morphology of the inner oxide was different for the two types of exposures. However, investigation using transmission electron microscopy (TEM) showed that the inner oxide in both cases consisted of particles of Fe-Mn-Cr spinel embedded in a metallic Fe-Ni matrix in the bulk of the (former) alloy grains and Cr-rich oxide layer along the (former) alloy grain boundaries. The main difference between the layers formed at the two locations is that the Cr-rich oxide layer is thicker for the samples exposed at the power plant than that for the samples exposed at the laboratory conditions. Furthermore, the depth of Cr depletion in the alloy adjacent the oxide layer is greater for the samples exposed at the power plant compared to those exposed in the laboratory. The microstructure investigation suggests that the slower oxidation rate of TP347H FG at the power plant as compared to the laboratory is due to a larger reservoir of Cr for the samples exposed at the power plant probably combined with a higher mobility of Cr within the alloy. (orig.)

  15. Concordant and opposite roles of DNA-PK and the "facilitator of chromatin transcription" (FACT in DNA repair, apoptosis and necrosis after cisplatin

    Directory of Open Access Journals (Sweden)

    Calkins Anne S

    2011-06-01

    Full Text Available Abstract Background Platinum-containing chemotherapy produces specific DNA damage and is used to treat several human solid tumors. Tumors initially sensitive to platinum-based drugs frequently become resistant. Inhibition of DNA repair is a potential strategy to enhance cisplatin effectiveness. After cisplatin treatment, a balance between repair and apoptosis determines whether cancer cells proliferate or die. DNA-dependent protein kinase (DNA-PK binds to DNA double strand breaks (DSBs through its Ku subunits and initiates non-homologous end joining. Inhibition of DNA-PK sensitizes cancer cells to cisplatin killing. The goal of this study is to elucidate the mechanism underlying the effects of DNA-PK on cisplatin sensitivity. Results Silencing the expression of the catalytic subunit of DNA-PK (DNA-PKcs increased sensitivity to cisplatin and decreased the appearance of γH2AX after cisplatin treatment. We purified DNA-PK by its Ku86 subunit and identified interactors by tandem mass spectrometry before and after cisplatin treatment. The structure specific recognition protein 1 (SSRP1, Spt16 and γH2AX appeared in the Ku86 complex 5 hours after cisplatin treatment. SSRP1 and Spt16 form the facilitator of chromatin transcription (FACT. The cisplatin-induced association of FACT with Ku86 and γH2AX was abrogated by DNase treatment. In living cells, SSRP1 and Ku86 were recruited at sites of DSBs induced by laser beams. Silencing SSRP1 expression increased sensitivity to cisplatin and decreased γH2AX appearance. However, while silencing SSRP1 in cisplatin-treated cells increased both apoptosis and necrosis, DNA-PKcs silencing, in contrast, favored necrosis over apoptosis. Conclusions DNA-PK and FACT both play roles in DNA repair. Therefore both are putative targets for therapeutic inhibition. Since DNA-PK regulates apoptosis, silencing DNA-PKcs redirects cells treated with cisplatin toward necrosis. Silencing FACT however, allows both apoptosis and

  16. Evaluation of different confirmatory algorithms using seven treponemal tests on Architect Syphilis TP-positive/RPR-negative sera.

    Science.gov (United States)

    Jonckheere, S; Berth, M; Van Esbroeck, M; Blomme, S; Lagrou, K; Padalko, E

    2015-10-01

    The Architect Syphilis TP is considered to be a suitable screening test due to its high sensitivity and full automation. According to the International Union against Sexually Transmitted Infections (IUSTI) 2014 guidelines, however, positive screening tests need confirmation with Treponema pallidum particle agglutination (TP.PA). Among Architect-positive results, samples with a negative non-treponemal test present the major diagnostic challenge. In this multicenter study, we investigated if other, preferable less labor-intensive treponemal tests could replace TP.PA. A total of 178 rapid plasma reagin (RPR)-negative sera with an Architect value between 1 and 15 S/CO were prospectively selected in three centers. These sera were analyzed with TP.PA and six alternative treponemal tests: three immunoblots and three tests on random-access analyzers. The diagnostic performance of the treponemal tests differed substantially, with the overall agreement between the six alternative tests ranging from 44.6 to 82.0%. Based on TP.PA as the gold standard, the INNO-LIA IgG blot, the BioPlex 2200 IgG, and the Syphilis TPA showed a high sensitivity, while the EUROLINE-WB IgG blot, recomLine Treponema IgG blot, and the Chorus Syphilis screen showed a high specificity. However, an Architect cut-off of 5.6 S/CO can serve as an alternative for these confirmatory treponemal tests in case of an RPR-negative result. Treponemal tests show poor agreement in this challenging group of Architect-positive/RPR-negative sera. The most optimal algorithm is obtained by assigning sera with an Architect value >5.6 S/CO as true-positives and sera with a value between 1 and 5.6 S/CO as undetermined, requiring further testing with TP.PA.

  17. Cytogenetic comparison of restorers TP-4 and Dminghui63 with maintainer D46B of autotetraploid rice

    Institute of Scientific and Technical Information of China (English)

    Wenbo LONG; Li LUAN; Xing WANG; Yuhua LIU; Shengbin TU; Fanlun KONG; Tao HE

    2008-01-01

    Cytogenetical comparison was made between high seed setting restorers TP-4 and Dminghui63 with eminent maintainer line D46B of autotetraploid rice. The meiosis observation demonstrated that the genomes of our autotetraploid materials were all 2n = 48, which was the same as those in mitosis observation. Low percentages of univalent and trivalent in diakinesis-metaphase I (MI) of restorers TP-4 and Dminghui63 as well as maintainer line D46B of autotetraploid rice were observed. And the percent-ages of chromosome pairing were all over 99%, showing eminent cytological character. The frequency of TP-4 and Dminghui63 in diakinesis-metaphase I was 2.00/PMC (pollen mother cell) and 2.26/PMC, respectively. However, the frequency of D46B was 6.00/PMC, significantly higher than those of TP-4 and Dminghui63. It indicated that the maintainer D46B had better chromosome pairing capability in diakinesis-metaphase. While, the frequency of lagging chromosomes of the maintainer D46B in anaphase I (AI) was 10.62%, significantly lower than that of TP-4 (19.44%) or Dminghui63 (23.14%), and close to the level of diploid con-trol (7.30%). In telophase I (TI), maintainer D46B exhibited lower frequency of microkernel, and in telophase Ⅱ (TII) the frequency of normal quartered microspore of maintainer D46B was not only higher than that of TP-4 or Dminghui63 but also than that of diploid control. The percentage of the cell observed chromosome lagging in AI and the percentage of abnormal cell in TI showed a greatly significant positive cor-relation. That may demonstrate that chromosome separation in AI and microkernel formation in TI are controlled by the same dominant single gene or the major gene of a QTL.

  18. Association between TP53 gene Arg72Pro polymorphism and Wilms' tumor risk in a Chinese population.

    Science.gov (United States)

    Fu, Wen; Zhuo, Zhen-Jian; Jia, Wei; Zhu, Jinhong; Zhu, Shi-Bo; Lin, Ze-Feng; Wang, Feng-Hua; Xia, Huimin; He, Jing; Liu, Guo-Chang

    2017-01-01

    Wilms' tumor is one of the most prevalent pediatric malignancies, ranking fourth in childhood cancer worldwide. TP53 is a critical tumor suppressor gene, which encodes a 53 kDa protein, p53. The p53 functions to protect against cancer by regulating cell cycle and apoptosis and maintaining DNA integrity. TP53 gene is highly polymorphic. Several TP53 gene polymorphisms have been considered to be associated with cancer risk. Of them, a nonsynonymous polymorphism, Arg72Pro (rs1042522 C>G), has been most extensively studied for the association with cancer risk; however, few studies have investigated its effect on Wilms' tumor. Because of the central role of p53 in cell cycle control, the TP53 gene Arg72Pro polymorphism is also a good potential candidate predisposition locus for this pediatric cancer. We genotyped this polymorphism in 145 patients and 531 cancer-free controls recruited from Chinese children by Taqman methodology. Overall, our result suggested a lack of association between the TP53 gene Arg72Pro polymorphism and Wilms' tumor. In the stratified analysis, we found that carriers of CG/GG genotypes had a significantly increased Wilms' tumor risk in children not older than 18 months (adjusted odds ratio =2.04, 95% confidence interval =1.003-4.13, P=0.049) compared with CC genotype carriers. Our study indicated that the TP53 gene Arg72Pro polymorphism may have a weak, age-related effect on Wilms' tumor risk in Chinese children. These findings need further validations in other populations with larger sample size.

  19. Association between TP53 gene Arg72Pro polymorphism and Wilms’ tumor risk in a Chinese population

    Science.gov (United States)

    Fu, Wen; Zhuo, Zhen-Jian; Jia, Wei; Zhu, Jinhong; Zhu, Shi-Bo; Lin, Ze-Feng; Wang, Feng-Hua; Xia, Huimin; He, Jing; Liu, Guo-Chang

    2017-01-01

    Wilms’ tumor is one of the most prevalent pediatric malignancies, ranking fourth in childhood cancer worldwide. TP53 is a critical tumor suppressor gene, which encodes a 53 kDa protein, p53. The p53 functions to protect against cancer by regulating cell cycle and apoptosis and maintaining DNA integrity. TP53 gene is highly polymorphic. Several TP53 gene polymorphisms have b