Science.gov

Sample records for maarja pik mari

  1. Marie

    NASA Image and Video Library

    2003-02-03

    Marie Curie rover drives down the rear ramp during Operational Readiness Test ORT 4. NASA Pathfinder, a low-cost Discovery mission, is the first of a new fleet of spacecraft that are planned to explore Mars.

  2. Marie

    NASA Image and Video Library

    2003-02-03

    Marie Curie sits on the lander petal prior to deployment during the pre-launch Operations Readiness Test ORT 6. NASA Pathfinder, a low-cost Discovery mission, is the first of a new fleet of spacecraft that are planned to explore Mars.

  3. PIK-20 Aircraft in Flight

    NASA Technical Reports Server (NTRS)

    1991-01-01

    This photo shows NASA's PIK-20E motor-glider sailplane during a research flight from the Ames-Dryden Flight Research Facility (later, the Dryden Flight Research Center), Edwards, California, in 1991. The PIK-20E was a sailplane flown at NASA's Ames-Dryden Flight Research Facility (now Dryden Flight Research Center, Edwards, California) beginning in 1981. The vehicle, bearing NASA tail number 803, was used as a research vehicle on projects calling for high lift-over-drag and low-speed performance. Later NASA used the PIK-20E to study the flow of fluids over the aircraft's surface at various speeds and angles of attack as part of a study of airflow efficiency over lifting surfaces. The single-seat aircraft was used to begin developing procedures for collecting sailplane glide performance data in a program carried out by Ames-Dryden. It was also used to study high-lift aerodynamics and laminar flow on high-lift airfoils. Built by Eiri-Avion in Finland, the PIK-20E is a sailplane with a two-cylinder 43-horsepower, retractable engine. It is made of carbon fiber with sandwich construction. In this unique configuration, it takes off and climbs to altitude on its own. After reaching the desired altitude, the engine is shut down and folded back into the fuselage and the aircraft is then operated as a conventional sailplane. Construction of the PIK-20E series was rather unusual. The factory used high-temperature epoxies cured in an autoclave, making the structure resistant to deformation with age. Unlike today's normal practice of laying glass over gelcoat in a mold, the PIK-20E was built without gelcoat. The finish is the result of smooth glass lay-up, a small amount of filler, and an acrylic enamel paint. The sailplane was 21.4 feet long and had a wingspan of 49.2 feet. It featured a wooden, fixed-pitch propeller, a roomy cockpit, wingtip wheels, and a steerable tailwheel.

  4. Carcinogenesis of PIK3CA

    PubMed Central

    2013-01-01

    PIK3CA is the most frequently mutated oncogene in human cancers. PIK3CA is phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha. It controls cell growth, proliferation, motility, survival, differentiation and intracellular trafficking. In most of human cancer alteration occurred frequently in the alpha isoform of phosphatidylinositol 3 kinase. PIK3CA mutations were most frequent in endometrial, ovarian, colorectal, breast, cervical, squamous cell cancer of the head and neck, chondroma, thyroid carcinoma and in cancer family syndrome. Inhibition of PI3K signaling can diminish cell proliferation, and in some circumstances, promote cell death. Consequently, components of this pathway present attractive targets for cancer therapeutics. A number of PI3K pathway inhibitors have been developed and used. PI3K inhibitors (both pan-PI3K and isoform-specific PI3K inhibitors), dual PI3K-mTOR inhibitors that are catalytic site inhibitors of the p110 isoforms and mTOR (the kinase component of both mTORC1 and mTORC2), mTOR catalytic site inhibitors, and AKT inhibitors are the most advanced in the clinic. They are approved for the treatment of several carcinomas. PMID:23768168

  5. Arms race co-evolution of Magnaporthe oryzae AVR-Pik and rice Pik genes driven by their physical interactions.

    PubMed

    Kanzaki, Hiroyuki; Yoshida, Kentaro; Saitoh, Hiromasa; Fujisaki, Koki; Hirabuchi, Akiko; Alaux, Ludovic; Fournier, Elisabeth; Tharreau, Didier; Terauchi, Ryohei

    2012-12-01

    Attack and counter-attack impose strong reciprocal selection on pathogens and hosts, leading to development of arms race evolutionary dynamics. Here we show that Magnaporthe oryzae avirulence gene AVR-Pik and the cognate rice resistance (R) gene Pik are highly variable, with multiple alleles in which DNA replacements cause amino acid changes. There is tight recognition specificity of the AVR-Pik alleles by the various Pik alleles. We found that AVR-Pik physically binds the N-terminal coiled-coil domain of Pik in a yeast two-hybrid assay as well as in an in planta co-immunoprecipitation assay. This binding specificity correlates with the recognition specificity between AVR and R genes. We propose that AVR-Pik and Pik are locked into arms race co-evolution driven by their direct physical interactions. © 2012 The Authors. The Plant Journal © 2012 Blackwell Publishing Ltd.

  6. PIK3CA mutant tumors depend on oxoglutarate dehydrogenase.

    PubMed

    Ilic, Nina; Birsoy, Kıvanç; Aguirre, Andrew J; Kory, Nora; Pacold, Michael E; Singh, Shambhavi; Moody, Susan E; DeAngelo, Joseph D; Spardy, Nicole A; Freinkman, Elizaveta; Weir, Barbara A; Tsherniak, Aviad; Cowley, Glenn S; Root, David E; Asara, John M; Vazquez, Francisca; Widlund, Hans R; Sabatini, David M; Hahn, William C

    2017-04-25

    Oncogenic PIK3CA mutations are found in a significant fraction of human cancers, but therapeutic inhibition of PI3K has only shown limited success in clinical trials. To understand how mutant PIK3CA contributes to cancer cell proliferation, we used genome scale loss-of-function screening in a large number of genomically annotated cancer cell lines. As expected, we found that PIK3CA mutant cancer cells require PIK3CA but also require the expression of the TCA cycle enzyme 2-oxoglutarate dehydrogenase (OGDH). To understand the relationship between oncogenic PIK3CA and OGDH function, we interrogated metabolic requirements and found an increased reliance on glucose metabolism to sustain PIK3CA mutant cell proliferation. Functional metabolic studies revealed that OGDH suppression increased levels of the metabolite 2-oxoglutarate (2OG). We found that this increase in 2OG levels, either by OGDH suppression or exogenous 2OG treatment, resulted in aspartate depletion that was specifically manifested as auxotrophy within PIK3CA mutant cells. Reduced levels of aspartate deregulated the malate-aspartate shuttle, which is important for cytoplasmic NAD(+) regeneration that sustains rapid glucose breakdown through glycolysis. Consequently, because PIK3CA mutant cells exhibit a profound reliance on glucose metabolism, malate-aspartate shuttle deregulation leads to a specific proliferative block due to the inability to maintain NAD(+)/NADH homeostasis. Together these observations define a precise metabolic vulnerability imposed by a recurrently mutated oncogene.

  7. Frequent PIK3CA-activating mutations in hidradenoma papilliferums.

    PubMed

    Liau, Jau-Yu; Lan, Jui; Hong, Jin-Bon; Tsai, Jia-Huei; Kuo, Kuan-Tin; Chu, Chia-Yu; Sheen, Yi-Shuan; Huang, Wen-Chang

    2016-09-01

    Hidradenoma papilliferum (HP) is a benign epithelial tumor most commonly seen in the vulva. It is proposed to be derived from the anogenital mammary-like glands and is histologically very similar to the mammary intraductal papilloma (IP). Approximately 60% of mammary IPs have activating mutations in either PIK3CA or AKT1, with each gene accounting for 30% of cases. In this study, we screened the mutation statuses of PIK3CA, AKT1, RAS, and BRAF in 30 HPs. The results showed that activating mutations in either PIK3CA or AKT1 were identified in 20 tumors (67%); 19 tumors had PIK3CA mutations (63%; 13 in exon 20 and 6 in exon 9), and 1 had an AKT1 E17K mutation (3%). BRAF V600E mutation was found in an HP that also had a PIK3CA H1047R mutation. No RAS mutation was found. The mutation status was not correlated with the degree of epithelial cell hyperplasia. We conclude that although there might be site-related variations in the mutation frequencies of PIK3CA and AKT1 genes, HP is histologically and also genetically very similar to the mammary IP, suggesting that HP can be viewed as the extramammary counterpart of mammary IP. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Development of a Heavy Water Detritiation Plant for PIK Reactor

    SciTech Connect

    Alekseev, I.A.; Bondarenko, S.D.; Fedorchenko, O.A.; Konoplev, K.A.; Vasyanina, T.V.; Arkhipov, E.A.; Uborsky, V.V

    2005-07-15

    The research reactor PIK should be supplied with a Detritiation Plant (DP) to remove tritium from heavy water in order to reduce operator radiation dose and tritium emissions. The original design of the reactor PIK Detritiation Plant was completed several years ago. A number of investigations have been made to obtain data for the DP design. Nowadays the design of the DP is being revised on a basis of our investigations. The Combined Electrolysis and Catalytic Exchange (CECE) process will be used at the Detritiation Plant instead of Vapor Phase Catalytic Exchange. The experimental industrial plant for hydrogen isotope separation on the basis of the CECE process is under operation in Petersburg Nuclear Physics Institute. The plant was updated to provide a means for heavy water detritiation. Very high detritiation factors have been achieved in the plant. The use of the CECE process will allow the development of a more compact and less expensive detritiation plant for heavy water reactor PIK.

  9. PIK3CA mutations in human solid tumors

    PubMed Central

    Ligresti, Giovanni; Militello, Loredana; Steelman, Linda S.; Cavallaro, Andrea; Basile, Francesco; Nicoletti, Ferdinando; Stivala, Franca; McCubrey, James A.; Libra, Massimo

    2009-01-01

    Phosphatidylinositol 3-kinases (PI3Ks) are a group of lipid kinases that regulate signaling pathways involved in cell proliferation, adhesion, survival and motility. The PI3K pathway is considered to play an important role in tumorigenesis. Activating mutations of the p110α subunit of PI3K (PIK3CA) have been identified in a broad spectrum of tumors. Analyses of PIK3CA mutations reveals that they increase the PI3K signal, stimulate downstream Akt signaling, promote growth factor-independent growth and increase cell invasion and metastasis. In this review, we analyze the contribution of the PIK3CA mutations in cancer, and their possible implications for diagnosis and therapy. PMID:19305151

  10. Öpik (Opik), Ernst Julius (1893-1985)

    NASA Astrophysics Data System (ADS)

    Murdin, P.

    2000-11-01

    Born in Estonia, Öpik studied at Moscow University, and helped establish Turkestan University in Tashkent, becoming the Astronomer (director) at Tartu Observatory in Estonia. He fled the Red Army by horse cart during the Second World War and went to Armagh Observatory (Northern Ireland) in 1948. His wide-ranging interests are reflected in his discoveries and theories. These include the discovery ...

  11. PIK-20 and LRV Vehicles Parked on Ramp

    NASA Technical Reports Server (NTRS)

    1981-01-01

    This photo shows NASA's PIK-20 motor-glider sailplane on the ramp at the Dryden Flight Research Center, Edwards, California. Next to the PIK-20 is the Low Reynolds Number Vehicle (LRV) remotely-piloted research vehicle. The PIK-20E was a sailplane flown at NASA's Ames-Dryden Flight Research Facility (now Dryden Flight Research Center, Edwards, California) beginning in 1981. The vehicle, bearing NASA tail number 803, was used as a research vehicle on projects calling for high lift-over-drag and low-speed performance. Later NASA used the PIK-20E to study the flow of fluids over the aircraft's surface at various speeds and angles of attack as part of a study of airflow efficiency over lifting surfaces. The single-seat aircraft was used to begin developing procedures for collecting sailplane glide performance data in a program carried out by Ames-Dryden. It was also used to study high-lift aerodynamics and laminar flow on high-lift airfoils. Built by Eiri-Avion in Finland, the PIK-20E is a sailplane with a two-cylinder 43-horsepower, retractable engine. It is made of carbon fiber with sandwich construction. In this unique configuration, it takes off and climbs to altitude on its own. After reaching the desired altitude, the engine is shut down and folded back into the fuselage and the aircraft is then operated as a conventional sailplane. Construction of the PIK-20E series was rather unusual. The factory used high-temperature epoxies cured in an autoclave, making the structure resistant to deformation with age. Unlike today's normal practice of laying glass over gelcoat in a mold, the PIK-20E was built without gelcoat. The finish is the result of smooth glass lay-up, a small amount of filler, and an acrylic enamel paint. The sailplane was 21.4 feet long and had a wingspan of 49.2 feet. It featured a wooden, fixed-pitch propeller, a roomy cockpit, wingtip wheels, and a steerable tailwheel.

  12. PIK3CA and AKT1 mutations in hidradenoma papilliferum.

    PubMed

    Goto, Keisuke; Maeda, Daichi; Kudo-Asabe, Yukitsugu; Hibiya, Takashi; Hayashi, Akimasa; Fukayama, Masashi; Ohashi, Kenichi; Goto, Akiteru

    2017-05-01

    Hidradenoma papilliferum (HP) is a benign vulvar neoplasm that arises from anogenital mammary-like glands, and its morphology is similar to mammary intraductal papilloma. The aim of this study was to investigate oncogenic mutations involved in the tumourigenesis of HP. We focused specifically on PIK3CA and AKT1 mutations, which are both reported to be detected in 33% of mammary intraductal papillomas. In total, seven HP cases were analysed. Clinicopathological analyses and immunohistochemistry for oestrogen receptor, p63, smooth muscle actin (SMA), p53 and β-catenin were performed. Furthermore, PIK3CA, AKT1, BRAF and KRAS hot spot mutations were examined by Sanger sequencing. Morphologically, all HPs had a papillary and tubular architecture with a biphasic pattern of epithelial and myoepithelial cells. Immunohistochemistry revealed that oestrogen receptor expression was restricted to epithelial cells, whereas p63 and SMA were exclusively expressed in myoepithelial cells. The patterns of p53 and β-catenin immunostaining suggested wild-type genotypes. Direct sequencing revealed the presence of somatic PIK3CA mutations (Ex9. c.1633G>A, p.E545K and Ex20. c.3140A>G, p.H1047R) in two of the HPs and an AKT1 (c.49G>A, p.E17K) mutation in one. BRAF and KRAS mutations were not found in any of the HP cases. PIK3CA and AKT1 are frequently mutated in HP tumours (29% and 14%, respectively). PIK3CA/AKT1 pathway alterations in HP further support the hypothesis that HP is the vulvar (anogenital mammary-like gland) analogue of breast intraductal papilloma. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  13. Prognostic Role of PIK3CA Mutation in Colorectal Cancer: Cohort Study and Literature Review

    PubMed Central

    Liao, Xiaoyun; Morikawa, Teppei; Lochhead, Paul; Imamura, Yu; Kuchiba, Aya; Yamauchi, Mai; Nosho, Katsuhiko; Qian, Zhi Rong; Nishihara, Reiko; Meyerhardt, Jeffrey A; Fuchs, Charles S; Ogino, Shuji

    2013-01-01

    Purpose Mutations in PIK3CA (the gene encoding the p110α catalytic subunit of phosphatidylinositide-3-kinase, PI3K) play an important role in colorectal carcinogenesis. Experimental evidence suggests that PIK3CA exon 9 and exon 20 mutations trigger different biological effects, and that concomitant mutations in both exons 9 and 20 synergistically enhance tumorigenic effects. Thus, we hypothesized that PIK3CA exon 9 and exon 20 mutations might have differential effects on clinical outcome in colorectal cancer, and that concomitant PIK3CA exon 9 and 20 mutations might confer aggressive tumor behavior. Experimental Design We sequenced PIK3CA by pyrosequencing in 1170 rectal and colon cancers in two prospective cohort studies, and found 189 (16%) PIK3CA-mutated tumors. Mortality hazard ratio (HR) according to PIK3CA status was computed using Cox proportional hazards model, adjusting for clinical and molecular features including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, and BRAF and KRAS mutations. Results Compared to PIK3CA wild-type cases, patients with concomitant PIK3CA mutations in exons 9 and 20 experienced significantly worse cancer-specific survival [log-rank P=0.031; multivariate HR=3.51; 95% confidence interval (CI), 1.28–9.62] and overall survival (log-rank P=0.0008 ; multivariate HR=2.68; 95% CI, 1.24–5.77). PIK3CA mutation in either exon 9 or 20 alone was not significantly associated with patient survival. No significant interaction of PIK3CA mutation with BRAF or KRAS mutation was observed in survival analysis. Conclusion Co-existence of PIK3CA (the PI3K p110α subunit) exon 9 and 20 mutations, but not PIK3CA mutation in either exon 9 or 20 alone, is associated with poor prognosis of colorectal cancer patients. PMID:22357840

  14. piK Scattering in Three Flavour ChPT

    NASA Astrophysics Data System (ADS)

    Bijnens, Johan; Dhonte, Pierre; Talavera, Pere

    2004-05-01

    We present the scattering lengths for the piK processes in the three flavour Chiral Perturbation Theory (ChPT) framework at next-to-next-to-leading order (NNLO). The calculation has been performed analytically but we only include analytical results for the dependence on the low-energy constants (LECs) at NNLO due to the size of the expressions. These results, together with resonance estimates of the NNLO LECs are used to obtain constraints on the Zweig rule suppressed LECs at NLO, L4r and L6r. Contrary to expectations from NLO order calculations we find them to be compatible with zero. We do a preliminary study of combining the results from pipi scattering, piK scattering and the scalar form-factors and find only a marginal compatibility with all experimental/dispersive input data.

  15. Jean-Marie Straub.

    ERIC Educational Resources Information Center

    Roud, Richard

    This book covers the life and aesthetic qualities of the work of the European film-maker Jean-Marie Straub (1933- ). It contains introductory chapters on the biography and artistic milieu of Straub and continues with a chapter-by-chapter critical treatment of each of his films: "Machorka-Muff"; "Not Reconciled"; "Chronicle…

  16. Jean-Marie Straub.

    ERIC Educational Resources Information Center

    Roud, Richard

    This book covers the life and aesthetic qualities of the work of the European film-maker Jean-Marie Straub (1933- ). It contains introductory chapters on the biography and artistic milieu of Straub and continues with a chapter-by-chapter critical treatment of each of his films: "Machorka-Muff"; "Not Reconciled"; "Chronicle…

  17. MARI mini-manual

    NASA Astrophysics Data System (ADS)

    Bennington, S. M.; Eccleston, R. S.

    1994-09-01

    The MARI spectrometer is funded by the Japanese Ministry of Education, Culture and Science (Monbusho) as part of the UK-Japan collaboration in neutron scattering. MARI is a direct geometry chopper spectrometer. It uses a Fermi chopper to monochromatic the incident neutron beam to give incident energies in the range 10 to 2000 meV. It is very similar in design to its sister machine HET, but with a detector bank that continuously covers the angular range from 3 to 135 degrees, MARI is able to map large regions of Q-E space in a single measurement. At present about 600 of the full complement of 1000 detectors are installed. All are 10 bar (3)He gas proportional counters and all come from the same manufacturer, this means that their efficiency and background are almost the same. The beam size at the sample position is 50 by 50 mm, but motorized jaws in the Fermi chopper pit and in the sample tank can be used to reduce this size. Chapter headings are the following: Introduction; The hardware on MARI; Controlling the Instrument; Data Analysis and Visualization; Appendices.

  18. Mutational profiling reveals PIK3CA mutations in gallbladder carcinoma

    PubMed Central

    2011-01-01

    Background The genetics of advanced biliary tract cancers (BTC), which encompass intra- and extra-hepatic cholangiocarcinomas as well as gallbladder carcinomas, are heterogeneous and remain to be fully defined. Methods To better characterize mutations in established known oncogenes and tumor suppressor genes we tested a mass spectrometric based platform to interrogate common cancer associated mutations across a panel of 77 formalin fixed paraffin embedded archived BTC cases. Results Mutations among three genes, KRAS, NRAS and PIK3CA were confirmed in this cohort. Activating mutations in PIK3CA were identified exclusively in GBC (4/32, 12.5%). KRAS mutations were identified in 3 (13%) intra-hepatic cholangiocarcinomas and 1 (33%) perihillar cholangiocarcinoma but were not identified in gallbladder carcinomas and extra-hepatic cholangiocarcinoma. Conclusions The presence of activating mutations in PIK3CA specifically in GBC has clinical implications in both the diagnosis of this cancer type, as well as the potential utility of targeted therapies such as PI3 kinase inhibitors. PMID:21303542

  19. Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer.

    PubMed

    Hao, Yujun; Samuels, Yardena; Li, Qingling; Krokowski, Dawid; Guan, Bo-Jhih; Wang, Chao; Jin, Zhicheng; Dong, Bohan; Cao, Bo; Feng, Xiujing; Xiang, Min; Xu, Claire; Fink, Stephen; Meropol, Neal J; Xu, Yan; Conlon, Ronald A; Markowitz, Sanford; Kinzler, Kenneth W; Velculescu, Victor E; Brunengraber, Henri; Willis, Joseph E; LaFramboise, Thomas; Hatzoglou, Maria; Zhang, Guo-Fang; Vogelstein, Bert; Wang, Zhenghe

    2016-06-20

    Cancer cells often require glutamine for growth, thereby distinguishing them from most normal cells. Here we show that PIK3CA mutations reprogram glutamine metabolism by upregulating glutamate pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells, making them more dependent on glutamine. Compared with isogenic wild-type (WT) cells, PIK3CA mutant CRCs convert substantially more glutamine to α-ketoglutarate to replenish the tricarboxylic acid cycle and generate ATP. Mutant p110α upregulates GPT2 gene expression through an AKT-independent, PDK1-RSK2-ATF4 signalling axis. Moreover, aminooxyacetate, which inhibits the enzymatic activity of aminotransferases including GPT2, suppresses xenograft tumour growth of CRCs with PIK3CA mutations, but not with WT PIK3CA. Together, these data establish oncogenic PIK3CA mutations as a cause of glutamine dependency in CRCs and suggest that targeting glutamine metabolism may be an effective approach to treat CRC patients harbouring PIK3CA mutations.

  20. Function and Interaction of the Coupled Genes Responsible for Pik-h Encoded Rice Blast Resistance

    PubMed Central

    Yao, Nan; Lin, Fei; Liu, Zhe; Dong, Zhongqiu; Wang, Ling; Pan, Qinghua

    2014-01-01

    Pik-h, an allele of Pik, confers resistance against the rice blast pathogen Magnaporthe oryzae. Its positional cloning has shown that it comprises a pair of NBS-LRR genes, Pikh-1 and Pikh-2. While Pikh-1 appears to be constitutively transcribed, the transcript abundance of Pikh-2 responds to pathogen challenge. The Pikh-1 CC (coiled coil) domain interacts directly with both AvrPik-h and Pikh-2. Transient expression assays demonstrated that Pikh-2 mediates the initiation of the host defence response. Nucleocytoplasmic partitioning of both Pikh-1 and Pikh-2 is required for their functionalities. In a proposed mechanistic model of Pik-h resistance, it is suggested that Pikh-1 acts as an adaptor between AvrPik-h and Pikh-2, while Pikh-2 transduces the signal to trigger Pik-h-specific resistance. PMID:24896089

  1. Prognostic implications of PIK3CA amplification in curatively resected liposarcoma

    PubMed Central

    Kim, Eo Jin; Park, Kyu Hyun; Kim, Ki Hyang; Yi, Seong Yoon; Kim, Han Seong; Cho, Yong Jin; Shin, Kyoo-Ho; Ahn, Joong Bae; Hu, Hyuk; Kim, Kyung Sik; Choi, Young Deuk; Kim, Sunghoon; Lee, Young Han; Suh, Jin-Suck; Noh, Sung Hoon; Rha, Sun Young; Kim, Hyo Song

    2016-01-01

    Background We investigated the epidemiologic characteristics and prognostic significance of PIK3CA mutations/amplifications in curative resected liposarcoma. Patients and methods A total of 125 liposarcoma tissue samples were collected over a 12-year period. PIK3CA mutations and gene copy number amplifications were analyzed by pyrosequencing and fluorescence in situ hybridization (FISH). Results Nine of the 105 liposarcomas (8.6%) had activating PIK3CA mutation. PIK3CA mutations were more frequent in myxoid/round cell and pleomorphic tumors compared with well-differentiated/dedifferentiated tumors (13.3% vs. 2.2%, P=0.043). In FISH PIK3CA analysis, copy number gain was detected in 14 of the 101 tumors (13.9%): 11 (10.9%) tumors had increased gene copy number (polysomy) and 3 (3.0%) exhibited gene amplification. In survival analysis, patients with PIK3CA copy number gain had a worse prognosis compared to patients without PIK3CA amplification (median disease-free survival [DFS] 22.2 vs. 107.6 months p=0.005). By multivariate analysis, PIK3CA copy number gain was an independent prognostic factor for worse DFS (P=0.027; hazard ratio, 2.400; 95% confidence interval 1.105 to 5.213). PIK3CA mutation was not associated with DFS and overall survival. Conclusions We demonstrated PIK3CA mutation and amplification in liposarcoma. PIK3CA copy number gain was an independent poor prognostic factor for DFS. Further studies are needed to evaluate the potential diagnostic and therapeutic role of PIK3CA mutations and amplifications in liposarcoma. PMID:27016421

  2. PIK3CA mutant tumors depend on oxoglutarate dehydrogenase | Office of Cancer Genomics

    Cancer.gov

    Oncogenic PIK3CA mutations are found in a significant fraction of human cancers, but therapeutic inhibition of PI3K has only shown limited success in clinical trials. To understand how mutant PIK3CA contributes to cancer cell proliferation, we used genome scale loss-of-function screening in a large number of genomically annotated cancer cell lines. As expected, we found that PIK3CA mutant cancer cells require PIK3CA but also require the expression of the TCA cycle enzyme 2-oxoglutarate dehydrogenase (OGDH).

  3. Predictive and Prognostic Analysis of PIK3CA Mutation in Stage III Colon Cancer Intergroup Trial

    PubMed Central

    Liao, Xiaoyun; Imamura, Yu; Yamauchi, Mai; McCleary, Nadine J.; Ng, Kimmie; Niedzwiecki, Donna; Saltz, Leonard B.; Mayer, Robert J.; Whittom, Renaud; Hantel, Alexander; Benson, Al B.; Mowat, Rex B.; Spiegelman, Donna; Goldberg, Richard M.; Bertagnolli, Monica M.; Meyerhardt, Jeffrey A.; Fuchs, Charles S.

    2013-01-01

    Background Somatic mutations in PIK3CA (phosphatidylinositol-4,5-bisphosphonate 3-kinase [PI3K], catalytic subunit alpha gene) activate the PI3K-AKT signaling pathway and contribute to pathogenesis of various malignancies, including colorectal cancer. Methods We examined associations of PIK3CA oncogene mutation with relapse, survival, and treatment efficacy in 627 stage III colon carcinoma case subjects within a randomized adjuvant chemotherapy trial (5-fluorouracil and leucovorin [FU/LV] vs irinotecan [CPT11], fluorouracil and leucovorin [IFL]; Cancer and Leukemia Group B 89803 [Alliance]). We detected PIK3CA mutation in exons 9 and 20 by polymerase chain reaction and pyrosequencing. Cox proportional hazards model was used to assess prognostic and predictive role of PIK3CA mutation, adjusting for clinical features and status of routine standard molecular pathology features, including KRAS and BRAF mutations and microsatellite instability (mismatch repair deficiency). All statistical tests were two-sided. Results Compared with PIK3CA wild-type cases, overall status of PIK3CA mutation positivity or the presence of PIK3CA mutation in either exon 9 or 20 alone was not statistically significantly associated with recurrence-free, disease-free, or overall survival (log-rank P > .70; P > .40 in multivariable regression models). There was no statistically significant interaction between PIK3CA and KRAS (or BRAF) mutation status in survival analysis (P interaction > .18). PIK3CA mutation status did not appear to predict better or worse response to IFL therapy compared with FU/LV therapy (P interaction > .16). Conclusions Overall tumor PIK3CA mutation status is not associated with stage III colon cancer prognosis. PIK3CA mutation does not appear to serve as a predictive tumor molecular biomarker for response to irinotecan-based adjuvant chemotherapy. PMID:24231454

  4. Pik3ip1 Modulates Cardiac Hypertrophy by Inhibiting PI3K Pathway

    PubMed Central

    Song, Hong Ki; Kim, Jiyeon; Lee, Jong Sub; Nho, Kyoung Jin; Jeong, Hae Chang; Kim, Jihwa; Ahn, Youngkeun; Park, Woo Jin; Kim, Do Han

    2015-01-01

    Cardiac hypertrophy is an adaptive response to various physiological and pathological stimuli. Phosphoinositide-3 kinase (PI3K) is a highly conserved lipid kinase involved in physiological cardiac hypertrophy (PHH). PI3K interacting protein1 (Pik3ip1) shares homology with the p85 regulatory subunit of PI3K and is known to interact with the p110 catalytic subunit of PI3K, leading to attenuation of PI3K activity in liver and immune cells. However, the role of Pik3ip1 in the heart remains unknown. In the present study, the effects of Pik3ip1 on cardiac hypertrophy were examined. We found that the expression level of Pik3ip1 was markedly higher in cardiomyocytes than in fibroblasts. The interaction of Pik3ip1 with the p110a subunit of PI3K in the heart was identified by immunoprecipitation using neonatal rat cardiomyocytes (NRCM). Approximately 35% knockdown of Pik3ip1 was sufficient to induce myocardial hypertrophy. Pik3ip1 deficiency was shown to lead to activation of PI3K/protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) signaling pathway, increasing protein synthesis and cell size. However, adenovirus-mediated overexpression of Pik3ip1 attenuated PI3K-mediated cardiac hypertrophy. Pik3ip1 was upregulated by PHH due to swimming training, but not by pathological cardiac hypertrophy (PAH) due to pressure-overload, suggesting that Pik3ip1 plays a compensatory negative role for PHH. Collectively, our results elucidate the mechanisms for the roles of Pik3ip1 in PI3K/AKT signaling pathway. PMID:25826393

  5. Area contingency plan Sault Ste. Marie. (COTP Sault Ste. Marie)

    SciTech Connect

    1995-06-01

    The Area Contingency Plan, mandated under the Oil Pollution Act, was developed by Sault Ste. Marie Area Committee, which is chaired by the U.S. Coast Guard and consists of local, state, federal, and private members. The plan prepares in advance for an oil or hazardous substance spill in the CTOP Sault Ste. Marie Coastal Zone.

  6. PIK3CA Mutation in Colorectal Cancer: Relationship with Genetic and Epigenetic Alterations1

    PubMed Central

    Nosho, Katsuhiko; Kawasaki, Takako; Ohnishi, Mutsuko; Suemoto, Yuko; Kirkner, Gregory J; Zepf, Dimity; Yan, Liying; Longtine, Janina A; Fuchs, Charles S; Ogino, Shuji

    2008-01-01

    Somatic PIK3CA mutations are often present in colorectal cancer. Mutant PIK3CA activates AKT signaling, which up-regulates fatty acid synthase (FASN). Microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) are important molecular classifiers in colorectal cancer. However, the relationship between PIK3CA mutation, MSI and CIMP remains uncertain. Using Pyrosequencing technology, we detected PIK3CA mutations in 91 (15%) of 590 population-based colorectal cancers. To determine CIMP status, we quantified DNA methylation in eight CIMP-specific promoters [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by real-time polymerase chain reaction (MethyLight). PIK3CA mutation was significantly associated with mucinous tumors [P = .0002; odds ratio (OR) = 2.44], KRAS mutation (P < .0001; OR = 2.68), CIMP-high (P = .03; OR = 2.08), phospho-ribosomal protein S6 expression (P = .002; OR = 2.19), and FASN expression (P = .02; OR = 1.85) and inversely with p53 expression (P = .01; OR = 0.54) and β-catenin (CTNNB1) alteration (P = .004; OR = 0.43). In addition, PIK3CA G-to-A mutations were associated with MGMT loss (P = .001; OR = 3.24) but not with MGMT promoter methylation. In conclusion, PIK3CA mutation is significantly associated with other key molecular events in colorectal cancer, and MGMT loss likely contributes to the development of PIK3CA G>A mutation. In addition, Pyrosequencing is useful in detecting PIK3CA mutation in archival paraffin tumor tissue. PIK3CA mutational data further emphasize heterogeneity of colorectal cancer at the molecular level. PMID:18516290

  7. Mary, dogma, and psychoanalysis.

    PubMed

    Todd, E H

    1985-06-01

    Why does Mary hold her prominent place in Catholic theology to the extent that five specific dogmas have developed around her? Psychoanalytic theory suggests dogma arises out of the psychic needs of people and psychic needs of people are expressed in dogma. The early views of Erich Fromm, a disciple of Freud, are presented to demonstrate that Marian dogma arose from the psychic needs of the people. The views of both Catholic and Protestant thinkers are presented, as well as theological and psychiatric views.

  8. AN ELECTRICAL HAIL MARY.

    PubMed

    Neubert, David

    2016-05-01

    Double sequential defibrillation is currently being employed in a number of EMS systems across the United States, including Wake County, N.C.; Fort Worth, Texas; and New Orleans. Even though there isn't a large body of literature surrounding this technique, it's been demonstrated successful in the electrophysiology lab, ED and prehospital settings. Since access to procainamide--another treatment for refractory v fib--is limited, this may be the only available option when faced with a patient who's failed standard ACLS defibrillation and medication administration. It's an intervention that has little chance to do harm, and it may represent the "hail Mary" pass to a successful ROSC touchdown.

  9. Characterization and analysis of the PikD regulatory factor in the pikromycin biosynthetic pathway of Streptomyces venezuelae.

    PubMed

    Wilson, D J; Xue, Y; Reynolds, K A; Sherman, D H

    2001-06-01

    The Streptomyces venezuelae pikD gene from the pikromycin biosynthetic cluster was analyzed, and its deduced product (PikD) was found to have amino acid sequence homology with a small family of bacterial regulatory proteins. Database comparisons revealed two hypothetical domains, including an N-terminal triphosphate-binding domain and a C-terminal helix-turn-helix DNA-binding motif. Analysis of PikD was initiated by deletion of the corresponding gene (pikD) from the chromosome of S. venezuelae, resulting in complete loss of antibiotic production. Complementation by a plasmid carrying pikD restored macrolide biosynthesis, demonstrating that PikD is a positive regulator. Mutations were made in the predicted nucleotide triphosphate-binding domain, confirming the active-site amino acid residues of the Walker A and B motifs. Feeding of macrolide intermediates was carried out to gauge the points of operon control by PikD. Although the pikD mutant strain was unable to convert macrolactones (10-deoxymethynolide and narbonolide) to glycosylated products, macrolide intermediates (YC-17 and narbomycin) were hydroxylated with high efficiency. To study further the control of biosynthesis, presumed promoter regions from pik cluster loci were linked to the xylE reporter and placed in S. venezuelae wild-type and pikD mutant strains. This analysis demonstrated that PikD-mediated transcriptional regulation occurs at promoters controlling expression of pikRII, pikAI, and desI but not those controlling pikRI or pikC.

  10. Mutations in PIK3CA sensitize breast cancer cells to physiologic levels of aspirin.

    PubMed

    Turturro, Sanja B; Najor, Matthew S; Ruby, Carl E; Cobleigh, Melody A; Abukhdeir, Abde M

    2016-02-01

    A review of the literature finds that women diagnosed with breast cancer, who were on an aspirin regimen, experienced a decreased risk of distant metastases and death. Several recent studies have reported an improvement in overall survival in colorectal cancer patients who harbored mutations in the oncogene PIK3CA and received a daily aspirin regimen. Breast cancer patients on a daily aspirin regimen experienced decreased risk of distant metastases and death. PIK3CA is the most frequently mutated oncogene in breast cancer, occurring in up to 45 % of all breast cancers. In order to determine if mutations in PIK3CA sensitized breast cancers to aspirin treatment, we employed the use of isogenic cellular clones of the non-tumorigenic, breast epithelial cell line MCF-10A that harbored mutations in either PIK3CA or KRAS or both. We report that mutations in both PIK3CA and KRAS are required for the greatest aspirin sensitivity in breast cancer, and that the GSK3β protein was hyperphosphorylated in aspirin-treated double knockin cells, but not in other clones/treatments. A more modest effect was observed with single mutant PIK3CA, but not KRAS alone. These observations were further confirmed in a panel of breast cancer cell lines. Our findings provide the first evidence that mutations in PIK3CA sensitize breast cancer cells to aspirin.

  11. PIK3CA mutation detection in metastatic biliary cancer using cell-free DNA

    PubMed Central

    Deng, Shibing; Lee, Sujin; Park, Young Suk; Lim, Ho Yeong; Kang, Won Ki; Mao, Mao; Heo, Jin Seok; Kwon, Wooil; Jang, Kee-Taek; Lee, Jeeyun; Park, Joon Oh

    2015-01-01

    PIK3CA mutation is considered a good candidate for targeted therapies in cancers, especially biliary tract cancer (BTC). We evaluated the utility of cell free DNA (cfDNA) from serum by using droplet digital PCR (ddPCR) as an alternative source for PIK3CA mutation analysis. To identify matching archival tumour specimens from serum samples of advanced BTC patients, mutation detection using ddPCR with Bio-Rad's PrimePCR mutation and wild type assays were performed for PIK3CA p.E542K, p.E545K, and p.H1047R. Thirty-eight patients with metastatic BTC were enrolled. Only one (BTC 29T) sample (n = 38) was positive for PIK3CA p.E542K and another (BTC 27T) for p.H1047R mutation; none was positive for PIK3CA p.E545K. Matched serum sample (BTC 29P) was positive for PIK3CA p.E542K with 28 mutant copies detected, corresponding to 48 copies/ml of serum and an allelic prevalence of 0.3%. Another matched serum sample (BTC 27P) was positive for PIK3CA p.H1047R with 10 mutant copies detected, i.e. 18 copies/ml and an allelic frequency of 0.2%. High correlation was noted in the PIK3CA mutation status between tumour gDNA and serum cfDNA. Low-level PIK3CA mutations were detectable in the serum indicating the utility of cfDNA as a DNA source to detect cancer-derived mutations in metastatic biliary cancers. PMID:26498688

  12. PIK3CA is implicated as an oncogene in ovarian cancer

    SciTech Connect

    Shayesteh, Laleh; Lu, Yiling; Kuo, Wen-Lin; Baldocchi, Russell; Godfrey, Tony; Collins, Colin; Pinkel, Daniel; Powell, Bethan; Mills,Gordon B.; Gray, Joe W.

    1998-03-25

    Ovarian cancer is the leading cause of death from gynecological malignancy and the fourth leading cause of cancer death among American women, yet little is known about its molecular aetiology. Studies using comparative genomic hybridization (CGH) have revealed several regions of recurrent, abnormal, DNA sequence copy number that may encode genes involved in the genesis or progression of the disease. One region at 3q26 found to be increased in copy number in approximately 40 percent of ovarian and other cancers contains PIK3CA, which encodes the p110 a catalytic subunit of phosphatidylinositol 3-kinase(PI3-kinase). The association between PIK3CA copy number and PI3-kinase activity makes PIK3CA a candidate oncogene because a broad range of cancer-related functions have been associated with PI3-kinase mediated signaling. These include proliferation, glucose transport and catabolism, cell adhesion, apoptosis, RAS signaling and oncogenic transformation. In addition, downstream effectors of PI3-kinase,AKT1 and AKT2, have been found to be amplified or activated in human tumors, including ovarian cancer. We show here that PIK3CA is frequently increased in copy number in ovarian cancers, that the increased copy number is associated with increased PIK3CA transcription, p110 a protein expression and PI3-kinase activity and that treatment with the PI3-kinase inhibitor LY294002 decreases proliferation and increases apoptosis. Our observations suggest PIK3CA is an oncogene that has an important role in ovarian cancer.

  13. Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer

    PubMed Central

    Hao, Yujun; Samuels, Yardena; Li, Qingling; Krokowski, Dawid; Guan, Bo-Jhih; Wang, Chao; Jin, Zhicheng; Dong, Bohan; Cao, Bo; Feng, Xiujing; Xiang, Min; Xu, Claire; Fink, Stephen; Meropol, Neal J.; Xu, Yan; Conlon, Ronald A.; Markowitz, Sanford; Kinzler, Kenneth W.; Velculescu, Victor E.; Brunengraber, Henri; Willis, Joseph E.; LaFramboise, Thomas; Hatzoglou, Maria; Zhang, Guo-Fang; Vogelstein, Bert; Wang, Zhenghe

    2016-01-01

    Cancer cells often require glutamine for growth, thereby distinguishing them from most normal cells. Here we show that PIK3CA mutations reprogram glutamine metabolism by upregulating glutamate pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells, making them more dependent on glutamine. Compared with isogenic wild-type (WT) cells, PIK3CA mutant CRCs convert substantially more glutamine to α-ketoglutarate to replenish the tricarboxylic acid cycle and generate ATP. Mutant p110α upregulates GPT2 gene expression through an AKT-independent, PDK1–RSK2–ATF4 signalling axis. Moreover, aminooxyacetate, which inhibits the enzymatic activity of aminotransferases including GPT2, suppresses xenograft tumour growth of CRCs with PIK3CA mutations, but not with WT PIK3CA. Together, these data establish oncogenic PIK3CA mutations as a cause of glutamine dependency in CRCs and suggest that targeting glutamine metabolism may be an effective approach to treat CRC patients harbouring PIK3CA mutations. PMID:27321283

  14. Automatic and Interactive Key Posture Design by Combing the PIK with Parametric Posture Splicing

    NASA Astrophysics Data System (ADS)

    Li, Shilei; Wu, Bing; Liang, Jiahong; Su, Jiongming

    Key posture design is commonly needed in computer animation. This paper presents an automatic and interactive whole body posture designing technique by combining the PIK (prioritized inverse kinematics) with the proposed parametric human posture splicing technique. The key feature of PIK is that the user can design a posture by adding high level constraints with different priorities. However, the PIK is essentially a numerical IK algorithm which relies on the iterative optimization starting from a good enough initial posture to get the final result. To speed up the running efficiency and ensure the lifelikeness of the final posture, the parametric posture splicing technique is proposed to generate the initial guess of the PIK. According to the set of the high level constraints, the whole body is divided into some partial parts, whose postures are then generated by the parametric posture synthesis from a single posture database. Then an initial posture guess with some main characteristics of the finally acceptable posture can be generated approximately by splicing these partial body postures together. Starting from this initial guess and with all constraints considered at different priority levels, the PIK can be initialized with a bias defined by this particularly initial guess and iterated step by step to get a final posture. The total process of the whole body posture generation is automatic and interactive. The experimental results show that this combination method can not only improve the computation efficiency of the PIK but also can simultaneously ensure the naturalness of the final posture.

  15. PIK3CA Mutations in Patients with Advanced Cancers Treated with PI3K/AKT/mTOR Axis Inhibitors

    PubMed Central

    Janku, Filip; Tsimberidou, Apostolia M.; Garrido-Laguna, Ignacio; Wang, Xuemei; Luthra, Rajyalakshmi; Hong, David S.; Naing, Aung; Falchook, Gerald S.; Moroney, John W.; Piha-Paul, Sarina A.; Wheler, Jennifer J.; Moulder, Stacy L.; Fu, Siqing; Kurzrock, Razelle

    2011-01-01

    Preclinical data suggest that PIK3CA mutations predict response to PI3K/AKT/mTOR inhibitors. Concomitant KRAS or BRAF mutations may mediate resistance. Therefore tumors from patients referred to the Phase I Program for targeted therapy starting in October 2008 were analyzed for PIK3CA mutations using PCR-based DNA sequencing of exons 9 and 20. Consecutive patients with diverse tumor types and PIK3CA mutations were treated whenever possible with agents targeting the PI3K/AKT/mTOR pathway. Overall, PIK3CA mutations were detected in 25 of 217 patients (11.5%) (exon 9, n=11; exon 20, n=14). In tumor types with >10 patients tested, PIK3CA mutations were most frequent in endometrial (3/14, 21%), ovarian (5/30, 17%), colorectal (9/54, 17%), breast (2/14, 14%), cervical (2/15, 13%), and squamous cell cancer of head and neck (1/11, 9%). Seventeen of the 25 patients (68%) with PIK3CA mutations were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor, and 6 (35%) achieved a partial response. In contrast, only 15 of 241 patients (6%) without documented PIK3CA mutations treated on the same protocols responded (p=0.001). Six of the 17 (35%) patients with PIK3CA mutations had simultaneous KRAS or BRAF mutations (colorectal, n=4; ovarian, n=2). Colorectal cancer patients with PIK3CA and KRAS mutations did not respond to therapy, while both ovarian cancer patients with PIK3CA and KRAS or BRAF mutations did. In conclusion, PIK3CA mutations were detected in 11.5% of patients with diverse solid tumors. The response rate was significantly higher for patients with PIK3CA mutations treated with PI3K/AKT/mTOR pathway inhibitors than for those without documented mutations. PMID:21216929

  16. Prognostic significance of PIK3CA and SOX2 in Asian patients with lung squamous cell carcinoma.

    PubMed

    Iijima, Yoshihito; Seike, Masahiro; Noro, Rintaro; Ibi, Takayuki; Takeuchi, Shingo; Mikami, Iwao; Koizumi, Kiyoshi; Usuda, Jitsuo; Gemma, Akihiko

    2015-02-01

    The recent development of human genome studies has demonstrated the possibility of alteration of several genes as oncogenic driver mutations of lung squamous cell carcinoma (SQCC). FGFR1, PIK3CA and SOX2 genes have been recognized as candidate driver genes of SQCC. The aim of the present study was to evaluate FGFR1, PIK3CA and SOX2 protein expression in SQCC and determine whether the expression of these can be used as prognostic biomarkers. We evaluated the relationships between FGFR1, PIK3CA and SOX2 expression by immunohistochemical analysis and overall survival in lung SQCC patients with stage I-III that originated from China, United States and Japan. FGFR1-positive, PIK3CA-negative and SOX2-positive staining each showed trends toward better survival, although the differences were not statistically significant in a Chinese cohort of 57 patients. Patients with PIK3CA-negative and SOX2-positive staining (PIK3CA(-)/SOX2(+)) showed better prognosis compared with those with PIK3CA-positive or SOX2-negative staining in the Chinese cohort (p=0.04). The robustness of PIK3CA(-)/SOX2(+) classification as having prognostic significance was validated in an independent set of 66 Japanese cohort patients (p=0.007). Japanese SQCC patients with stage I were evaluated separately and PIK3CA(-)/SOX2(+) cases had significantly better survival than the group with PIK3CA-positive or SOX2-negative status (p=0.03). In univariate and multivariable Cox proportional hazards models of Asian stage I patients, the PIK3CA(-)/SOX2(+) classification was statistically significantly associated with survival and was an independent prognostic factor. Classification by PIK3CA and SOX2 protein expression is useful for predicting the prognosis of Asian patients with lung SQCC with stage I.

  17. Program for studying fundamental interactions at the PIK reactor facilities

    SciTech Connect

    Serebrov, A. P. Vassiljev, A. V.; Varlamov, V. E.; Geltenbort, P.; Gridnev, K. A.; Dmitriev, S. P.; Dovator, N. A.; Egorov, A. I.; Ezhov, V. F.; Zherebtsov, O. M.; Zinoviev, V. G.; Ivochkin, V. G.; Ivanov, S. N.; Ivanov, S. A.; Kolomensky, E. A.; Konoplev, K. A.; Krasnoschekova, I. A.; Lasakov, M. S.; Lyamkin, V. A.; Martemyanov, V. P.; and others

    2016-05-15

    A research program aimed at studying fundamental interactions by means of ultracold and polarized cold neutrons at the GEK-4-4′ channel of the PIK reactor is presented. The apparatus to be used includes a source of cold neutrons in the heavy-water reflector of the reactor, a source of ultracold neutrons based on superfluid helium and installed in a cold-neutron beam extracted from the GEK-4 channel, and a number of experimental facilities in neutron beams. An experiment devoted to searches for the neutron electric dipole moment and an experiment aimed at a measurement the neutron lifetime with the aid of a large gravitational trap are planned to be performed in a beam of ultracold neutrons. An experiment devoted to measuring neutron-decay asymmetries with the aid of a superconducting solenoid is planned in a beam of cold polarized neutrons from the GEK-4′ channel. The second ultracold-neutron source and an experiment aimed at measuring the neutron lifetime with the aid of a magnetic trap are planned in the neutron-guide system of the GEK-3 channel. In the realms of neutrino physics, an experiment intended for sterile-neutrino searches is designed. The state of affairs around the preparation of the experimental equipment for this program is discussed.

  18. Program for studying fundamental interactions at the PIK reactor facilities

    NASA Astrophysics Data System (ADS)

    Serebrov, A. P.; Vassiljev, A. V.; Varlamov, V. E.; Geltenbort, P.; Gridnev, K. A.; Dmitriev, S. P.; Dovator, N. A.; Egorov, A. I.; Ezhov, V. F.; Zherebtsov, O. M.; Zinoviev, V. G.; Ivochkin, V. G.; Ivanov, S. N.; Ivanov, S. A.; Kolomensky, E. A.; Konoplev, K. A.; Krasnoschekova, I. A.; Lasakov, M. S.; Lyamkin, V. A.; Martemyanov, V. P.; Murashkin, A. N.; Neustroev, P. V.; Onegin, M. S.; Petelin, A. L.; Pirozhkov, A. N.; Polyushkin, A. O.; Prudnikov, D. V.; Ryabov, V. L.; Samoylov, R. M.; Sbitnev, S. V.; Fomin, A. K.; Fomichev, A. V.; Zimmer, O.; Cherniy, A. V.; Shoka, I. V.

    2016-05-01

    A research program aimed at studying fundamental interactions by means of ultracold and polarized cold neutrons at the GEK-4-4' channel of the PIK reactor is presented. The apparatus to be used includes a source of cold neutrons in the heavy-water reflector of the reactor, a source of ultracold neutrons based on superfluid helium and installed in a cold-neutron beam extracted from the GEK-4 channel, and a number of experimental facilities in neutron beams. An experiment devoted to searches for the neutron electric dipole moment and an experiment aimed at a measurement the neutron lifetime with the aid of a large gravitational trap are planned to be performed in a beam of ultracold neutrons. An experiment devoted to measuring neutron-decay asymmetries with the aid of a superconducting solenoid is planned in a beam of cold polarized neutrons from the GEK-4' channel. The second ultracold-neutron source and an experiment aimed at measuring the neutron lifetime with the aid of a magnetic trap are planned in the neutron-guide system of the GEK-3 channel. In the realms of neutrino physics, an experiment intended for sterile-neutrino searches is designed. The state of affairs around the preparation of the experimental equipment for this program is discussed.

  19. An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice.

    PubMed

    Kinross, Kathryn M; Montgomery, Karen G; Kleinschmidt, Margarete; Waring, Paul; Ivetac, Ivan; Tikoo, Anjali; Saad, Mirette; Hare, Lauren; Roh, Vincent; Mantamadiotis, Theo; Sheppard, Karen E; Ryland, Georgina L; Campbell, Ian G; Gorringe, Kylie L; Christensen, James G; Cullinane, Carleen; Hicks, Rodney J; Pearson, Richard B; Johnstone, Ricky W; McArthur, Grant A; Phillips, Wayne A

    2012-02-01

    Mutations in the gene encoding the p110α subunit of PI3K (PIK3CA) that result in enhanced PI3K activity are frequently observed in human cancers. To better understand the role of mutant PIK3CA in the initiation or progression of tumorigenesis, we generated mice in which a PIK3CA mutation commonly detected in human cancers (the H1047R mutation) could be conditionally knocked into the endogenous Pik3ca locus. Activation of this mutation in the mouse ovary revealed that alone, Pik3caH1047R induced premalignant hyperplasia of the ovarian surface epithelium but no tumors. Concomitantly, we analyzed several human ovarian cancers and found PIK3CA mutations coexistent with KRAS and/or PTEN mutations, raising the possibility that a secondary defect in a co-regulator of PI3K activity may be required for mutant PIK3CA to promote transformation. Consistent with this notion, we found that Pik3caH1047R mutation plus Pten deletion in the mouse ovary led to the development of ovarian serous adenocarcinomas and granulosa cell tumors. Both mutational events were required for early, robust Akt activation. Pharmacological inhibition of PI3K/mTOR in these mice delayed tumor growth and prolonged survival. These results demonstrate that the Pik3caH1047R mutation with loss of Pten is enough to promote ovarian cell transformation and that we have developed a model system for studying possible therapies.

  20. A unique spectrum of somatic PIK3CA (p110alpha) mutations within primary endometrial carcinomas.

    PubMed

    Rudd, Meghan L; Price, Jessica C; Fogoros, Sarah; Godwin, Andrew K; Sgroi, Dennis C; Merino, Maria J; Bell, Daphne W

    2011-03-15

    The goal of this study was to comprehensively define the incidence of mutations in all exons of PIK3CA in both endometrioid endometrial cancer (EEC) and nonendometrioid endometrial cancer (NEEC). We resequenced all coding exons of PIK3CA and PTEN, and exons 1 and 2 of KRAS, from 108 primary endometrial tumors. Somatic mutations were confirmed by sequencing matched normal DNAs. The biochemical properties of a subset of novel PIK3CA mutations were determined by exogenously expressing wild type and mutant constructs in U2OS cells and measuring levels of AKT(Ser473) phosphorylation. Somatic PIK3CA mutations were detected in 52.4% of 42 EECs and 33.3% of 66 NEECs. Half (29 of 58) of all nonsynonymous PIK3CA mutations were in exons 1-7 and half were in exons 9 and 20. The exons 1-7 mutations localized to the ABD, ABD-RBD linker and C2 domains of p110α. Within these regions, Arg88, Arg93, Gly106, Lys111, Glu365, and Glu453, were recurrently mutated; Arg88, Arg93, and Lys111 formed mutation hotspots. The p110α-R93W, -G106R, -G106V, -K111E, -delP449-L455, and -E453K mutants led to increased levels of phospho-AKT(Ser473) compared to wild-type p110α. Overall, 62% of exons 1-7 PIK3CA mutants and 64% of exons 9-20 PIK3CA mutants were activating; 72% of exon 1-7 mutations have not previously been reported in endometrial cancer. Our study identified a new subgroup of endometrial cancer patients with activating mutations in the amino-terminal domains of p110α; these patients might be appropriate for consideration in clinical trials of targeted therapies directed against the PI3K pathway. ©2011 AACR.

  1. A unique spectrum of somatic PIK3CA (p110α) mutations within primary endometrial carcinomas

    PubMed Central

    Rudd, Meghan L.; Price, Jessica C.; Fogoros, Sarah; Godwin, Andrew K.; Sgroi, Dennis C.; Merino, Maria J.; Bell, Daphne W.

    2011-01-01

    Purpose The goal of this study was to comprehensively define the incidence of mutations in all exons of PIK3CA in both endometrioid endometrial cancer (EEC) and non-endometrioid endometrial cancer (NEEC). Experimental design We resequenced all coding exons of PIK3CA and PTEN, and exons 1 and 2 of KRAS, from 108 primary endometrial tumors. Somatic mutations were confirmed by sequencing matched normal DNAs. The biochemical properties of a subset of novel PIK3CA mutations were determined by exogenously expressing wildtype and mutant constructs in U2OS cells and measuring levels of AKTSer473 phosphorylation. Results Somatic PIK3CA mutations were detected in 52.4% of 42 EECs and 33.3% of 66 NEECs. Half (29 of 58) of all nonsynonymous PIK3CA mutations were in exons 1–7 and half were in exons 9 and 20. The exons 1–7 mutations localized to the ABD, ABD-RBD linker and C2 domains of p110α. Within these regions, Arg88, Arg93, Gly106, Lys111, Glu365, and Glu453, were recurrently mutated; Arg88, Arg93 and Lys111 formed mutation hotspots. The p110α-R93W, -G106R, -G106V, -K111E, -delP449-L455, and -E453K mutants led to increased levels of phospho-AKTSer473 compared to wild-type p110α. Overall, 62% of exons 1–7 PIK3CA mutants and 64% of exon 9–20 PIK3CA mutants were activating; 72% of exon 1–7 mutations have not previously been reported in endometrial cancer. Conclusions Our study identified a new subgroup of endometrial cancer patients with activating mutations in the amino-terminal domains of p110α; these patients might be appropriate for consideration in clinical trials of targeted therapies directed against the PI3K pathway. PMID:21266528

  2. Mary Shelley: Teaching and Learning through "Frankenstein"

    ERIC Educational Resources Information Center

    Girard, Theresa M.

    2009-01-01

    In the writing of "Frankenstein", Mary Shelley was able to change the course of women's learning, forever. Her life started from an elite standpoint as the child of Mary Wollstonecraft and William Godwin. As such, she was destined to grow to be a major influence in the world. Mary Shelley's formative years were spent with her father and his many…

  3. The Capsicum annuum class IV chitinase ChitIV interacts with receptor-like cytoplasmic protein kinase PIK1 to accelerate PIK1-triggered cell death and defence responses.

    PubMed

    Kim, Dae Sung; Kim, Nak Hyun; Hwang, Byung Kook

    2015-04-01

    The pepper receptor-like cytoplasmic protein kinase, CaPIK1, which mediates signalling of plant cell death and defence responses was previously identified. Here, the identification of a class IV chitinase, CaChitIV, from pepper plants (Capsicum annuum), which interacts with CaPIK1 and promotes CaPIK1-triggered cell death and defence responses, is reported. CaChitIV contains a signal peptide, chitin-binding domain, and glycol hydrolase domain. CaChitIV expression was up-regulated by Xanthomonas campestris pv. vesicatoria (Xcv) infection. Notably, avirulent Xcv infection rapidly induced CaChitIV expression in pepper leaves. Bimolecular fluorescence complementation and co-immunoprecipitation revealed that CaPIK1 interacts with CaChitIV in planta, and that the CaPIK1-CaChitIV complex is localized mainly in the cytoplasm and plasma membrane. CaChitIV is also localized in the endoplasmic reticulum. Transient co-expression of CaChitIV with CaPIK1 enhanced CaPIK1-triggered cell death response and reactive oxygen species (ROS) and nitric oxide (NO) bursts. Co-silencing of both CaChitIV and CaPIK1 in pepper plants conferred enhanced susceptibility to Xcv infection, which was accompanied by a reduced induction of cell death response, ROS and NO bursts, and defence response genes. Ectopic expression of CaPIK1 in Arabidopsis enhanced basal resistance to Hyaloperonospora arabidopsidis infection. Together, the results suggest that CaChitIV positively regulates CaPIK1-triggered cell death and defence responses through its interaction with CaPIK1. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  4. The Capsicum annuum class IV chitinase ChitIV interacts with receptor-like cytoplasmic protein kinase PIK1 to accelerate PIK1-triggered cell death and defence responses

    PubMed Central

    Kim, Dae Sung; Kim, Nak Hyun; Hwang, Byung Kook

    2015-01-01

    The pepper receptor-like cytoplasmic protein kinase, CaPIK1, which mediates signalling of plant cell death and defence responses was previously identified. Here, the identification of a class IV chitinase, CaChitIV, from pepper plants (Capsicum annuum), which interacts with CaPIK1 and promotes CaPIK1-triggered cell death and defence responses, is reported. CaChitIV contains a signal peptide, chitin-binding domain, and glycol hydrolase domain. CaChitIV expression was up-regulated by Xanthomonas campestris pv. vesicatoria (Xcv) infection. Notably, avirulent Xcv infection rapidly induced CaChitIV expression in pepper leaves. Bimolecular fluorescence complementation and co-immunoprecipitation revealed that CaPIK1 interacts with CaChitIV in planta, and that the CaPIK1–CaChitIV complex is localized mainly in the cytoplasm and plasma membrane. CaChitIV is also localized in the endoplasmic reticulum. Transient co-expression of CaChitIV with CaPIK1 enhanced CaPIK1-triggered cell death response and reactive oxygen species (ROS) and nitric oxide (NO) bursts. Co-silencing of both CaChitIV and CaPIK1 in pepper plants conferred enhanced susceptibility to Xcv infection, which was accompanied by a reduced induction of cell death response, ROS and NO bursts, and defence response genes. Ectopic expression of CaPIK1 in Arabidopsis enhanced basal resistance to Hyaloperonospora arabidopsidis infection. Together, the results suggest that CaChitIV positively regulates CaPIK1-triggered cell death and defence responses through its interaction with CaPIK1. PMID:25694549

  5. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival.

    PubMed

    Liao, Xiaoyun; Lochhead, Paul; Nishihara, Reiko; Morikawa, Teppei; Kuchiba, Aya; Yamauchi, Mai; Imamura, Yu; Qian, Zhi Rong; Baba, Yoshifumi; Shima, Kaori; Sun, Ruifang; Nosho, Katsuhiko; Meyerhardt, Jeffrey A; Giovannucci, Edward; Fuchs, Charles S; Chan, Andrew T; Ogino, Shuji

    2012-10-25

    Regular use of aspirin after a diagnosis of colon cancer has been associated with a superior clinical outcome. Experimental evidence suggests that inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2) (also known as cyclooxygenase-2) by aspirin down-regulates phosphatidylinositol 3-kinase (PI3K) signaling activity. We hypothesized that the effect of aspirin on survival and prognosis in patients with cancers characterized by mutated PIK3CA (the phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit alpha polypeptide gene) might differ from the effect among those with wild-type PIK3CA cancers. We obtained data on 964 patients with rectal or colon cancer from the Nurses' Health Study and the Health Professionals Follow-up Study, including data on aspirin use after diagnosis and the presence or absence of PIK3CA mutation. We used a Cox proportional-hazards model to compute the multivariate hazard ratio for death. We examined tumor markers, including PTGS2, phosphorylated AKT, KRAS, BRAF, microsatellite instability, CpG island methylator phenotype, and methylation of long interspersed nucleotide element 1. Among patients with mutated-PIK3CA colorectal cancers, regular use of aspirin after diagnosis was associated with superior colorectal cancer-specific survival (multivariate hazard ratio for cancer-related death, 0.18; 95% confidence interval [CI], 0.06 to 0.61; P<0.001 by the log-rank test) and overall survival (multivariate hazard ratio for death from any cause, 0.54; 95% CI, 0.31 to 0.94; P=0.01 by the log-rank test). In contrast, among patients with wild-type PIK3CA, regular use of aspirin after diagnosis was not associated with colorectal cancer-specific survival (multivariate hazard ratio, 0.96; 95% CI, 0.69 to 1.32; P=0.76 by the log-rank test; P=0.009 for interaction between aspirin and PIK3CA variables) or overall survival (multivariate hazard ratio, 0.94; 95% CI, 0.75 to 1.17; P=0.96 by the log-rank test; P=0.07 for interaction). Regular

  6. Charcot-Marie-Tooth Disease

    MedlinePlus

    Charcot-Marie-Tooth disease (CMT) is a group of genetic nerve disorders. It is named after the three doctors who first identified it. ... a nerve biopsy. There is no cure. The disease can be so mild you don't realize ...

  7. The Displacement of Mary Jones.

    ERIC Educational Resources Information Center

    McCaslin, Sharon

    1990-01-01

    Describes the experiences of Mary Jones as librarian at the University of Nebraska (1892-97), her resignation attributed to sex discrimination, the impact of her resignation on the library, and her subsequent positions at the University of Illinois, University of Iowa, and Los Angeles Public Library. A sidebar discusses women's career paths in the…

  8. Klippel-Trenaunay syndrome belongs to the PIK3CA-related overgrowth spectrum (PROS).

    PubMed

    Vahidnezhad, Hassan; Youssefian, Leila; Uitto, Jouni

    2016-01-01

    Klippel-Trenaunay syndrome (KTS), originally described as a triad of cutaneous capillary malformation, bone and soft-tissue hypertrophy, as well as venous and lymphatic malformations, has been considered by dermatologists as a distinct diagnostic entity. However, cases with KTS have also been reported to have neurological disorders, developmental delay and digital abnormalities, indicating multisystem involvement. Recently, a number of overgrowth syndromes, with overlapping phenotypic features with KTS, have been identified; these include MCAP and CLOVES syndromes as well as fibroadipose hyperplasia. These conditions harbour mutations in the PIK3CA gene, and they have been included in the PIK3CA-related overgrowth spectrum (PROS). Based on recent demonstrations of PIK3CA mutations also in KTS, it appears that, rather than being a distinct diagnostic entity, KTS belongs to PROS. These observations have potential diagnostic and therapeutic implications for KTS. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. PIK3CA mutations in human solid tumors: role in sensitivity to various therapeutic approaches.

    PubMed

    Ligresti, Giovanni; Militello, Loredana; Steelman, Linda S; Cavallaro, Andrea; Basile, Francesco; Nicoletti, Ferdinando; Stivala, Franca; McCubrey, James A; Libra, Massimo

    2009-05-01

    Phosphatidylinositol 3-kinases (PI3Ks) are a group of lipid kinases that regulate signaling pathways involved in cell proliferation, adhesion, survival and motility. The PI3K pathway is considered to play an important role in tumorigenesis. Activating mutations of the p110alpha subunit of PI3K (PIK3CA) have been identified in a broad spectrum of tumors. Analyses of PIK3CA mutations reveals that they increase the PI3K signal, stimulate downstream Akt signaling, promote growth factor-independent growth and increase cell invasion and metastasis. In this review, we analyze the contribution of the PIK3CA mutations in cancer, and their possible implications for diagnosis and therapy.

  10. Mucinous breast carcinomas lack PIK3CA and AKT1 mutations.

    PubMed

    Kehr, Elizabeth L; Jorns, Julie M; Ang, Daphne; Warrick, Andrea; Neff, Tanaya; Degnin, Michelle; Lewis, Rebecca; Beadling, Carol; Corless, Christopher L; Troxell, Megan L

    2012-12-01

    Activating point mutations in the phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) are among the most common molecular defects in invasive breast cancer. Point mutations in the downstream kinase AKT1 are seen in a minority of carcinomas. These mutations are found preferentially in estrogen receptor-positive and Her2-positive breast carcinomas; however, special morphologic types of breast cancer have not been well studied. Twenty-nine cases of pure invasive mucinous carcinoma and 9 cases of ductal carcinoma with mucinous differentiation were screened for a panel of point mutations (>321 mutations in 30 genes) using a multiplex polymerase chain reaction panel with mass spectroscopy readout. In addition, associated ductal carcinoma in situ, hyperplasia, or columnar cell lesions were separately tested where available (25 lesions). In 3 invasive cases and 15 ductal carcinoma in situ/proliferative lesions, PIK3CA hotspot mutations were, instead, tested by direct sequencing. No point mutations were identified in invasive mucinous breast carcinoma. This contrasts with the 35% frequency of PIK3CA mutations in a comparative group of invasive ductal carcinomas of no special type. Interestingly, PIK3CA hotspot point mutations were identified in associated ductal carcinoma in situ (3/14) and hyperplasia (atypical ductal hyperplasia [2/3], usual ductal hyperplasia [2/3], columnar cell change [1/5]), suggesting that PIK3CA mutations may play a role in breast epithelial proliferation. This series represents the largest study, to date, of PIK3CA genotyping in mucinous carcinoma and supports the unique pathogenetics of invasive mucinous breast carcinoma.

  11. Frequent PIK3CA Mutations in Colorectal and Endometrial Cancer with Double Somatic Mismatch Repair Mutations

    PubMed Central

    Cohen, Stacey A.; Turner, Emily H.; Beightol, Mallory B.; Jacobson, Angela; Gooley, Ted A.; Salipante, Stephen J.; Haraldsdottir, Sigurdis; Smith, Christina; Scroggins, Sheena; Tait, Jonathan F.; Grady, William M.; Lin, Edward H.; Cohn, David E.; Goodfellow, Paul J.; Arnold, Mark W.; de la Chapelle, Albert; Pearlman, Rachel; Hampel, Heather; Pritchard, Colin C.

    2016-01-01

    Background & Aims Double somatic mutations in mismatch repair (MMR) genes have recently been described in colorectal and endometrial cancers with microsatellite instability (MSI) not attributable to MLH1 hypermethylation or germline mutation. We sought to define the molecular phenotype of this newly recognized tumor subtype. Methods From two prospective Lynch syndrome screening studies, we identified patients with colorectal and endometrial tumors harboring ≥2 somatic MMR mutations, but normal germline MMR testing (“double somatic”). We determined the frequencies of tumor PIK3CA, BRAF, KRAS, NRAS, and PTEN mutations by targeted next-generation sequencing and used logistic-regression models to compare them to: Lynch syndrome, MLH1 hypermethylated, and microsatellite stable (MSS) tumors. We validated our findings using independent datasets from The Cancer Genome Atlas (TCGA). Results Among colorectal cancer cases, we found that 14/21 (67%) of double somatic cases had PIK3CA mutations vs. 4/18 (22%) Lynch syndrome, 2/10 (20%) MLH1 hypermethylated, and 12/78 (15%) MSS tumors; p<0.0001. PIK3CA mutations were detected in 100% of 13 double somatic endometrial cancers (p=0.04). BRAF mutations were absent in double somatic and Lynch syndrome colorectal tumors. We found highly similar results in a validation cohort from TCGA (113 colorectal, 178 endometrial cancer), with 100% of double somatic cases harboring a PIK3CA mutation (p<0.0001). Conclusions PIK3CA mutations are present in double somatic mutated colorectal and endometrial cancers at substantially higher frequencies than other MSI subgroups. PIK3CA mutation status may better define an emerging molecular entity in colorectal and endometrial cancers, with the potential to inform screening and therapeutic decision making. PMID:27302833

  12. Mutation of the PIK3CA gene in anaplastic thyroid cancer.

    PubMed

    García-Rostán, Ginesa; Costa, Angela M; Pereira-Castro, Isabel; Salvatore, Giuliana; Hernandez, Radhames; Hermsem, Mario J A; Herrero, Agustin; Fusco, Alfredo; Cameselle-Teijeiro, Jose; Santoro, Massimo

    2005-11-15

    The phosphatidylinositol 3'-kinase (PI3K) pathway is frequently activated in thyroid carcinomas through the constitutive activation of stimulatory molecules (e.g., Ras) and/or the loss of expression and/or function of the inhibitory PTEN protein that results in Akt activation. Recently, it has been reported that somatic mutations within the PI3K catalytic subunit, PIK3CA, are common (25-40%) among colorectal, gastric, breast, ovarian cancers, and high-grade brain tumors. Moreover, PIK3CA mutations have a tendency to cluster within the helical (exon 9) and the kinase (exon 20) domains. In this study, 13 thyroid cancer cell lines, 80 well-differentiated thyroid carcinomas of follicular (WDFC) and papillary (WDPC) type, and 70 anaplastic thyroid carcinomas (ATC) were investigated, by PCR-direct sequencing, for activating PIK3CA mutations at exons 9 and 20. Nonsynonymous somatic mutations were found in 16 ATC (23%), two WDFC (8%), and one WDPC (2%). In 18 of the 20 ATC cases showing coexisting differentiated carcinoma, mutations, when present, were restricted to the ATC component and located primarily within the kinase domain. Three cell lines of papillary and follicular lineage (K1, K2, and K5) were also found mutated. In addition, activation of Akt was observed in most of the ATC harboring PIK3CA mutations. These findings indicate that mutant PIK3CA is likely to function as an oncogene among ATC and less frequently well-differentiated thyroid carcinomas. The data also argue for a role of PIK3CA targeting in the treatment of ATC patients.

  13. MiR-124 suppresses cell proliferation in hepatocellular carcinoma by targeting PIK3CA

    SciTech Connect

    Lang, Qingbo; Ling, Changquan

    2012-09-21

    Highlights: Black-Right-Pointing-Pointer PIK3CA is a novel target of miR-124 in HepG2 cells. Black-Right-Pointing-Pointer MiR-124 suppresses cell proliferation by downregulating PIK3CA expression. Black-Right-Pointing-Pointer MiR-124 regulates the PI3K/Akt pathway in HepG2 cells. Black-Right-Pointing-Pointer MiR-124 overexpression inhibits the tumorigenesis in nude mice. -- Abstract: MicroRNAs (miRNAs) have crucial roles in the development and progression of human cancers, including hepatocellular carcinoma (HCC). Recent studies have shown that microRNA-124 (miR-124) was downregulated in HCC; however, the underlying mechanisms by which miR-124 suppresses tumorigenesis in HCC are largely unknown. In this study, we report that phosphoinositide 3-kinase catalytic subunit alpha (PIK3CA) is a novel target of miR-124 in HepG2 cells. Overexpression of miR-124 resulted in decreased expression of PIK3CA at both mRNA and protein levels. We found that miR-124 overexpression markedly suppressed cell proliferation by inducing G1-phase cell-cycle arrest in vitro. Consistent with the restoring miR-124 expression, PIK3CA knockdown suppressed cell proliferation, whereas overexpression of PIK3CA abolished the suppressive effect of miR-124. Mechanistic studies showed that miR-124-mediated reduction of PIK3CA resulted in suppression of PI3K/Akt pathway. The expressions of Akt and mTOR, key components of the PI3K/Akt pathway, were all downregulated. Moreover, we found overexpressed miR-124 effectively repressed tumor growth in xenograft animal experiments. Taken together, our results demonstrate that miR-124 functions as a growth-suppressive miRNA and plays an important role in inhibiting the tumorigenesis through targeting PIK3CA.

  14. M-ary Laguerre detection.

    NASA Technical Reports Server (NTRS)

    Mohanty, N. C.

    1973-01-01

    In a communication system using optical devices, the receiver is modeled as a counter of electrons which are emitted from a photodetector when a modulated optical wave is incident on it. The synthesis of the optimal receiver processing and its resulting performance depend upon the statistics associated with this counting. In an M-ary system, the transmitter selects one of a set of M intensities for the optical process. Questions of error probability are investigated.

  15. Martian Radiation Environment Experiment (MARIE)

    NASA Astrophysics Data System (ADS)

    Lee, Kerry T.

    The radiation environment between Earth and Mars and particularly at Mars, must be known prior to sending astronauts on lengthy exploratory missions. In an effort to understand the radiation environment that future astronauts will be exposed to, the Martian Radiation Environment Experiment (MARIE) was sent to Mars aboard the 2001 Odyssey spacecraft. Odyssey left Earth April 7, 2001 and arrived at Mars on October 23, 2001. MARIE collected data from April 2001 - August 2001 and from March 2002 - October 2003. MARIE is capable of detecting charged nuclei with energies greater than 30 MeV/u, and elements can be distinguished for charges of Z < 11. The average dose at Mars is about twice that measured by instruments aboard the International Space Station. Although the radiation level at Mars is higher than that experienced in low-Earth orbit (LEO), the measured radiation level does not necessarily preclude a manned Mars mission. However, the measurement does conclude that proper shielding materials must be used in the habitation module of any spacecraft and a highly shielded area must be provided as shelter from intense solar particle events (SPE) in order to minimize the total radiation dose received by any exploration crew. The data presented here are the absolute flux measurements of protons and He in Mars orbit in the energy range of 50 - 240 MeV/u.

  16. PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models

    PubMed Central

    Sabha, Nesrin; Volpatti, Jonathan R.; Gonorazky, Hernan; Davidson, Ann E.; Li, Xingli; Eltayeb, Nadine M.; Dall’Armi, Claudia; Di Paolo, Gilbert; Brooks, Susan V.; Buj-Bello, Ana; Feldman, Eva L.; Dowling, James J.

    2016-01-01

    Myotubular myopathy (MTM) is a devastating pediatric neuromuscular disorder of phosphoinositide (PIP) metabolism resulting from mutations of the PIP phosphatase MTM1 for which there are no treatments. We have previously shown phosphatidylinositol-3-phosphate (PI3P) accumulation in animal models of MTM. Here, we tested the hypothesis that lowering PI3P levels may prevent or reverse the MTM disease process. To test this, we targeted class II and III PI3 kinases (PI3Ks) in an MTM1-deficient mouse model. Muscle-specific ablation of Pik3c2b, but not Pik3c3, resulted in complete prevention of the MTM phenotype, and postsymptomatic targeting promoted a striking rescue of disease. We confirmed this genetic interaction in zebrafish, and additionally showed that certain PI3K inhibitors prevented development of the zebrafish mtm phenotype. Finally, the PI3K inhibitor wortmannin improved motor function and prolonged lifespan of the Mtm1-deficient mice. In all, we have identified Pik3c2b as a genetic modifier of Mtm1 mutation and demonstrated that PIK3C2B inhibition is a potential treatment strategy for MTM. In addition, we set the groundwork for similar reciprocal inhibition approaches for treating other PIP metabolic disorders and highlight the importance of modifier gene pathways as therapeutic targets. PMID:27548528

  17. KRAS and PIK3CA mutations in colorectal adenocarcinomas correlate with aggressive histological features and behavior.

    PubMed

    Jang, Sejin; Hong, Mineui; Shin, Mi Kyung; Kim, Byung Chun; Shin, Hyung-Sik; Yu, Eunsil; Hong, Seung-Mo; Kim, Jihun; Chun, Sung Min; Kim, Tae-Im; Choi, Kyung-Chan; Ko, Young Woong; Kim, Jeong Won

    2017-02-08

    Tumor budding (TB) in colorectal carcinoma (CRC) is related to epithelial-mesenchymal transition (EMT) and has been recently characterized as an indicator of poor prognosis along with lymphovascular tumor emboli (LVE), perineural invasion (PNI), and an infiltrative growth pattern. Mutations in the genes of the Ras-MAPK and PI3K pathways are associated with EMT and an aggressive CRC phenotype and have been used in patient stratification for anti-EGF receptor therapies; however, the impact of these mutations on CRC morphology and behavior remains unclear. In this study, using a multi-gene panel, we detected KRAS, NRAS, BRAF, PIK3CA, TP53, and POLE mutations in 90 CRCs and investigated their associations with clinicopathological parameters, including TB. Our results showed that 21 of 34 tumors with high-grade TB had KRAS mutations (P=.001) and KRAS G12D and PIK3CA exon 9 variants were significantly associated with high-grade TB (P=.002 and .006, respectively); furthermore, tumors with KRAS mutations in exons 3 and 4 tended to have LVE and PNI (P=.044 and .049, respectively). PIK3CA exon 9 mutations indicated a tendency for shorter disease-free survival (P=.030), whereas BRAF mutations were associated with extracellular mucin deposition (P=.016). Our study revealed a correlation of KRAS mutations with high-grade TB, an association of certain KRAS and PIK3CA variants with aggressive clinicopathological features, as well as a possible relationship between BRAF mutations and mucin production in CRC.

  18. Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.

    PubMed

    Castillo, Sandra D; Tzouanacou, Elena; Zaw-Thin, May; Berenjeno, Inma M; Parker, Victoria E R; Chivite, Iñigo; Milà-Guasch, Maria; Pearce, Wayne; Solomon, Isabelle; Angulo-Urarte, Ana; Figueiredo, Ana M; Dewhurst, Robert E; Knox, Rachel G; Clark, Graeme R; Scudamore, Cheryl L; Badar, Adam; Kalber, Tammy L; Foster, Julie; Stuckey, Daniel J; David, Anna L; Phillips, Wayne A; Lythgoe, Mark F; Wilson, Valerie; Semple, Robert K; Sebire, Neil J; Kinsler, Veronica A; Graupera, Mariona; Vanhaesebroeck, Bart

    2016-03-30

    Venous malformations (VMs) are painful and deforming vascular lesions composed of dilated vascular channels, which are present from birth. Mutations in the TEK gene, encoding the tyrosine kinase receptor TIE2, are found in about half of sporadic (nonfamilial) VMs, and the causes of the remaining cases are unknown. Sclerotherapy, widely accepted as first-line treatment, is not fully efficient, and targeted therapy for this disease remains underexplored. We have generated a mouse model that faithfully mirrors human VM through mosaic expression of Pik3ca(H1047R), a constitutively active mutant of the p110α isoform of phosphatidylinositol 3-kinase (PI3K), in the embryonic mesoderm. Endothelial expression of Pik3ca(H1047R)resulted in endothelial cell (EC) hyperproliferation, reduction in pericyte coverage of blood vessels, and decreased expression of arteriovenous specification markers. PI3K pathway inhibition with rapamycin normalized EC hyperproliferation and pericyte coverage in postnatal retinas and stimulated VM regression in vivo. In line with the mouse data, we also report the presence of activating PIK3CA mutations in human VMs, mutually exclusive with TEK mutations. Our data demonstrate a causal relationship between activating Pik3ca mutations and the genesis of VMs, provide a genetic model that faithfully mirrors the normal etiology and development of this human disease, and establish the basis for the use of PI3K-targeted therapies in VMs. Copyright © 2016, American Association for the Advancement of Science.

  19. p55PIK-PI3K stimulates angiogenesis in colorectal cancer cell by activating NF-κB pathway.

    PubMed

    Wang, Guihua; Chen, Cheng; Yang, Rui; Cao, Xiaonian; Lai, Senyan; Luo, Xuelai; Feng, Yongdong; Xia, Xianmin; Gong, Jianping; Hu, Junbo

    2013-07-01

    Vascular growth factor (VEGF) is an important mediator of angiogenesis. PI3K plays essential roles in angiogenesis; however, the mechanisms and specific functions of individual isoforms of PI3K members in tumor angiogenesis regulation are still not fully understood. In this study, we evaluate the role of p55PIK, a PI3K regulatory subunit encoded by PIK3R3 gene, in tumor angiogenesis. We reported that overexpression of p55PIK in cancer cells up-regulated HIF-1α expression and increased VEGF expression. Furthermore, overexpression of p55PIK increased tumor angiogenesis in vivo and in vitro. Moreover, data indicated enhanced HIF-1α expression by p55PIK-PI3K depended on its ability to activate NF-кB signaling pathways, especially to increase the phosphorylation of p65 subunits of NF-κB. Our study suggested that p55PIK-PI3K was essential in regulating cancer cell-mediated angiogenesis and contributed to tumor growth and that the p55PIK provides a potential and specific target for new anti-angiogenesis drug development.

  20. Common and distinct features of mammary tumors driven by Pten-deletion or activating Pik3ca mutation

    PubMed Central

    Liu, Jeff C.; Wang, Dong-Yu; Egan, Sean E.; Zacksenhaus, Eldad

    2016-01-01

    PTEN loss and PIK3CA activation both promote the accumulation of phosphatidylinositol (3, 4, 5)-trisphosphate (PIP3). While these proteins also have distinct biochemical functions, beyond the regulation of PIP3, little is known about the consequences of these differences in vivo. Here, we directly compared cancer signalling in mammary tumors from MMTV-Cre:Ptenf/f and MMTV-Cre:Pik3caLSL-H1047R mice. Using unsupervised hierarchical clustering we found that whereas MMTV-Cre:Pik3caLSL-H1047R-derived tumors fall into two separate groups, designated squamous-likeEx and class14Ex, MMTV-Cre:Ptenf/f tumors cluster as one group together with PIK3CAH1047R class14Ex, exhibiting a ‘luminal’ expression profile. Gene Set Enrichment Analysis (GSEA) of PtenΔ and PIK3CAH1047R class14Ex tumors revealed very similar profiles of signalling pathways as well as some interesting differences. Analysis of 18 signalling signatures revealed that PI3K signalling is significantly induced whereas EGFR signalling is significantly reduced in PtenΔ versus PIK3CAH1047R tumors. Thus, PtenΔ and PIK3CAH1047R tumors exhibit discernable differences that may impact tumorigenesis and response to therapy. PMID:26814435

  1. Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations

    PubMed Central

    Dogruluk, Turgut; Tsang, Yiu Huen; Espitia, Maribel; Chen, Fengju; Chen, Tenghui; Chong, Zechen; Appadurai, Vivek; Dogruluk, Armel; Eterovic, Agna Karina; Bonnen, Penelope E.; Creighton, Chad J.; Chen, Ken; Mills, Gordon B.; Scott, Kenneth L.

    2015-01-01

    Large-scale sequencing efforts are uncovering the complexity of cancer genomes, which are comprised of causal “driver” mutations that promote tumor progression along with many more pathologically-neutral “passenger” events. The majority of mutations, both in known cancer drivers and uncharacterized genes, are generally of low occurrence, highlighting the need to functionally annotate the long tail of infrequent mutations present in heterogeneous cancers. Here we describe a mutation assessment pipeline enabled by high-throughput engineering of molecularly-barcoded gene variant expression clones identified by tumor sequencing. We first used this platform to functionally assess tail mutations observed in PIK3CA, which encodes the catalytic subunit alpha of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) frequently mutated in cancer. Orthogonal screening for PIK3CA variant activity using in vitro and in vivo cell growth and transformation assays differentiated driver from passenger mutations, revealing that PIK3CA variant activity correlates imperfectly with its mutation frequency across breast cancer populations. While PIK3CA mutations with frequencies above 5% were significantly more oncogenic than wild-type in all assays, mutations occurring at 0.07 – 5.0% included those with and without oncogenic activities that ranged from weak to strong in at least one assay. Proteomic profiling coupled with therapeutic sensitivity assays on PIK3CA variant-expressing cell models revealed variant-specific activation of PI3K signaling as well as other pathways that include the MEK1/2 module of Mitogen-Activated Protein (MAP) Kinase pathway. Our data indicate that cancer treatments will need to increasingly consider the functional relevance of specific mutations in driver genes rather than considering all mutations in drivers as equivalent. PMID:26627007

  2. MicroRNA-375 inhibits colorectal cancer growth by targeting PIK3CA

    SciTech Connect

    Wang, Yihui; Tang, Qingchao; Li, Mingqi; Jiang, Shixiong; Wang, Xishan

    2014-02-07

    Highlights: • miR-375 is downregulated in colorectal cancer cell lines and tissues. • miR-375 inhibits colorectal cancer cell growth by targeting PIK3CA. • miR-375 inhibits colorectal cancer cell growth in xenograft nude mice model. - Abstract: Colorectal cancer (CRC) is the second most common cause of death from cancer. MicroRNAs (miRNAs) represent a class of small non-coding RNAs that control gene expression by triggering RNA degradation or interfering with translation. Aberrant miRNA expression is involved in human disease including cancer. Herein, we showed that miR-375 was frequently down-regulated in human colorectal cancer cell lines and tissues when compared to normal human colon tissues. PIK3CA was identified as a potential miR-375 target by bioinformatics. Overexpression of miR-375 in SW480 and HCT15 cells reduced PIK3CA protein expression. Subsequently, using reporter constructs, we showed that the PIK3CA untranslated region (3′-UTR) carries the directly binding site of miR-375. Additionally, miR-375 suppressed CRC cell proliferation and colony formation and led to cell cycle arrest. Furthermore, miR-375 overexpression resulted in inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. SiRNA-mediated silencing of PIK3CA blocked the inhibitory effect of miR-375 on CRC cell growth. Lastly, we found overexpressed miR-375 effectively repressed tumor growth in xenograft animal experiments. Taken together, we propose that overexpression of miR-375 may provide a selective growth inhibition for CRC cells by targeting PI3K/Akt signaling pathway.

  3. Development of in vitro PIK3C3/VPS34 complex protein assay for autophagy-specific inhibitor screening.

    PubMed

    Kim, Tae-Mi; Baek, Jong-Hyuk; Kim, Jeong Hee; Oh, Myung Sook; Kim, Joungmok

    2015-07-01

    Autophagy is an important catabolic program to respond to a variety of cellular stresses by forming a double membrane vesicle, autophagosome. Autophagy plays key roles in various cellular functions. Accordingly, dysregulation of autophagy is closely associated with diseases such as diabetes, neurodegenerative diseases, cardiomyopathy, and cancer. In this sense, autophagy is emerging as an important therapeutic target for disease control. Among the autophagy machineries, PIK3C3/VPS34 complex functions as an autophagy-triggering kinase to recruit the subsequent autophagy protein machineries on the phagophore membrane. Accumulating evidence showing that inhibition of PIK3C3/VPS34 complex successfully inhibits autophagy makes the complex an attractive target for developing autophagy inhibitors. However, one concern about PIK3C3/VPS34 complex is that many different PIK3C3/VPS34 complexes have distinct cellular functions. In this study, we have developed an in vitro PIK3C3/VPS34 complex monitoring assay for autophagy inhibitor screening in a high-throughput assay format instead of targeting the catalytic activity of the PIK3C3/VPS34 complex, which shuts down all PIK3C3/VPS34 complexes. We performed in vitro reconstitution of an essential autophagy-promoting PIK3C3/VPS34 complex, Vps34-Beclin1-ATG14L complex, in a microwell plate (96-well format) and successfully monitored the complex formation in many different conditions. This PIK3C3/VPS34 complex protein assay would provide a reliable tool for the screening of autophagy-specific inhibitors.

  4. An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice

    PubMed Central

    Kinross, Kathryn M.; Montgomery, Karen G.; Kleinschmidt, Margarete; Waring, Paul; Ivetac, Ivan; Tikoo, Anjali; Saad, Mirette; Hare, Lauren; Roh, Vincent; Mantamadiotis, Theo; Sheppard, Karen E.; Ryland, Georgina L.; Campbell, Ian G.; Gorringe, Kylie L.; Christensen, James G.; Cullinane, Carleen; Hicks, Rodney J.; Pearson, Richard B.; Johnstone, Ricky W.; McArthur, Grant A.; Phillips, Wayne A.

    2012-01-01

    Mutations in the gene encoding the p110α subunit of PI3K (PIK3CA) that result in enhanced PI3K activity are frequently observed in human cancers. To better understand the role of mutant PIK3CA in the initiation or progression of tumorigenesis, we generated mice in which a PIK3CA mutation commonly detected in human cancers (the H1047R mutation) could be conditionally knocked into the endogenous Pik3ca locus. Activation of this mutation in the mouse ovary revealed that alone, Pik3caH1047R induced premalignant hyperplasia of the ovarian surface epithelium but no tumors. Concomitantly, we analyzed several human ovarian cancers and found PIK3CA mutations coexistent with KRAS and/or PTEN mutations, raising the possibility that a secondary defect in a co-regulator of PI3K activity may be required for mutant PIK3CA to promote transformation. Consistent with this notion, we found that Pik3caH1047R mutation plus Pten deletion in the mouse ovary led to the development of ovarian serous adenocarcinomas and granulosa cell tumors. Both mutational events were required for early, robust Akt activation. Pharmacological inhibition of PI3K/mTOR in these mice delayed tumor growth and prolonged survival. These results demonstrate that the Pik3caH1047R mutation with loss of Pten is enough to promote ovarian cell transformation and that we have developed a model system for studying possible therapies. PMID:22214849

  5. PIK3CA mutations in the kinase domain (exon 20) of uterine endometrial adenocarcinomas are associated with adverse prognostic parameters.

    PubMed

    Catasus, Lluis; Gallardo, Alberto; Cuatrecasas, Miriam; Prat, Jaime

    2008-02-01

    Mutations of the oncogene PIK3CA occur frequently in endometrial carcinomas, but their prognostic significance is unclear. To determine the clinicopathological and molecular implications of these mutations, PIK3CA status was investigated in 109 endometrial (102 endometrioid and 7 mixed) carcinomas and the results were compared with clinicopathological parameters associated with prognosis. Tumors were also investigated for microsatellite instability and PTEN, beta-catenin gene (CTNNB1), K-RAS, and B-RAF mutations. We found 35 PIK3CA somatic missense mutations in 32 (29%) endometrial carcinomas. Eighteen mutations occurred in exon 20 (kinase domain), and 17 in exon 9 (helical domain). Almost all mutated tumors were pure endometrioid adenocarcinomas. All tumors with PIK3CA mutations exhibited myometrial invasion (P=0.032). Lymphovascular invasion was found more frequently in mutated (28%) than nonmutated carcinomas (18%). Histological grade varied significantly according to the location of the PIK3CA mutations whether in exon 9 or exon 20 (P=0.033). The frequency of exon 9 mutations was higher in grade 1 carcinomas (57%) than in grade 2 (29%) or grade 3 (14%) tumors. Conversely, mutations in exon 20 were more common in grade 3 (60%) than in grade 2 (20%) or grade 1 (20%) carcinomas. None of the tumors confined to the endometrium (stage IA) had PIK3CA mutations. Furthermore, whereas 64% of adenocarcinomas with exon 9 mutations had invaded < or =(1/2) of the myometrial thickness (stage IB), 73% of tumors with exon 20 mutations had either deeper myometrial invasion (stage IC) or cervical involvement (stage II) (P=0.045). PIK3CA mutations coexisted with microsatellite instability and mutations in PTEN, CTNNB1, K-RAS, and B-RAF genes. These results favor that PIK3CA mutations are associated with myometrial invasion and, moreover, that tumors harboring PIK3CA mutations in exon 20 are frequently high-grade, deeply invasive endometrial carcinomas that tend to exhibit

  6. Development of PIK-75 nanosuspension formulation with enhanced delivery efficiency and cytotoxicity for targeted anti-cancer therapy.

    PubMed

    Talekar, Meghna; Ganta, Srinivas; Amiji, Mansoor; Jamieson, Stephen; Kendall, Jackie; Denny, William A; Garg, Sanjay

    2013-06-25

    PIK-75 is a phosphatidylinositol 3-kinase (PI3K) inhibitor that shows selectivity toward p110-α over the other PI3K class Ia isoforms p110-β and p110-δ, but it lacks solubility, stability and other kinase selectivity. The purpose of this study was to develop folate-targeted PIK-75 nanosuspension for tumor targeted delivery and to improve therapeutic efficacy in human ovarian cancer model. High pressure homogenization was used to prepare the non-targeted and targeted PIK-75 nanosuspensions which were characterized for size, zeta potential, entrapment efficiency, morphology, saturation solubility and dissolution velocity. In vitro analysis of drug uptake, cell viability and cell survival was conducted in SKOV-3 cells. Drug pharmacokinetics and pAkt expression were determined in SKOV-3 tumor bearing mice. PIK-75 nanosuspensions showed an improvement in dissolution velocity and an 11-fold increase in saturation solubility over pre-milled PIK-75. In vitro studies in SKOV-3 cells indicated a 2-fold improvement in drug uptake and 0.4-fold decrease in IC50 value of PIK-75 following treatment with targeted nanosuspension compared to non-targeted nanosuspension. The improvement in cytotoxicity was attributed to an increase in caspase 3/7 and hROS activity. In vivo studies indicated a 5-10-fold increased PIK-75 accumulation in the tumor with both the nanosuspension formulations compared to PIK-75 suspension. The targeted nanosuspension showed an enhanced downregulation of pAkt compared to non-targeted formulation system. These results illustrate the opportunity to formulate PIK-75 as a targeted nanosuspension to enhance uptake and cytotoxicity of the drug in tumor.

  7. Mutations in PIK3R1 can lead to APDS2, SHORT syndrome or a combination of the two.

    PubMed

    Bravo García-Morato, M; García-Miñaúr, S; Molina Garicano, J; Santos Simarro, F; López-Grandos, E; Ferreira Cerdán, A; Rodríguez Pena, R

    2017-03-13

    Mutations in PIK3R1 gene have been associated to two different conditions: a primary immunodeficiency, called APDS2, of recent description and SHORT syndrome. 47 patients with APDS2 have been reported to date, only one of them sharing both PIK3R1-related phenotypes. Here we describe two more patients affected by APDS2 and SHORT syndrome, which highlights that this association may not be so infrequent. We recommend that patients with mutations in PIK3R1 gene should be assessed by both clinical immunologists and clinical geneticists.

  8. Nunaput Negeqlirmi (Our Village of St. Mary's).

    ERIC Educational Resources Information Center

    Alaska State Dept. of Education, Juneau.

    Yup'ik Eskimo children from the fifth and sixth grades of St. Mary's Public School, St. Mary's, Alaska, wrote this collection of 28 short stories. The 55 page book is printed in both Yup'ik and English. It features large type and illustrations drawn by the children and is intended for use in a bilingual education program. Some of the stories deal…

  9. Theresa Marie Schiavo's Long Road to Peace

    ERIC Educational Resources Information Center

    Cerminara, Kathy L.

    2006-01-01

    The death of Theresa Marie Schiavo came about only after almost 7 years of argument among her family members. Her husband, Michael Schiavo, was convinced that she would have refused the medically supplied nutrition and hydration maintaining her life. Her parents, Robert and Mary Schindler, and her siblings were equally convinced that her condition…

  10. University of Texas MD Anderson Cancer Center: Characterization of PIK3R1 Neomorphic Mutations | Office of Cancer Genomics

    Cancer.gov

    The goal of this project was to functionally characterize the most frequent mutation of the PIK3R1 gene and to explore potential therapeutic approaches to target the aberration. Read the abstract Experimental Approaches Cytotoxicity Screen

  11. Identification and characterisation of a novel constitutional PIK3CA mutation in a child lacking the typical segmental overgrowth of “PIK3CA-Related Overgrowth Spectrum” (PROS)

    PubMed Central

    Di Donato, Nataliya; Rump, Andreas; Mirzaa, Ghayda M.; Alcantara, Diana; Oliver, Antony; Schrock, Evelin; Dobyns, William B.; O’Driscoll, Mark

    2015-01-01

    Activating somatic PIK3CA mutations underlie a growing heterogeneous spectrum of segmental overgrowth disorders. We report the identification and evaluation of a novel de novo constitutional PIK3CA mutation (NM_006218.2:c.335T>A, p.Ile112Asn) in a child with congenital megalencephaly and macrosomia. Functional characterization of patient cells using a variety of endpoints demonstrates increased Phosphatidylinositol-3-kinase (PI3K) activity. The mutation lies in a linker region adjacent to the p85 (PIK3R2) binding domain of the p110α (PIK3CA) catalytic subunit of PI3K. We show that altered stoichiometry within the p85-p110 complex likely underlies the hyperactive PI3K-AKT-mTOR signaling in this instance. Our findings expand upon the recently proposed “PIK3CA-Related Overgrowth Spectrum” (PROS) associated with PIKC3A-mutations and PI3K hyper-activation, adding constitutional PIK3CA mutations as an underlying cause of megalencephaly and macrosomia in newborns. PMID:26593112

  12. PIK3R1 (p85α) is somatically mutated at high frequency in primary endometrial cancer.

    PubMed

    Urick, Mary E; Rudd, Meghan L; Godwin, Andrew K; Sgroi, Dennis; Merino, Maria; Bell, Daphne W

    2011-06-15

    Phosphoinositide 3-kinase (PI3K) is an important therapeutic target. Mutations in PIK3CA, which encodes p110α, the catalytic subunit of PI3K, occur in endometrioid endometrial cancers (EEC) and nonendometrioid endometrial cancers (NEEC). The goal of this study was to determine whether PIK3R1, which encodes p85α, the inhibitory subunit of PI3K, is mutated in endometrial carcinoma. We carried out exonic sequencing of PIK3R1 from 42 EECs and 66 NEECs. The pattern of PIK3R1 mutations was compared with the patterns of PIK3CA, PTEN, and KRAS mutations. The biochemical effect of seven PIK3R1 mutations was examined by stable expression in U2OS cells, followed by coimmunoprecipitation analysis of p110α, and Western blotting of phospho-AKT(Ser473) (p-AKT(Ser473)). We found that PIK3R1 was somatically mutated in 43% of EECs and 12% of NEECs. The majority of mutations (93.3%) were localized to the p85α-nSH2 and -iSH2 domains. Several mutations were recurrent. PIK3R1 mutations were significantly (P = 0.0015) more frequent in PIK3CA-wild type EECs (70%) than in PIK3CA mutant EECs (18%). Introduction of wild-type p85α into U2OS cells reduced the level of p-AKT(Ser473) compared with the vector control. Five p85α mutants, p85αdelH450-E451, p85αdelK459, p85αdelY463-L466, p85αdelR574-T576, and the p85αN564D positive control, were shown to bind p110α and led to increased levels of p-AKT(Ser473). The p85αR348X and p85αK511VfsX2 mutants did not bind p110α and showed no appreciable change in p-AKT(Ser473) levels. In conclusion, our study has revealed a new mode of PI3K alteration in primary endometrial tumors and warrants future studies to determine whether PIK3R1 mutations correlate with clinical outcome to targeted therapies directed against the PI3K pathway in EEC and NEEC.

  13. Enhanced heterologous production of desosaminyl macrolides and their hydroxylated derivatives by overexpression of the pikD regulatory gene in Streptomyces venezuelae.

    PubMed

    Jung, Won Seok; Jeong, Soon Jeong; Park, Sung Ryeol; Choi, Cha Yong; Park, Byoung Chul; Park, Je Won; Yoon, Yeo Joon

    2008-04-01

    To elevate the production level of heterologous polyketide in Streptomyces venezuelae, an additional copy of the positive regulatory gene pikD was introduced into the pikromycin (Pik) polyketide synthase (PKS) deletion mutant of S. venezuelae ATCC 15439 expressing tylosin PKS genes. The resulting mutant strain showed enhanced production of both tylactone (TL) and desosaminyl tylactone (DesTL) of 2.7- and 17.1-fold, respectively. The notable increase in DesTL production strongly suggested that PikD upregulates the expression of the desosamine (des) biosynthetic gene cluster. In addition, two hydroxylated forms of DesTL were newly detected from the extract of this mutant. These hydroxylated forms presumably resulted from a PikD-dependent increase in expression of the pikC gene that encodes P450 hydroxylase. Gene expression analysis by reverse transcriptase PCR and bioconversion experiments of 10-deoxymethynolide, narbonolide, and TL into the corresponding desosaminyl macrolides indicated that PikD is a positive regulator of the des and pikC genes, as well as the Pik PKS genes. These results demonstrate the role of PikD as a pathway-specific positive regulator of the entire Pik biosynthetic pathway and its usefulness in the development of a host-vector system for efficient heterologous production of desosaminyl macrolides and novel hydroxylated compounds.

  14. An integrative genomic and proteomic analysis of PIK3CA, PTEN and AKT mutations in breast cancer

    SciTech Connect

    Stemke-Hale, Katherine; Gonzalez-Angulo, Ana Maria; Lluch, Ana; Neve, Richard M.; Kuo, Wen-Lin; Davies, Michael; Carey, Mark; Hu, Zhi; Guan, Yinghui; Sahin, Aysegul; Symmans, W. Fraser; Pusztai, Lajos; Nolden, Laura K.; Horlings, Hugo; Berns, Katrien; Hung, Mien-Chie; van de Vijver, Marc J.; Valero, Vicente; Gray, Joe W.; Bernards, Rene; Mills, Gordon B.; Hennessy, Bryan T.

    2008-05-06

    Phosphatidylinositol-3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy-based sequencing and reverse phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT and PTEN mutations, and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in-vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor positive (33.8%) and HER2-positive (24.6%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor-positive cancers with PTEN protein levels also being significantly lower in hormone receptor-positive cancers. Unlike AKT1 mutations, PIK3CA (39%) and PTEN (20%) mutations were more common in cell lines than tumors, suggesting a selection for these but not AKT1 mutations during adaptation to culture. PIK3CA mutations did not have a significant impact on outcome in 166 hormone receptor-positive breast cancer patients after adjuvant tamoxifen. PIK3CA mutations, in comparison with PTEN loss and AKT1 mutations, were associated with significantly less and indeed inconsistent activation of AKT and of downstream PI3K/AKT signaling in tumors and cell lines, and PTEN loss and PIK3CA mutation were frequently concordant, suggesting different contributions to pathophysiology. PTEN loss but not PIK3CA mutations rendered cells sensitive to growth inhibition by the PI3K inhibitor LY294002. Thus, PI3K pathway aberrations likely play a distinct role in the pathogenesis of different breast cancer subtypes. The specific aberration may have implications for the selection of PI3K-targeted therapies in hormone receptor-positive breast cancer.

  15. PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution

    PubMed Central

    Timms, Andrew E.; Conti, Valerio; Girisha, Katta M.; Martin, Beth; Olds, Carissa; Collins, Sarah; Park, Kaylee; Carter, Melissa; Krägeloh-Mann, Inge; Chitayat, David; Parikh, Aditi Shah; Bradshaw, Rachael; Torti, Erin; Braddock, Stephen; Burke, Leah; Ghedia, Sondhya; Stephan, Mark; Stewart, Fiona; Prasad, Chitra; Napier, Melanie; Saitta, Sulagna; Straussberg, Rachel; Gabbett, Michael; O’Connor, Bridget C.; Yin, Lim Jiin; Lai, Angeline Hwei Meeng; Martin, Nicole; McKinnon, Margaret; Addor, Marie-Claude; Schwartz, Charles E.; Lanoel, Agustina; Conway, Robert L.; Devriendt, Koenraad; Tatton-Brown, Katrina; Pierpont, Mary Ella; Painter, Michael; Worgan, Lisa; Reggin, James; Hennekam, Raoul; Pritchard, Colin C.; Aracena, Mariana; Gripp, Karen W.; Cordisco, Maria; Van Esch, Hilde; Garavelli, Livia; Curry, Cynthia; Goriely, Anne; Kayserilli, Hulya; Shendure, Jay; Graham, John; Guerrini, Renzo; Dobyns, William B.

    2016-01-01

    Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targeted-panel testing (n = 6), whole-exome sequencing (n = 5), or Sanger sequencing (n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations. PMID:27631024

  16. PIK3CA mutations define favorable prognostic biomarkers in operable breast cancer: a systematic review and meta-analysis.

    PubMed

    Liu, Yi-Rong; Jiang, Yi-Zhou; Zuo, Wen-Jia; Yu, Ke-Da; Shao, Zhi-Ming

    2014-01-01

    Mutations of the p110α catalytic subunit of phosphatidylinositol 3-kinase (PIK3CA) are among the most common genetic aberrations in human breast cancer. At present, controversy exists concerning the prognostic value of the mutations. We performed a systematic review and meta-analysis to clarify the association between PIK3CA mutations and survival outcomes. A comprehensive, computerized literature search of PubMed, Web of Science databases, the Chinese Biomedical Literature Database, and Wangfang Data until August 27, 2013 was carried out. Eligible studies were included according to specific inclusion criteria. Pooled hazard ratio was estimated by using the fixed effects model or random effects model according to heterogeneity between studies. Eight eligible studies were included in the analysis, all of which were retrospective cohort studies. The overall meta-analysis demonstrated that the PIK3CA mutations were associated with better clinical outcomes (hazard ratio 0.72; 95% confidence interval: 0.57-0.91; P=0.006). None of the single studies materially altered the original results and no evidence of publication bias was found. Further subgroup analysis of mutations in exons 9 and 20 did not show statistical significance. PIK3CA mutations in operable primary breast cancer indicate a good prognosis. Further studies should be conducted to investigate the effect of PIK3CA mutations on clinical outcomes in different histologic types, different molecular subtypes of breast cancer, and different exons of PIK3CA.

  17. PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.

    PubMed

    Mirzaa, Ghayda; Timms, Andrew E; Conti, Valerio; Boyle, Evan August; Girisha, Katta M; Martin, Beth; Kircher, Martin; Olds, Carissa; Juusola, Jane; Collins, Sarah; Park, Kaylee; Carter, Melissa; Glass, Ian; Krägeloh-Mann, Inge; Chitayat, David; Parikh, Aditi Shah; Bradshaw, Rachael; Torti, Erin; Braddock, Stephen; Burke, Leah; Ghedia, Sondhya; Stephan, Mark; Stewart, Fiona; Prasad, Chitra; Napier, Melanie; Saitta, Sulagna; Straussberg, Rachel; Gabbett, Michael; O'Connor, Bridget C; Keegan, Catherine E; Yin, Lim Jiin; Lai, Angeline Hwei Meeng; Martin, Nicole; McKinnon, Margaret; Addor, Marie-Claude; Boccuto, Luigi; Schwartz, Charles E; Lanoel, Agustina; Conway, Robert L; Devriendt, Koenraad; Tatton-Brown, Katrina; Pierpont, Mary Ella; Painter, Michael; Worgan, Lisa; Reggin, James; Hennekam, Raoul; Tsuchiya, Karen; Pritchard, Colin C; Aracena, Mariana; Gripp, Karen W; Cordisco, Maria; Esch, Hilde Van; Garavelli, Livia; Curry, Cynthia; Goriely, Anne; Kayserilli, Hulya; Shendure, Jay; Graham, John; Guerrini, Renzo; Dobyns, William B

    2016-06-16

    Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targeted-panel testing (n = 6), whole-exome sequencing (n = 5), or Sanger sequencing (n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.

  18. 18. Photocopy, 'St. Mary's School,' from the commemorative booklet published ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    18. Photocopy, 'St. Mary's School,' from the commemorative booklet published for the 125th anniversary of St. Mary's Parish, 1980. View Southwest, North Front and East Side, at St. John Street and Church Street (Original in possession of St. Mary's Parish) - St. Mary's Roman Catholic School, Northwest corner of Church Avenue & Guthrie Street, McKees Rocks, Allegheny County, PA

  19. PIK3R1 Mutations Cause Syndromic Insulin Resistance with Lipoatrophy

    PubMed Central

    Thauvin-Robinet, Christel; Auclair, Martine; Duplomb, Laurence; Caron-Debarle, Martine; Avila, Magali; St-Onge, Judith; Le Merrer, Martine; Le Luyer, Bernard; Héron, Delphine; Mathieu-Dramard, Michèle; Bitoun, Pierre; Petit, Jean-Michel; Odent, Sylvie; Amiel, Jeanne; Picot, Damien; Carmignac, Virginie; Thevenon, Julien; Callier, Patrick; Laville, Martine; Reznik, Yves; Fagour, Cédric; Nunes, Marie-Laure; Capeau, Jacqueline; Lascols, Olivier; Huet, Frédéric; Faivre, Laurence; Vigouroux, Corinne; Rivière, Jean-Baptiste

    2013-01-01

    Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutaneous fat. We ascertained two unrelated individuals with SHORT syndrome, hypothesized that the observed phenotype was most likely due to de novo mutations in the same gene, and performed whole-exome sequencing in the two probands and their unaffected parents. We then confirmed our initial observations in four other subjects with SHORT syndrome from three families, as well as 14 unrelated subjects presenting with syndromic insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation. Overall, we identified in nine affected individuals from eight families de novo or inherited PIK3R1 mutations, including a mutational hotspot (c.1945C>T [p.Arg649Trp]) present in four families. PIK3R1 encodes the p85α, p55α, and p50α regulatory subunits of class IA phosphatidylinositol 3 kinases (PI3Ks), which are known to play a key role in insulin signaling. Functional data from fibroblasts derived from individuals with PIK3R1 mutations showed severe insulin resistance for both proximal and distal PI3K-dependent signaling. Our findings extend the genetic causes of severe insulin-resistance syndromes and provide important information with respect to the function of PIK3R1 in normal development and its role in human diseases, including growth delay, Rieger anomaly and other ocular affections, insulin resistance, diabetes, paucity of fat, and ovarian cysts. PMID:23810378

  20. Genome Analysis of Latin American Cervical Cancer: Frequent Activation of the PIK3CA Pathway

    PubMed Central

    Lou, Hong; Villagran, Guillermo; Boland, Joseph F.; Im, Kate M.; Polo, Sarita; Zhou, Weiyin; Odey, Ushie; Juárez-Torres, Eligia; Medina-Martínez, Ingrid; Roman-Basaure, Edgar; Mitchell, Jason; Roberson, David; Sawitzke, Julie; Garland, Lisa; Rodríguez-Herrera, Maria; Wells, David; Troyer, Jennifer; Pinto, Francisco Castillo; Bass, Sara; Zhang, Xijun; Castillo, Miriam; Gold, Bert; Morales, Hesler; Yeager, Meredith; Berumen, Jaime; Alvirez, Enrique; Gharzouzi, Eduardo; Dean, Michael

    2015-01-01

    Purpose Cervical cancer is one of the most common causes of cancer mortality for women living in poverty, causing over 28,000 deaths annually in Latin America and 266,000 worldwide. To better understand the molecular basis of the disease we ascertained blood and tumor samples from Guatemala and Venezuela and performed genomic characterization. Experimental Design We performed HPV typing and identified somatically mutated genes using exome and ultra-deep targeted sequencing with confirmation in samples from Mexico. Copy number changes were also assessed in the exome sequence. Results Cervical cancer cases in Guatemala and Venezuela have an average age-of-diagnosis of 50 years, and 5.6 children. Analysis of 675 tumors revealed activation of PIK3CA and other phosphatidyl inositol (PI3K)/AKT pathway genes in 31% of squamous carcinomas and 24% of adeno- and adenosquamous tumors, predominantly at two sites (E542K, E545K) in the helical domain of the PIK3CA gene. This distribution of PIK3CA mutations is distinct from most other cancer types, and does not result in the in vitro phosphorylation of AKT. Somatic mutations were more frequent in squamous carcinomas diagnosed after age 50. Frequent gain of chromosome 3q was found and low PIK3CA mutation fractions in many tumors suggest that PI3K mutation can be a late event in tumor progression. Conclusions PI3K pathway mutation is important to cervical carcinogenesis in Latin America. Therapeutic agents that directly target PI3K could play a role in the therapy of this common malignancy. PMID:26080840

  1. Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations

    PubMed Central

    Huang-Doran, Isabel; Tomlinson, Patsy; Payne, Felicity; Gast, Alexandra; Sleigh, Alison; Bottomley, William; Harris, Julie; Daly, Allan; Rocha, Nuno; Rudge, Simon; Clark, Jonathan; Kwok, Albert; Romeo, Stefano; McCann, Emma; Müksch, Barbara; Dattani, Mehul; Zucchini, Stefano; Wakelam, Michael; Foukas, Lazaros C.; Savage, David B.; Murphy, Rinki; O’Rahilly, Stephen; Semple, Robert K.

    2016-01-01

    Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657X PIK3R1 mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85α with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85α overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus, PIK3R1 C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome. PMID:27766312

  2. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes

    PubMed Central

    Rivière, Jean-Baptiste; Mirzaa, Ghayda M.; O’Roak, Brian J.; Beddaoui, Margaret; Alcantara, Diana; Conway, Robert L.; St-Onge, Judith; Schwartzentruber, Jeremy A.; Gripp, Karen W.; Nikkel, Sarah M.; Worthylake, Thea; Sullivan, Christopher T.; Ward, Thomas R.; Butler, Hailly E.; Kramer, Nancy A.; Albrecht, Beate; Armour, Christine M.; Armstrong, Linlea; Caluseriu, Oana; Cytrynbaum, Cheryl; Drolet, Beth A.; Innes, A. Micheil; Lauzon, Julie L.; Lin, Angela E.; Mancini, Grazia M. S.; Meschino, Wendy S.; Reggin, James D.; Saggar, Anand K.; Lerman-Sagie, Tally; Uyanik, Gökhan; Weksberg, Rosanna; Zirn, Birgit; Beaulieu, Chandree L.; Majewski, Jacek; Bulman, Dennis E.; O’Driscoll, Mark; Shendure, Jay; Graham, John M.; Boycott, Kym M.; Dobyns, William B.

    2012-01-01

    Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features1-5. We performed exome sequencing in three families with MCAP or MPPH and confirmed our initial observations in exomes from 7 MCAP and 174 control individuals, as well as in 40 additional megalencephaly subjects using a combination of Sanger sequencing, restriction-enzyme assays, and targeted deep sequencing. We identified de novo germline or postzygotic mutations in three core components of the phosphatidylinositol-3-kinase (PI3K)/AKT pathway. These include two mutations of AKT3, one recurrent mutation of PIK3R2 in 11 unrelated MPPH families, and 15 mostly postzygotic mutations of PIK3CA in 23 MCAP and one MPPH patients. Our data highlight the central role of PI3K/AKT signaling in vascular, limb and brain development, and emphasize the power of massively parallel sequencing in a challenging context of phenotypic and genetic heterogeneity combined with postzygotic mosaicism. PMID:22729224

  3. Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy

    PubMed Central

    Roy, Achira; Skibo, Jonathan; Kalume, Franck; Ni, Jing; Rankin, Sherri; Lu, Yiling; Dobyns, William B; Mills, Gordon B; Zhao, Jean J; Baker, Suzanne J; Millen, Kathleen J

    2015-01-01

    Mutations in the catalytic subunit of phosphoinositide 3-kinase (PIK3CA) and other PI3K-AKT pathway components have been associated with cancer and a wide spectrum of brain and body overgrowth. In the brain, the phenotypic spectrum of PIK3CA-related segmental overgrowth includes bilateral dysplastic megalencephaly, hemimegalencephaly and focal cortical dysplasia, the most common cause of intractable pediatric epilepsy. We generated mouse models expressing the most common activating Pik3ca mutations (H1047R and E545K) in developing neural progenitors. These accurately recapitulate all the key human pathological features including brain enlargement, cortical malformation, hydrocephalus and epilepsy, with phenotypic severity dependent on the mutant allele and its time of activation. Underlying mechanisms include increased proliferation, cell size and altered white matter. Notably, we demonstrate that acute 1 hr-suppression of PI3K signaling despite the ongoing presence of dysplasia has dramatic anti-epileptic benefit. Thus PI3K inhibitors offer a promising new avenue for effective anti-epileptic therapy for intractable pediatric epilepsy patients. DOI: http://dx.doi.org/10.7554/eLife.12703.001 PMID:26633882

  4. Patterns of PIK3CA alterations in familial colorectal and endometrial carcinoma.

    PubMed

    Ollikainen, Miina; Gylling, Annette; Puputti, Marjut; Nupponen, Nina N; Abdel-Rahman, Wael M; Butzow, Ralf; Peltomäki, Päivi

    2007-08-15

    While the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is known to be activated in multiple sporadic cancers, the role of this pathway in familial tumors is mostly unknown. We searched for alterations in the catalytic domain of PI3K (PIK3CA), PTEN and KRAS, all of which may contribute to PI3K/AKT pathway activation, in a total of 160-familial colorectal (CRC) and endometrial carcinomas (EC), stratified by the presence vs. absence of germline mutations in DNA mismatch repair (MMR) genes. PIK3CA alterations (consisting of point mutations or low-level amplification, which were mutually exclusive with 1 exception) occurred in 10/70 (14%) of CRCs and 19/90 (21%) of ECs. Within ECs, amplification was significantly associated with the subgroup lacking germline mutations in MMR genes (familial site-specific endometrial cancer) (p = 0.015). Decreased or lost PTEN expression was characteristic of endometrial tumourigenesis (51/81, 63%, in EC compared with 24/62, 39%, in CRC, p = 0.004) and KRAS mutations of colorectal tumourigenesis (19/70, 27% in CRC vs. 9/89, 10%, in EC, p = 0.006) regardless of the MMR gene mutation status. PIK3CA alterations frequently coexisted with PTEN or KRAS changes. Combined with published studies on sporadic tumors, our data broaden the understanding of the role for PI3K pathway genes in human tumorigenesis.

  5. Activation of diverse signaling pathways by oncogenic PIK3CA mutations

    PubMed Central

    Wu, Xinyan; Renuse, Santosh; Sahasrabuddhe, Nandini A.; Zahari, Muhammad Saddiq; Chaerkady, Raghothama; Kim, Min-Sik; Nirujogi, Raja S.; Mohseni, Morassa; Kumar, Praveen; Raju, Rajesh; Zhong, Jun; Yang, Jian; Neiswinger, Johnathan; Jeong, Jun-Seop; Newman, Robert; Powers, Maureen A.; Somani, Babu Lal; Gabrielson, Edward; Sukumar, Saraswati; Stearns, Vered; Qian, Jiang; Zhu, Heng; Vogelstein, Bert; Park, Ben Ho; Pandey, Akhilesh

    2014-01-01

    The PIK3CA gene is frequently mutated in human cancers. Here we carry out a SILAC-based quantitative phosphoproteomic analysis using isogenic knockin cell lines containing ‘driver’ oncogenic mutations of PIK3CA to dissect the signaling mechanisms responsible for oncogenic phenotypes induced by mutant PIK3CA. From 8,075 unique phosphopeptides identified, we observe that aberrant activation of PI3K pathway leads to increased phosphorylation of a surprisingly wide variety of kinases and downstream signaling networks. Here, by integrating phosphoproteomic data with human protein microarray-based AKT1 kinase assays, we discover and validate six novel AKT1 substrates, including cortactin. Through mutagenesis studies, we demonstrate that phosphorylation of cortactin by AKT1 is important for mutant PI3K enhanced cell migration and invasion. Our study describes a quantitative and global approach for identifying mutation-specific signaling events and for discovering novel signaling molecules as readouts of pathway activation or potential therapeutic targets. PMID:25247763

  6. Marie Curie during ORT6

    NASA Technical Reports Server (NTRS)

    2003-01-01

    Marie Curie sits on the lander petal prior to deployment during the pre launch Operations Readiness Test (ORT) 6.

    Pathfinder, a low-cost Discovery mission, is the first of a new fleet of spacecraft that are planned to explore Mars over thenext ten years. Mars Global Surveyor, already en route, arrives at Mars on September 11 to begin a two year orbital reconnaissance of the planet's composition, topography, and climate. Additional orbiters and landers will follow every 26 months.

    The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

  7. Marie Curie during ORT4

    NASA Technical Reports Server (NTRS)

    2003-01-01

    Marie Curie rover drives down the rear ramp during Operational Readiness Test (ORT) 4.

    Pathfinder, a low-cost Discovery mission, is the first of a new fleet of spacecraft that are planned to explore Mars over thenext ten years. Mars Global Surveyor, already en route, arrives at Mars on September 11 to begin a two year orbital reconnaissance of the planet's composition, topography, and climate. Additional orbiters and landers will follow every 26 months.

    The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

  8. Prognostic role of PIK3CA mutations of cell-free DNA in early-stage triple negative breast cancer.

    PubMed

    Takeshita, Takashi; Yamamoto, Yutaka; Yamamoto-Ibusuki, Mutsuko; Inao, Toko; Sueta, Aiko; Fujiwara, Saori; Omoto, Yoko; Iwase, Hirotaka

    2015-11-01

    PIK3CA is an oncogene that encodes the p110α component of phosphatidylinositol 3-kinase (PI3K); it is the second most frequently mutated gene following the TP53 gene. In the clinical setting, PIK3CA mutations may have favorable prognostic value for hormone receptor-positive breast cancer patients and, during the past few years, PIK3CA mutations of cell-free DNA (cfDNA) have attracted attention as a potential noninvasive biomarker of cancer. However, there are few reports on the clinical implications of PIK3CA mutations for TNBC patients. We investigated the PIK3CA major mutation status of cfDNA as a noninvasive biomarker of cancer using droplet digital polymerase chain reaction (ddPCR), which has high level sensitivity and specificity for cancer mutation, in early-stage 49 triple negative breast cancer (TNBC) patients. A total of 12 (24.4%) of 49 patients had PIK3CA mutations of cfDNA. In a median follow up of 54.4 months, the presence of PIK3CA mutations of cfDNA had significant impacts on relapse-free survival (RFS; P = 0.0072) and breast cancer-specific survival (BCSS; P = 0.016), according to the log-lank test. In a Cox proportional hazards model, the presence of PIK3CA mutations of cfDNA had significant prognostic value in the univariate and multivariate analysis. Additionally, the presence of PIK3CA mutations of cfDNA was significantly correlated with positive androgen receptor phosphorylated form depending on PI3K signaling pathway (pAR) which is independent favorable prognostic factors of TNBC. We demonstrated that the presence of PIK3CA major mutations of cfDNA could be a discriminatory predictor of RFS and BCSS in early-stage TNBC patients and it was associated with PI3K pathway-dependent AR phosphorylation. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  9. Loss of a 1.6 Mb chromosome in Pyricularia oryzae harboring two alleles of AvrPik leads to acquisition of virulence to rice cultivars containing resistance alleles at the Pik locus.

    PubMed

    Kusaba, Motoaki; Mochida, Taiga; Naridomi, Takeshi; Fujita, Yoshikatsu; Chuma, Izumi; Tosa, Yukio

    2014-11-01

    A small and extra chromosome of 1.6 Mb was previously identified in a Pyricularia oryzae strain, 84R-62B. To understand a role of the 1.6 Mb chromosome in the pathogenic changeability of P. oryzae, we performed experiments designed to characterize the 1.6 Mb chromosome in the present study. A gene family encoding secreted protein Pex31s in P. oryzae consists of five homologs, Pex31-A to -E. Among them, Pex31-A and -D are known to be recognized by Pik-m and Pik/Pik-m/Pik-p, respectively. In the present study, we identified Pex31-A and -D in the genome of 84R-62B. Segregation analyses using an F1 population between 84R-62B and another rice blast strain, Y93-245c-2, revealed a strong linkage between the two homologs and the 1.6 Mb chromosome of 84R-62B. A CHEF-Southern analysis revealed an association between the 1.6 Mb chromosome and the homologs, indicating that both homologs are located on the 1.6 Mb chromosome of 84R-62B. The loss of the 1.6 Mb chromosome was observed in subcultures of a F1 progeny, F1-327. These subcultures concomitantly acquired virulence on Pik, Pik-m, and Pik-p. The present study is the first report showing that loss of a small and extra chromosome leads to pathogenic mutation of P. oryzae and may provide a new insight into the mechanisms generating pathogenic variation of this fungus.

  10. Mutant PIK3CA Induces EMT in a Cell Type Specific Manner

    PubMed Central

    Bhagirath, Divya; Zhao, Xiangshan; Mirza, Sameer; West, William W.; Band, Hamid; Band, Vimla

    2016-01-01

    Breast cancer is characterized into different molecular subtypes, and each subtype is characterized by differential gene expression that are associated with distinct survival outcomes in patients. PIK3CA mutations are commonly associated with most breast cancer subtypes. More recently PIK3CA mutations have been shown to induce tumor heterogeneity and are associated with activation of EGFR-signaling and reduced relapse free survival in basal subtype of breast cancer. Thus, understanding what determines PIK3CA induced heterogeneity and oncogenesis, is an important area of investigation. In this study, we assessed the effect of mutant PIK3CA together with mutant Ras plus mutant p53 on oncogenic behavior of two distinct stem/progenitor breast cell lines, designated as K5+/K19- and K5+/K19+. Constructs were ectopically overexpressed in K5+/K19- and K5+/K19+ stem/progenitor cells, followed by various in-vitro and in-vivo analyses. Oncogene combination m-Ras/m-p53/m-PIK3CA efficiently transformed both K5+/K19- and K5+/K19+ cell lines in-vitro, as assessed by anchorage-independent soft agar colony formation assay. Significantly, while this oncogene combination induced a complete epithelial-to-mesenchymal transition (EMT) in K5+/K19- cell line, mostly epithelial phenotype with minor EMT component was seen in K5+/K19+ cell line. However, both K5+/K19- and K5+/K19+ transformed cells exhibited increased invasion and migration abilities. Analyses of CD44 and CD24 expression showed both cell lines had tumor-initiating CD44+/CD24low cell population, however transformed K5+/K19- cells had more proportion of these cells. Significantly, both cell types exhibited in-vivo tumorigenesis, and maintained their EMT and epithelial nature in-vivo in mice tumors. Notably, while both cell types exhibited increase in tumor-initiating cell population, differential EMT phenotype was observed in these cell lines. These results suggest that EMT is a cell type dependent phenomenon and does not

  11. Mutant PIK3CA Induces EMT in a Cell Type Specific Manner.

    PubMed

    Bhagirath, Divya; Zhao, Xiangshan; Mirza, Sameer; West, William W; Band, Hamid; Band, Vimla

    2016-01-01

    Breast cancer is characterized into different molecular subtypes, and each subtype is characterized by differential gene expression that are associated with distinct survival outcomes in patients. PIK3CA mutations are commonly associated with most breast cancer subtypes. More recently PIK3CA mutations have been shown to induce tumor heterogeneity and are associated with activation of EGFR-signaling and reduced relapse free survival in basal subtype of breast cancer. Thus, understanding what determines PIK3CA induced heterogeneity and oncogenesis, is an important area of investigation. In this study, we assessed the effect of mutant PIK3CA together with mutant Ras plus mutant p53 on oncogenic behavior of two distinct stem/progenitor breast cell lines, designated as K5+/K19- and K5+/K19+. Constructs were ectopically overexpressed in K5+/K19- and K5+/K19+ stem/progenitor cells, followed by various in-vitro and in-vivo analyses. Oncogene combination m-Ras/m-p53/m-PIK3CA efficiently transformed both K5+/K19- and K5+/K19+ cell lines in-vitro, as assessed by anchorage-independent soft agar colony formation assay. Significantly, while this oncogene combination induced a complete epithelial-to-mesenchymal transition (EMT) in K5+/K19- cell line, mostly epithelial phenotype with minor EMT component was seen in K5+/K19+ cell line. However, both K5+/K19- and K5+/K19+ transformed cells exhibited increased invasion and migration abilities. Analyses of CD44 and CD24 expression showed both cell lines had tumor-initiating CD44+/CD24low cell population, however transformed K5+/K19- cells had more proportion of these cells. Significantly, both cell types exhibited in-vivo tumorigenesis, and maintained their EMT and epithelial nature in-vivo in mice tumors. Notably, while both cell types exhibited increase in tumor-initiating cell population, differential EMT phenotype was observed in these cell lines. These results suggest that EMT is a cell type dependent phenomenon and does not

  12. Neomorphic Mutations in PIK3R1 Confer Sensitivity to MAPK Inhibitors due to Activation of ERK and JNK Pathways | Office of Cancer Genomics

    Cancer.gov

    In a recent publication in Cancer Cell, CTD2 investigators discovered that a known cancer-associated gain-of-function alteration in phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) results in novel protein activity that confers sensitivity to mitogen-activated protein kinase (MAPK) inhibitors. The PIK3R1 gene encodes the p85α regulatory subunit of PIK3. Under normal conditions, p85α suppresses PIK3 mediated activation of downstream pathways that promote cell growth and survival.

  13. Activating PIK3CA Mutations Induce an Epidermal Growth Factor Receptor (EGFR)/Extracellular Signal-regulated Kinase (ERK) Paracrine Signaling Axis in Basal-like Breast Cancer*

    PubMed Central

    Young, Christian D.; Zimmerman, Lisa J.; Hoshino, Daisuke; Formisano, Luigi; Hanker, Ariella B.; Gatza, Michael L.; Morrison, Meghan M.; Moore, Preston D.; Whitwell, Corbin A.; Dave, Bhuvanesh; Stricker, Thomas; Bhola, Neil E.; Silva, Grace O.; Patel, Premal; Brantley-Sieders, Dana M.; Levin, Maren; Horiates, Marina; Palma, Norma A.; Wang, Kai; Stephens, Philip J.; Perou, Charles M.; Weaver, Alissa M.; O'Shaughnessy, Joyce A.; Chang, Jenny C.; Park, Ben Ho; Liebler, Daniel C.; Cook, Rebecca S.; Arteaga, Carlos L.

    2015-01-01

    Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K) have been shown to transform human mammary epithelial cells (MECs). These mutations are present in all breast cancer subtypes, including basal-like breast cancer (BLBC). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified 72 protein expression changes in human basal-like MECs with knock-in E545K or H1047R PIK3CA mutations versus isogenic MECs with wild-type PIK3CA. Several of these were secreted proteins, cell surface receptors or ECM interacting molecules and were required for growth of PIK3CA mutant cells as well as adjacent cells with wild-type PIK3CA. The proteins identified by MS were enriched among human BLBC cell lines and pointed to a PI3K-dependent amphiregulin/EGFR/ERK signaling axis that is activated in BLBC. Proteins induced by PIK3CA mutations correlated with EGFR signaling and reduced relapse-free survival in BLBC. Treatment with EGFR inhibitors reduced growth of PIK3CA mutant BLBC cell lines and murine mammary tumors driven by a PIK3CA mutant transgene, all together suggesting that PIK3CA mutations promote tumor growth in part by inducing protein changes that activate EGFR. PMID:25953087

  14. Activating PIK3CA Mutations Induce an Epidermal Growth Factor Receptor (EGFR)/Extracellular Signal-regulated Kinase (ERK) Paracrine Signaling Axis in Basal-like Breast Cancer.

    PubMed

    Young, Christian D; Zimmerman, Lisa J; Hoshino, Daisuke; Formisano, Luigi; Hanker, Ariella B; Gatza, Michael L; Morrison, Meghan M; Moore, Preston D; Whitwell, Corbin A; Dave, Bhuvanesh; Stricker, Thomas; Bhola, Neil E; Silva, Grace O; Patel, Premal; Brantley-Sieders, Dana M; Levin, Maren; Horiates, Marina; Palma, Norma A; Wang, Kai; Stephens, Philip J; Perou, Charles M; Weaver, Alissa M; O'Shaughnessy, Joyce A; Chang, Jenny C; Park, Ben Ho; Liebler, Daniel C; Cook, Rebecca S; Arteaga, Carlos L

    2015-07-01

    Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K) have been shown to transform human mammary epithelial cells (MECs). These mutations are present in all breast cancer subtypes, including basal-like breast cancer (BLBC). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified 72 protein expression changes in human basal-like MECs with knock-in E545K or H1047R PIK3CA mutations versus isogenic MECs with wild-type PIK3CA. Several of these were secreted proteins, cell surface receptors or ECM interacting molecules and were required for growth of PIK3CA mutant cells as well as adjacent cells with wild-type PIK3CA. The proteins identified by MS were enriched among human BLBC cell lines and pointed to a PI3K-dependent amphiregulin/EGFR/ERK signaling axis that is activated in BLBC. Proteins induced by PIK3CA mutations correlated with EGFR signaling and reduced relapse-free survival in BLBC. Treatment with EGFR inhibitors reduced growth of PIK3CA mutant BLBC cell lines and murine mammary tumors driven by a PIK3CA mutant transgene, all together suggesting that PIK3CA mutations promote tumor growth in part by inducing protein changes that activate EGFR. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. Radium, Marie Curie and modern science.

    PubMed

    Langevin-Joliot, H

    1998-11-01

    In 1898, the discovery of two new elements, polonium and radium, reawakened interest in the topic of uranic rays discovered 2 years before by H. Becquerel. Radioactivity, a name coined by Marie Curie, became a major research field for decades. The contrasting personalities of Pierre Curie, already a first-rank physicist, and of the young Marie Curie-Sklodowska as they undertook their common work are described. It is shown how a well-chosen quantitative method and a systematic approach combining physics and chemistry led to the discovery within less than 1 year. The special role of radium and the determination of its atomic weight by Marie Curie followed by her long-term program for accumulating pure radium salts are emphasized. The first woman with a full professorship at a French University, Marie Curie created and managed the Radium Institute.

  16. Improved survival associated with somatic PIK3CA mutations in copy-number low endometrioid endometrial adenocarcinoma

    PubMed Central

    LIN, DOUGLAS I.

    2015-01-01

    The phosphoinositide-3-kinase (PI3K) signaling pathway has been implicated in the development of endometrioid endometrial adenocarcinoma (EEC). Recently, The Cancer Genome Atlas (TCGA) project stratified EEC into four molecular subgroups, with the majority of tumors falling into the copy-number low-EEC (CNL-EEC) molecular subgroup. The aim of the present study was to investigate whether alterations of the PI3K pathway are associated with specific survival outcomes in patients with EEC. The clinical and genomic data of 307 patients with endometrioid-type tumors were obtained from TCGA project, including 90 patients in the CNL-EEC subgroup. Patients were evaluated in terms of survival and clinicopathological characteristics, as well as mutations in the PI3K catalytic subunit alpha (PIK3CA) gene and their effect on PIK3CA function. In CNL-EEC subgroup patients, somatic PIK3CA mutations (48/90 cases) were associated with significantly improved overall survival compared with that of wild-type PIK3CA (P=0.018). Furthermore, this improved survival was specific to the CNL-EEC subgroup and was not observed in other TCGA molecular subgroups. The majority of CNL-EEC cases were low-stage (stage I) and low-to-intermediate grade (grades 1–2) endometrioid tumors. There were no significant differences in age, stage, histology or International Federation of Gynecology and Obstetrics grade between PIK3CA-mutated and non-mutated patient groups (P>0.05). In addition, the majority of cases contained activating PIK3CA mutations. Overall, in the TCGA cohort, PIK3CA mutations had a favorable effect on the survival of patients with EEC, and this effect was dependent on tumoral molecular sub-stratification. Future studies on larger independent cohorts with long term follow-up are warranted to further analyze this association. PMID:26722235

  17. Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern

    PubMed Central

    Hafner, Christian; López-Knowles, Elena; Luis, Nuno M.; Toll, Agustí; Baselga, Eulàlia; Fernández-Casado, Alex; Hernández, Silvia; Ribé, Adriana; Mentzel, Thomas; Stoehr, Robert; Hofstaedter, Ferdinand; Landthaler, Michael; Vogt, Thomas; Pujol, Ramòn M.; Hartmann, Arndt; Real, Francisco X.

    2007-01-01

    Activating mutations of the p110 α subunit of PI3K (PIK3CA) oncogene have been identified in a broad spectrum of malignant tumors. However, their role in benign or preneoplastic conditions is unknown. Activating FGF receptor 3 (FGFR3) mutations are common in benign skin lesions, either as embryonic mutations in epidermal nevi (EN) or as somatic mutations in seborrheic keratoses (SK). FGFR3 mutations are also common in low-grade malignant bladder tumors, where they often occur in association with PIK3CA mutations. Therefore, we examined exons 9 and 20 of PIK3CA and FGFR3 hotspot mutations in EN (n = 33) and SK (n = 62), two proliferative skin lesions lacking malignant potential. Nine of 33 (27%) EN harbored PIK3CA mutations; all cases showed the E545G substitution, which is uncommon in cancers. In EN, R248C was the only FGFR3 mutation identified. By contrast, 10 of 62 (16%) SK revealed the typical cancer-associated PIK3CA mutations E542K, E545K, and H1047R. The same lesions displayed a wide range of FGFR3 mutations. Corresponding unaffected tissue was available for four EN and two mutant SK: all control samples displayed a WT sequence, confirming the somatic nature of the mutations found in lesional tissue. Forty of 95 (42%) lesions showed at least one mutation in either gene. PIK3CA and FGFR3 mutations displayed an independent distribution; 5/95 lesions harbored mutations in both genes. Our findings suggest that, in addition to their role in cancer, oncogenic PIK3CA mutations contribute to the pathogenesis of skin tumors lacking malignant potential. The remarkable genotype–phenotype correlation as observed in this study points to a distinct etiopathogenesis of the mutations in keratinocytes occuring either during fetal development or in adult life. PMID:17673550

  18. [When Marie Bonaparte turned a deaf ear].

    PubMed

    Amouroux, Rémy; Stouten, Hanna

    2014-01-01

    Between 1927 and 1931 Marie Bonaparte had herself operated upon her clitoris three times. She did so against Freud's advice with whom she was in analysis. Among psychoanalysts these operations are still often regarded as "errors" or aberrations. But for Marie Bonaparte, who was in various ways familiar with physics and a somatic approach, surgery was the first choice, psychoanalysis only a possible alternative. She was not impressed by the scepticism of her colleagues, and adhered even more emphatically to her own strategy.

  19. Charcot-Marie-Tooth disease: an update.

    PubMed

    Shy, Michael E

    2004-10-01

    The purpose of this review is to assist neurologists, neuroscientists and other interested readers in following the expanding volume of information relating to the inherited peripheral neuropathies collectively referred to as Charcot-Marie-Tooth disease. Currently, mutations in multiple different genes expressed in Schwann cells and neurons cause a variety of overlapping clinical phenotypes. Recent articles clarify molecular pathways involved in the pathogenesis of these disorders, and for the first time provide rational treatment strategies for the most common form of Charcot-Marie-Tooth disease. The identification of many new genes associated with neuropathy demonstrate the role of axonal transport and abnormal protein trafficking in causing various forms of Charcot-Marie-Tooth. They also further define the role of axonal signaling and the molecular architecture of both Schwann cells and neurons in maintaining normal peripheral nervous system function. Finally, recent reports have shown that progesterone antagonists and ascorbic acid can successfully treat rodent models of Charcot-Marie-Tooth disease type 1A. Taken together, results from these articles support the concept that genetic causes of Charcot-Marie-Tooth disease serve as a living microarray system to identify molecules necessary for normal peripheral nervous system function. When we can make sense of these microarrays we are likely to understand the pathogenesis and develop rational therapies for many neurodegenerative diseases including Charcot-Marie-Tooth.

  20. PIK3CA mutation is an early event in the development of endometriosis-associated ovarian clear cell adenocarcinoma.

    PubMed

    Yamamoto, Sohei; Tsuda, Hitoshi; Takano, Masashi; Iwaya, Keichi; Tamai, Seiichi; Matsubara, Osamu

    2011-10-01

    Clear cell adenocarcinoma (CCA), a highly lethal histological subtype of ovarian carcinoma, is a type of human cancer with a high frequency of activating mutations in the PIK3CA gene. In this study, we aimed to determine how these mutations contribute to tumour development of CCAs. Exons 9 and 20 of the PIK3CA gene were analysed by direct genomic DNA sequencing of 23 CCAs with synchronous putative precursor lesions (ie endometriosis adjacent to carcinoma, with or without cytological atypia) and their mutational statuses were compared. Somatic mutations of the PIK3CA gene were detected in 10/23 (43%) carcinomas and in all cases the type of mutation was H1047R in the kinase domain. The identical H1047R mutation was also detected in the coexisting endometriotic epithelium, adjacent to the CCAs, in nine of ten (90%) cases. Moreover, in six of the nine lesions, the H1047R mutation was identified even in the endometrioses lacking cytological atypia. These findings provide evidence that mutations of the PIK3CA gene occur in the putative precursor lesions of CCA, strongly suggesting that they are very early events in tumourigenesis, probably initiating the malignant transformation of endometriosis. A specific kinase inhibitor to mutated PIK3CA may potentially be an effective therapeutic reagent against these carcinomas. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  1. Opposing roles of PIK3CA gene alterations to EZH2 signaling in non-muscle invasive bladder cancer.

    PubMed

    Segovia, Cristina; Martínez-Fernández, Mónica; Dueñas, Marta; Rubio, Carolina; López-Calderón, Fernando F; Costa, Clotilde; Saiz-Ladera, Cristina; Fernández-Grajera, María; Duarte, José; Muñoz, Huberto García; de la Rosa, Federico; Villacampa, Felipe; Castellano, Daniel; Paramio, Jesús M

    2017-02-07

    The high rates of tumor recurrence and progression represent a major clinical problem in non-muscle invasive bladder cancer. Previous data showed that EZH2-dependent signaling mediates these processes, whereas the frequent alterations of PIK3CA gene (copy gains and mutations) are predictive of reduced recurrence. Here we show, using clinical samples and bladder cancer cell lines, a functional interaction between EZH2- and PIK3CA-dependent signaling pathways. PIK3CA alterations mediated, on the one hand, the increased expression of two miRNAs, miR-101 and miR-138, which posttranscriptionally downregulate EZH2 expression. On the other hand, PIK3CA alterations facilitate the activation of Akt which phosphorylates EZH2 on Ser21, precluding the trimethylation of histone H3 in K27. Remarkably the increased expression of miR101 or miR138 and the expression of Ser21-phosphorylated EZH2 are good prognostic factors regarding non-muscle invasive bladder cancer recurrence and progression. Collectively, this study provides molecular evidences indicating that the gene expression rewiring occurring in primary bladder tumors, associated with increased EZH2 expression and activity and mediating the increased recurrence and progression risk, are prevented by PIK3CA-dependent signaling. This molecular process may have deep implications in the management of bladder cancer patients and in the design of novel molecularly targeted therapeutic approaches.

  2. PIK3CAH1047R and Her2 initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling

    PubMed Central

    Cheng, Hailing; Liu, Pixu; Ohlson, Carolynn; Xu, Erbo; Symonds, Lynn; Isabella, Adam; Muller, William J.; Lin, Nancy U.; Krop, Ian E.; Roberts, Thomas M.; Winer, Eric P.; Arteaga, Carlos L.; Zhao, Jean J.

    2015-01-01

    Human breast cancers that have HER2 amplification/overexpression frequently carry PIK3CA mutations, and are often associated with a worse prognosis. However, the role of PIK3CA mutations in the initiation and maintenance of these breast cancers remains elusive. In the present study, we generated a compound mouse model that genetically mimics HER2 positive breast cancer with coexisting PIK3CAH1047R. Induction of PIK3CAH1047R expression in mouse mammary glands with constitutive expression of activated Her2/Neu resulted in accelerated mammary tumorigenesis with enhanced metastatic potential. Interestingly, inducible expression of mutant PIK3CA resulted in a robust activation of PI3K/AKT signaling but attenuation of Her2/Her3 signaling, and this can be reversed by deinduction of PIK3CAH1047R expression. Strikingly, while these Her2+ PIK3CAH1047R initiated primary mammary tumors are refractory to HER2-targeted therapy, all tumors responded to inactivation of the oncogenic PIK3CAH1047R, a situation closely mimicking the use of a highly effective inhibitor specifically targeting the mutant PIK3CA/p110a. Notably, these tumors eventually resumed growth, and a fraction of them escaped PI3K dependence by compensatory ERK activation, which can be blocked by combined inhibition of Her2 and MEK. Together, these results suggest that PIK3CA-specific inhibition as a monotherapy followed by combination therapy targeting MAPK and HER2 in a timely manner may be an effective treatment approach against HER2 positive cancers with coexisting PIK3CA-activating mutations. PMID:26640141

  3. Clinical Delineation and Natural History of the PIK3CA-Related Overgrowth Spectrum**

    PubMed Central

    Keppler-Noreuil, Kim M; Sapp, Julie C; Lindhurst, Marjorie J; Parker, Victoria ER; Blumhorst, Cathy; Darling, Thomas; Tosi, Laura L; Huson, Susan M; Whitehouse, Richard W; Jakkula, Eveliina; Grant, Ian; Balasubramanian, Meena; Chandler, Kate E; Fraser, Jamie L; Gucev, Zoran; Crow, Yanick J; Brennan, Leslie Manace; Clark, Robin; Sellars, Elizabeth A; Pena, Loren DM; Krishnamurty, Vidya; Shuen, Andrew; Braverman, Nancy; Cunningham, Michael L; Sutton, V Reid; Tasic, Velibor; Graham, John M; Geer, Joseph; Henderson, Alex; Semple, Robert K; Biesecker, Leslie G

    2014-01-01

    Somatic mutations in the phosphatidylinositol/AKT/mTOR pathway cause segmental overgrowth disorders. Diagnostic descriptors associated with PIK3CA mutations include fibroadipose overgrowth (FAO), Hemihyperplasia multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/skeletal and spinal (CLOVES) syndrome, macrodactyly, and the megalencephaly syndrome, Megalencephaly-Capillary malformation (MCAP) syndrome. We set out to refine the understanding of the clinical spectrum and natural history of these phenotypes, and now describe 35 patients with segmental overgrowth and somatic PIK3CA mutations. The phenotypic data show that these previously described disease entities have considerable overlap, and represent a spectrum. While this spectrum overlaps with Proteus syndrome (sporadic, mosaic, and progressive) it can be distinguished by the absence of cerebriform connective tissue nevi and a distinct natural history. Vascular malformations were found in 15/35 (43%) and epidermal nevi in 4/35 (11%) patients, lower than in Proteus syndrome. Unlike Proteus syndrome, 31/35 (89%) patients with PIK3CA mutations had congenital overgrowth, and in 35/35 patients this was asymmetric and disproportionate. Overgrowth was mild with little postnatal progression in most, while in others it was severe and progressive requiring multiple surgeries. Novel findings include: adipose dysregulation present in all patients, unilateral overgrowth that is predominantly left-sided, overgrowth that affects the lower extremities more than the upper extremities and progresses in a distal to proximal pattern, and in the most severely affected patients is associated with marked paucity of adipose tissue in unaffected areas. While the current data are consistent with some genotype–phenotype correlation, this cannot yet be confirmed. © The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc. PMID:24782230

  4. Prognostic role of PIK3CA mutations and their association with hormone receptor expression in breast cancer: a meta-analysis.

    PubMed

    Pang, Bo; Cheng, Shi; Sun, Shi-Peng; An, Cheng; Liu, Zhi-Yuan; Feng, Xue; Liu, Gui-Jian

    2014-09-01

    The phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene is frequently mutated in breast cancer (BCa). Sex hormone receptors (HRs), including estrogen receptor (ER) and progesterone receptor (PR) play pivotal roles in BCa. In this study, we evaluated the association between PIK3CA mutations and ER/PR expression and the prognostic role of PIK3CA mutations in BCa patients, and in particular, HR-positive BCa. Thirty-two studies involving 5719 cases of BCa obtained from database searches were examined. PIK3CA gene mutations correlated significantly with ER/PR expression (p < 0.00001) and relapse-free survival (RFS) (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.59-0.98, p = 0.03) but not overall survival (OS) (HR 1.14, 95%CI 0.72-1.82, p = 0.57) in unsorted BCa patients. PIK3CA mutations were not associated with OS (HR 1.06, 95%CI 0.67-1.67, p = 0.81) or RFS (HR 0.86, 95%CI 0.53-1.40, p = 0.55) in HR-positive BCa patients. In conclusion, PIK3CA mutations were significantly related to ER/PR expression and RFS in unsorted BCa patients. However, the clinical implications of PIK3CA mutations may vary according to different mutant exons. And PIK3CA mutations alone may have limited prognostic value for HR-positive BCa patients.

  5. Nucleocytoplasmic Shuttling of the Golgi Phosphatidylinositol 4-Kinase Pik1 Is Regulated by 14-3-3 Proteins and Coordinates Golgi Function with Cell Growth

    PubMed Central

    Demmel, Lars; Beck, Mike; Klose, Christian; Schlaitz, Anne-Lore; Gloor, Yvonne; Hsu, Peggy P.; Havlis, Jan; Shevchenko, Andrej; Krause, Eberhard; Kalaidzidis, Yannis

    2008-01-01

    The yeast phosphatidylinositol 4-kinase Pik1p is essential for proliferation, and it controls Golgi homeostasis and transport of newly synthesized proteins from this compartment. At the Golgi, phosphatidylinositol 4-phosphate recruits multiple cytosolic effectors involved in formation of post-Golgi transport vesicles. A second pool of catalytically active Pik1p localizes to the nucleus. The physiological significance and regulation of this dual localization of the lipid kinase remains unknown. Here, we show that Pik1p binds to the redundant 14-3-3 proteins Bmh1p and Bmh2p. We provide evidence that nucleocytoplasmic shuttling of Pik1p involves phosphorylation and that 14-3-3 proteins bind Pik1p in the cytoplasm. Nutrient deprivation results in relocation of Pik1p from the Golgi to the nucleus and increases the amount of Pik1p–14-3-3 complex, a process reversed upon restored nutrient supply. These data suggest a role of Pik1p nucleocytoplasmic shuttling in coordination of biosynthetic transport from the Golgi with nutrient signaling. PMID:18172025

  6. Dual PI3K/mTOR Inhibition in Colorectal Cancers with APC and PIK3CA Mutations.

    PubMed

    Foley, Tyler M; Payne, Susan N; Pasch, Cheri A; Yueh, Alex E; Van De Hey, Dana R; Korkos, Demetra P; Clipson, Linda; Maher, Molly E; Matkowskyj, Kristina A; Newton, Michael A; Deming, Dustin A

    2017-02-09

    Therapeutic targeting of the PI3K pathway is an active area of research in multiple cancer types, including breast and endometrial cancers. This pathway is commonly altered in cancer and plays an integral role in numerous vital cellular functions. Mutations in the PIK3CA gene, resulting in a constitutively active form of PI3K, often occur in colorectal cancer, though the population of patients who would benefit from targeting this pathway has yet to be identified. In human colorectal cancers, PIK3CA mutations most commonly occur concomitantly with loss of adenomatous polyposis coli (APC). Here, treatment strategies are investigated that target the PI3K pathway in colon cancers with mutations in APC and PIK3CA Colorectal cancer spheroids with Apc and Pik3ca mutations were generated and characterized confirming that these cultures represent the tumors from which they were derived. Pan and alpha isomer-specific PI3K inhibitors did not induce a significant treatment response, whereas the dual PI3K/mTOR inhibitors BEZ235 and LY3023414 induced a dramatic treatment response through decreased cellular proliferation and increased differentiation. The significant treatment responses were confirmed in mice with Apc and Pik3ca-mutant colon cancers as measured using endoscopy with a reduction in median lumen occlusion of 53% with BEZ235 and a 24% reduction with LY3023414 compared with an increase of 53% in controls (P < 0.001 and P = 0.03, respectively). This response was also confirmed with (18)F-FDG microPET/CT imaging.Implications: Spheroid models and transgenic mice suggest that dual PI3K/mTOR inhibition is a potential treatment strategy for APC and PIK3CA-mutant colorectal cancers. Thus, further clinical studies of dual PI3K/mTOR inhibitors are warranted in colorectal cancers with these mutations. Mol Cancer Res; 15(3); 1-11. ©2016 AACR.

  7. Meet EPA Scientist Marie O'Shea, Ph.D.

    EPA Pesticide Factsheets

    EPA Scientist Dr. Marie O'Shea is Region 2's Liaison to the Agency's Office of Research and Development (ORD). Marie has a background in research on urban watershed management, focused on characterizing and controlling nutrients in stormwater runoff.

  8. 21. Photocopy of drawing (from Sault Ste. Marie, MI city ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    21. Photocopy of drawing (from Sault Ste. Marie, MI city archives) showing ROADWAY ACROSS SECTION DETAILS - Spruce Street Bridge, East Spruce Street, 500 Block, spanning Power Canal, Sault Ste. Marie, Chippewa County, MI

  9. Overexpression of PIK3CA in murine head and neck epithelium drives tumor invasion and metastasis through PDK1 and enhanced TGFβ signaling

    PubMed Central

    Du, L; Chen, X; Cao, Y; Lu, L; Zhang, F; Bornstein, S; Li, Y; Owens, P; Malkoski, S; Said, S; Kulesz-Martin, M; Gross, N; Wang, X-J; Lu, S-L

    2015-01-01

    Head and neck squamous cell carcinoma (HNSCC) patients have a poor prognosis, with invasion and metastasis as major causes of mortality. The phosphatidylinositol 3-kinase (PI3K) pathway regulates a wide range of cellular processes crucial for tumorigenesis, and PIK3CA amplification and mutation are among the most common genetic alterations in human HNSCC. Compared to the well-documented roles of the PI3K pathway in cell growth and survival, the roles of the PI3K pathway in tumor invasion and metastasis have not been well delineated. We generated a PIK3CA-genetically engineered mouse model (PIK3CA-GEMM) in which wildtype PIK3CA is overexpressed in head and neck epithelium. Although PIK3CA overexpression alone was not sufficient to initiate HNSCC formation, it significantly increased tumor susceptibility in an oral-carcinogenesis mouse model. PIK3CA overexpression in mouse oral epithelium increased tumor invasiveness and metastasis by increasing epithelial-mesenchymal transition and by enriching a cancer stem cell phenotype in tumor epithelial cells. In addition to these epithelial alterations, we also observed marked inflammation in tumor stroma. AKT is a central signaling mediator of the PI3K pathway. However, molecular analysis suggested that progression of PIK3CA-driven HNSCC is facilitated by PDK1 and enhanced TGFβ signaling rather than by AKT. Examination of human HNSCC clinical samples revealed that both PIK3CA and PDK1 protein levels correlated with tumor progression, highlighting the significance of this pathway. In summary, our results offer significant insight into how PIK3CA-overexpression drives HNSCC invasion and metastasis, providing a rationale for targeting PI3K/PDK1 and TGFβ signaling in advanced HNSCC patients with PIK3CA amplification. PMID:26876212

  10. The pepper receptor-like cytoplasmic protein kinase CaPIK1 is involved in plant signaling of defense and cell-death responses.

    PubMed

    Kim, Dae Sung; Hwang, Byung Kook

    2011-05-01

    Certain protein kinases have been shown to be crucial for plant cell signaling pathways associated with plant immune responses. Here we identified a pepper (Capsicum annuum) receptor-like cytoplasmic protein kinase (RLCK) gene (CaPIK1) that is transcriptionally activated by infection with Xanthomonas campestris pv. vesicatoria (Xcv). Silencing of CaPIK1 in pepper plants confers enhanced susceptibility to Xcv infection. Salicylic acid-dependent defense responses are attenuated in the CaPIK1-silenced plants, including expression of salicylic acid-dependent genes, but not of a jasmonic acid-regulated gene. Induction of salicylic acid accumulation by Xcv infection is compromised in CaPIK1-silenced plants. The functional CaPIK1 protein not only autophosphorylates, but also phosphorylates myelin basic protein. CaPIK1 exists in the cytoplasm and also localizes to the plasma membrane of plant cells via its N-terminus. Transient expression of CaPIK1 in pepper leaves leads to generation of reactive oxygen species (ROS), ultimately leading to hypersensitive cell death. Over-expression (OX) of CaPIK1 in Arabidopsis enhances the basal resistance to infection with Pseudomonas syringae pv. tomato and Hyaloperonospora arabidopsidis, associated with elevated ROS bursts. Salicylic acid levels in CaPIK1-OX plants are higher than those in wild-type plants. Together, these results suggest that CaPIK1 modulates the signaling required for the salicylic acid-dependent defense response to pathogen infection. © 2011 The Authors. The Plant Journal © 2011 Blackwell Publishing Ltd.

  11. Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies.

    PubMed

    Hanker, Ariella B; Pfefferle, Adam D; Balko, Justin M; Kuba, María Gabriela; Young, Christian D; Sánchez, Violeta; Sutton, Cammie R; Cheng, Hailing; Perou, Charles M; Zhao, Jean J; Cook, Rebecca S; Arteaga, Carlos L

    2013-08-27

    Human epidermal growth factor receptor 2 (HER2; ERBB2) amplification and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations often co-occur in breast cancer. Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway has been shown to correlate with a diminished response to HER2-directed therapies. We generated a mouse model of HER2-overexpressing (HER2(+)), PIK3CA(H1047R)-mutant breast cancer. Mice expressing both human HER2 and mutant PIK3CA in the mammary epithelium developed tumors with shorter latencies compared with mice expressing either oncogene alone. HER2 and mutant PIK3CA also cooperated to promote lung metastases. By microarray analysis, HER2-driven tumors clustered with luminal breast cancers, whereas mutant PIK3CA tumors were associated with claudin-low breast cancers. PIK3CA and HER2(+)/PIK3CA tumors expressed elevated transcripts encoding markers of epithelial-to-mesenchymal transition and stem cells. Cells from HER2(+)/PIK3CA tumors more efficiently formed mammospheres and lung metastases. Finally, HER2(+)/PIK3CA tumors were resistant to trastuzumab alone and in combination with lapatinib or pertuzumab. Both drug resistance and enhanced mammosphere formation were reversed by treatment with a PI3K inhibitor. In sum, PIK3CA(H1047R) accelerates HER2-mediated breast epithelial transformation and metastatic progression, alters the intrinsic phenotype of HER2-overexpressing cancers, and generates resistance to approved combinations of anti-HER2 therapies.

  12. The Streptomyces venezuelae pikAV gene contains a transcription unit essential for expression of enzymes involved in glycosylation of narbonolide and 10-deoxymethynolide.

    PubMed

    Chen, S; Roberts, J B; Xue, Y; Sherman, D H; Reynolds, K A

    2001-01-24

    In Streptomyces venezuelae, four polyketide synthase (PKS) polypeptides encoded by pikAI-pikAIV are used to generate 10 and 12-membered macrocyclic structures, narbonolide and 10-deoxymethynolide. Sequence analysis suggests these genes are translationally coupled with downstream genes, pikAV (encoding a type II thioesterase), desVIII-desVI (encoding enzymes responsible for production of the final glycosylated products pikromycin, narbomycin, methymycin and neomethymycin) and desR (a resistance gene). Type II thioesterases have been suggested to have an editing function in polyketide biosynthesis and deletion of the corresponding genes often leads to decreased levels of polyketide production. Surprisingly an in-frame deletion of 687 bp of the 843 bp pikAV ORF led to a strain SC1022 that produced normal yields of polyketide products, but only in the aglycone form. Plasmid-based expression of the desVIII-VI and desR in the SC1022 strain completely restored production of glycosylated products, despite the absence of a functional pikAV gene product. Under these conditions the PikAV TEII therefore does not play an important role in polyketide biosynthesis, and its function remains an enigma. These observations also demonstrate that the region of pikAV DNA deleted in strain SC1022 contains a transcription unit essential for expression of the des genes. A sequence alignment of PikAV with members of the highly conserved type II thioesterases revealed a short divergent region at the carboxy terminus, suggesting a region of pikAV that might contain such a transcription unit. DNA containing this region of pikAV was shown to be able to increase plasmid-based expression of both crotonyl CoA reductase gene (ccr) and the erythromycin resistance gene (ermE) in S. venezuelae.

  13. The Role of PIK3CA Mutations among Lung Adenocarcinoma Patients with Primary and Acquired Resistance to EGFR Tyrosine Kinase Inhibition

    PubMed Central

    Wu, Shang-Gin; Chang, Yih-Leong; Yu, Chong-Jen; Yang, Pan-Chyr; Shih, Jin-Yuan

    2016-01-01

    To understand the impact of PIK3CA mutations on clinical characteristics and treatment response to epidermal growth factor tyrosine kinase inhibitors (EGFR TKIs) of lung adenocarcinoma, we examined PIK3CA and EGFR mutations in lung adenocarcinoma patients, and analyzed their clinical outcomes. Surgically excised tumor, bronchoscopy biopsy/brushing specimens and pleural effusions were prospectively collected from 1029 patients. PIK3CA and EGFR mutations were analyzed by RT-PCR and direct sequencing. In EGFR TKI-nave specimens, PIK3CA mutation rate was 1.8% (14/760). Twelve patients had coexisting PIK3CA and EGFR mutations. Among the 344 EGFR TKI-treated EGFR mutant patients, there was no significant difference in treatment response (p = 0.476) and progression-free survival (p = 0.401) of EGFR TKI between PIK3CA mutation-positive and negative patients. The PIK3CA mutation rate in lung adenocarcinoma with acquired resistance to EGFR TKI is not higher than that in EGFR TKI-naïve tissue specimens (2.9% (6/207) vs. 1.8%; p = 0.344). Of the 74 patients with paired specimens (TKI-naïve and acquired resistance to TKIs) only one patient (1.4%) developed acquired PIK3CA (E545K) mutation, and he also had acquired EGFR (T790M) mutation. In conclusion, PIK3CA mutation may not be associated with primary resistance to EGFR TKI among lung adenocarcinoma patients. Acquired PIK3CA mutation related to EGFR TKI treatment is rare. PMID:27734950

  14. The Potsdam Parallel Ice Sheet Model (PISM-PIK) - Part 1: Model description

    NASA Astrophysics Data System (ADS)

    Winkelmann, R.; Martin, M. A.; Haseloff, M.; Albrecht, T.; Bueler, E.; Khroulev, C.; Levermann, A.

    2011-09-01

    We present the Potsdam Parallel Ice Sheet Model (PISM-PIK), developed at the Potsdam Institute for Climate Impact Research to be used for simulations of large-scale ice sheet-shelf systems. It is derived from the Parallel Ice Sheet Model (Bueler and Brown, 2009). Velocities are calculated by superposition of two shallow stress balance approximations within the entire ice covered region: the shallow ice approximation (SIA) is dominant in grounded regions and accounts for shear deformation parallel to the geoid. The plug-flow type shallow shelf approximation (SSA) dominates the velocity field in ice shelf regions and serves as a basal sliding velocity in grounded regions. Ice streams can be identified diagnostically as regions with a significant contribution of membrane stresses to the local momentum balance. All lateral boundaries in PISM-PIK are free to evolve, including the grounding line and ice fronts. Ice shelf margins in particular are modeled using Neumann boundary conditions for the SSA equations, reflecting a hydrostatic stress imbalance along the vertical calving face. The ice front position is modeled using a subgrid-scale representation of calving front motion (Albrecht et al., 2011) and a physically-motivated calving law based on horizontal spreading rates. The model is tested in experiments from the Marine Ice Sheet Model Intercomparison Project (MISMIP). A dynamic equilibrium simulation of Antarctica under present-day conditions is presented in Martin et al. (2011).

  15. The Potsdam Parallel Ice Sheet Model (PISM-PIK) - Part 1: Model description

    NASA Astrophysics Data System (ADS)

    Winkelmann, R.; Martin, M. A.; Haseloff, M.; Albrecht, T.; Bueler, E.; Khroulev, C.; Levermann, A.

    2010-08-01

    We present the Potsdam Parallel Ice Sheet Model (PISM-PIK), developed at the Potsdam Institute for Climate Impact Research to be used for simulations of large-scale ice sheet-shelf systems. It is derived from the Parallel Ice Sheet Model (Bueler and Brown, 2009). Velocities are calculated by superposition of two shallow stress balance approximations within the entire ice covered region: the shallow ice approximation (SIA) is dominant in grounded regions and accounts for shear deformation parallel to the geoid. The plug-flow type shallow shelf approximation (SSA) dominates the velocity field in ice shelf regions and serves as a basal sliding velocity in grounded regions. Ice streams naturally emerge through this approach and can be identified diagnostically as regions with a significant contribution of membrane stresses to the local momentum balance. All lateral boundaries in PISM-PIK are free to evolve, including the grounding line and ice fronts. Ice shelf margins in particular are modeled using Neumann boundary conditions for the SSA equations, reflecting a hydrostatic stress imbalance along the vertical calving face. The ice front position is modeled using a subgrid scale representation of calving front motion (Albrecht et al., 2010) and a physically motivated dynamic calving law based on horizontal spreading rates. The model is validated within the Marine Ice Sheet Model Intercomparison Project (MISMIP) and is used for a dynamic equilibrium simulation of Antarctica under present-day conditions in the second part of this paper (Martin et al., 2010).

  16. PIK3CA and APC Mutations are Synergistic in the Development of Intestinal Cancers

    PubMed Central

    Deming, Dustin A.; Leystra, Alyssa A.; Nettekoven, Laura; Sievers, Chelsea; Miller, Devon; Middlebrooks, Malisa; Clipson, Linda; Albrecht, Dawn; Bacher, Jeff; Washington, Mary Kay; Weichert, Jamey; Halberg, Richard B.

    2013-01-01

    Human colorectal cancers are known to possess multiple mutations, though how these mutations interact in tumor development and progression has not been fully investigated. We have previously described the FCPIK3ca* murine colon cancer model which expresses a constitutively activated phosphoinositide-3 kinase (PI3K) in the intestinal epithelium. The expression of this dominantly active form of PI3K results in hyperplasia and invasive mucinous adenocarcinomas. These cancers form via a non-canonical mechanism of tumor initiation that is mediated through activation of PI3K and not through aberrations in WNT signaling. Since the Adenomatous Polyposis Coli (APC) gene is mutated in the vast majority of human colon cancers and often occurs simultaneously with PIK3CA mutations, we sought to better understand the interaction between APC and PIK3CA mutations in the mammalian intestine. In this study, we have generated mice in which the expression of a constitutively active PI3K and the loss of APC occur simultaneously in the distal small intestine and colon. Here we demonstrate that expression of a dominant active PI3K synergizes with loss of APC activity resulting in a dramatic changes in tumor multiplicity, size, morphology, and invasiveness. Activation of the PI3K pathway is not able to directly activate WNT signaling through the nuclear localization of CTNNB1 (β-catenin) in the absence of aberrant WNT signaling. Alterations at the transcriptional level, including increased CCND1, may be the etiology of synergy between these activated pathways. PMID:23708654

  17. PRKCI negatively regulates autophagy via PIK3CA/AKT–MTOR signaling

    SciTech Connect

    Qu, Liujing; Li, Ge; Xia, Dan; Hongdu, Beiqi; Xu, Chentong; Lin, Xin; Chen, Yingyu

    2016-02-05

    The atypical protein kinase C isoform PRKC iota (PRKCI) plays a key role in cell proliferation, differentiation, and carcinogenesis, and it has been shown to be a human oncogene. Here, we show that PRKCI overexpression in U2OS cells impaired functional autophagy in normal or cell stress conditions, as characterized by decreased levels of light chain 3B-II protein (LC3B-II) and weakened degradation of endogenous and exogenous autophagic substrates. Conversely, PRKCI knockdown by small interference RNA resulted in opposite effects. Additionally, we identified two novel PRKCI mutants, PRKCI{sup L485M} and PRKCI{sup P560R}, which induced autophagy and exhibited dominant negative effects. Further studies indicated that PRKCI knockdown–mediated autophagy was associated with the inactivation of phosphatidylinositol 3-kinase alpha/AKT–mammalian target of rapamycin (PIK3CA/AKT–MTOR) signaling. These data underscore the importance of PRKCI in the regulation of autophagy. Moreover, the finding may be useful in treating PRKCI-overexpressing carcinomas that are characterized by increased levels of autophagy. - Highlights: • The atypical protein kinase C iota isoform (PRKCI) is a human oncogene. • PRKCI overexpression impairs functional autophagy in U2OS cells. • It reduces LC3B-II levels and weakens SQSTM1 and polyQ80 aggregate degradation. • PRKCI knockdown has the opposite effect. • The effect of PRKCI knockdown is related to PIK3CA/AKT–MTOR signaling inactivation.

  18. EGFR, KRAS, BRAF, and PIK3CA characterization in squamous cell anal cancer.

    PubMed

    Martin, Vittoria; Zanellato, Elena; Franzetti-Pellanda, Alessandra; Molinari, Francesca; Movilia, Alessandra; Paganotti, Alessia; Deantonio, Letizia; De Dosso, Sara; Assi, Agnese; Crippa, Stefano; Boldorini, Renzo; Mazzucchelli, Luca; Saletti, Piercarlo; Frattini, Milo

    2014-04-01

    Combined chemoradiation therapy is the gold standard in the treatment of squamous cell anal cancer (SCAC). However, even if the response rate is very high, many patients eventually relapse or experience a reccurrence, thus requiring an invasive surgical procedure that has severe side effects. Most SCAC tumors overexpress epidermal growth factor receptor (EGFR); therefore, it is reasonable to consider anti-EGFR drugs as a new treatment option, as demonstrated by anecdotal reports. Promising results obtained in other solid tumors, both squamous and non-squamous, have revealed that an increase in the EGFR gene copy number may predict the efficacy of anti-EGFR therapies, while the presence of mutations in downstream members of the EGFR pathway may confer resistance. These markers have been only sporadically considered in SCAC. We investigated the status of the EGFR gene using FISH and examined KRAS, BRAF, and PIK3CA hot-spots mutations using sequencing analysis in a cohort of 84 patients affected by SCAC. Twenty-eight patients (34%) showed an increase in EGFR gene copy number due to amplification (4%) or to polysomy (30%). KRAS and PIK3CA gene mutations were found in 4 (5%) and 13 patients (16%), respectively. No mutations were found in the BRAF gene. The characterization of the EGFR pathway may help in identifying different subgroups of SCAC that have specific molecular features, which may have implications in what targeted therapies are used to treat each patient.

  19. Bit Error Rate of Coherent M-ary PSK

    NASA Technical Reports Server (NTRS)

    Lee, P. J.

    1985-01-01

    The bit error rate (BER) for the coherent detection of M-ary PSK signals with Gray code bit mapping is considered. A closed-form expression for the exact BER of M-ary PSK is presented. Tight upper and lower bounds on BER are also obtained for M-ary PSK with larger M.

  20. Precise and Efficient Retrieval of Captioned Images: The MARIE Project.

    ERIC Educational Resources Information Center

    Rowe, Neil C.

    1999-01-01

    The MARIE project explores knowledge-based information retrieval of captioned images of the kind found in picture libraries and on the Internet. MARIE's five-part approach exploits the idea that images are easier to understand with context, especially descriptive text near them, but it also does image analysis. Experiments show MARIE prototypes…

  1. Precise and Efficient Retrieval of Captioned Images: The MARIE Project.

    ERIC Educational Resources Information Center

    Rowe, Neil C.

    1999-01-01

    The MARIE project explores knowledge-based information retrieval of captioned images of the kind found in picture libraries and on the Internet. MARIE's five-part approach exploits the idea that images are easier to understand with context, especially descriptive text near them, but it also does image analysis. Experiments show MARIE prototypes…

  2. 17. Photocopy, 'St. Mary's New School,' from the commemorative booklet ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    17. Photocopy, 'St. Mary's New School,' from the commemorative booklet published for the dedication of the school, September 1923. View Southeast, North Front and West Side perspective at Church and Guthrie Street, including Rectory and Church (Original in possession of St. Mary's Parish) - St. Mary's Roman Catholic School, Northwest corner of Church Avenue & Guthrie Street, McKees Rocks, Allegheny County, PA

  3. MaRIE Undulator & XFEL Systems

    SciTech Connect

    Nguyen, Dinh Cong; Marksteiner, Quinn R.; Anisimov, Petr Mikhaylovich; Buechler, Cynthia Eileen

    2015-03-23

    The 22 slides in this presentation treat the subject under the following headings: MaRIE XFEL Performance Parameters, Input Electron Beam Parameters, Undulator Design, Genesis Simulations, Risks, and Summary It is concluded that time-dependent Genesis simulations show the MaRIE XFEL can deliver the number of photons within the required bandwidth, provided a number of assumptions are met; the highest risks are associated with the electron beam driving the XFEL undulator; and risks associated with the undulator and/or distributed seeding technique may be evaluated or retired by performing early validation experiments.

  4. Charcot-Marie-Tooth disease and vincristine.

    PubMed

    Orejana-García, Angel M; Pascual-Huerta, Javier; Pérez-Melero, Andrés

    2003-01-01

    This article reports on a case of sensorimotor neuropathy in a 55-year-old man that developed after vincristine therapy. Subsequent biopsy of the sural nerve and electromyographic studies revealed the presence of Charcot-Marie-Tooth disease. Only 17 patients who developed severe neuropathy with very low accumulated doses of vincristine have been described in the literature. Pain and lateral ankle instability were treated with a functional orthosis. Orthopedic treatment and the biomechanical basis of foot and ankle problems in patients with vincristine therapy-induced Charcot-Marie-Tooth disease are discussed.

  5. [The meadow Mari: inbreeding and endogamy].

    PubMed

    El'chinova, G I; Startseva, E A; Moshkina, I S; Rassanov, V P; Ginter, E K

    1996-09-01

    The genetic structure of Lugovye Maris was studied on the basis of marital migration. Malecot's parameters of isolation and endogamy index were estimated in four rations of the Marii El Republic, which is populated by Maris. High values of the endogamy index (0.80 and 0.88) never observed previously in any Russian populations, were revealed in two rations. The lack of significant correlation between endogamy and local inbreeding was analyzed. A significant correlation (0.70) between endogamy and effective population size was revealed.

  6. Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) Study

    PubMed Central

    Alexopoulou, Zoi; Kalogeras, Konstantine T.; Zagouri, Flora; Timotheadou, Eleni; Gogas, Helen; Pentheroudakis, George; Christodoulou, Christos; Koutras, Angelos; Bafaloukos, Dimitrios; Aravantinos, Gerasimos; Papakostas, Pavlos; Charalambous, Elpida; Papadopoulou, Kyriaki; Varthalitis, Ioannis; Efstratiou, Ioannis; Zaramboukas, Thomas; Patsea, Helen; Scopa, Chrisoula D.; Skondra, Maria; Kosmidis, Paris; Pectasides, Dimitrios; Fountzilas, George

    2015-01-01

    Background The PI3K-AKT pathway is frequently activated in breast cancer. PIK3CA mutations are most frequently found in the helical (exon 9) and kinase (exon 20) domains of this protein. The aim of the present study was to examine the role of different types of PIK3CA mutations in combination with molecular biomarkers related to PI3K-AKT signaling in patients with early breast cancer. Methods Tumor tissue samples from 1008 early breast cancer patients treated with adjuvant chemotherapy in two similar randomized trials of HeCOG were examined. Tumors were subtyped with immunohistochemistry (IHC) and FISH for ER, PgR, Ki67, HER2 and androgen receptor (AR). PIK3CA mutations were analyzed by Sanger sequencing (exon 20) and qPCR (exon 9) (Sanger/qPCR mutations). In 610 cases, next generation sequencing (NGS) PIK3CA mutation data were also available. PIK3CA mutations and PTEN protein expression (IHC) were analyzed in luminal tumors (ER and/or PgR positive), molecular apocrine carcinomas (MAC; ER/PgR negative / AR positive) and hormone receptor (ER/PgR/AR) negative tumors. Results PIK3CA mutations were detected in 235/1008 tumors (23%) with Sanger/qPCR and in 149/610 tumors (24%) with NGS. Concordance between the two methods was good with a Kappa coefficient of 0.76 (95% CI 0.69–0.82). Lobular histology, low tumor grade and luminal A tumors were associated with helical domain mutations (PIK3CAhel), while luminal B with kinase domain mutations (PIK3CAkin). The overall incidence of PIK3CA mutations was higher in luminal as compared to MAC and hormone receptor negative tumors (p = 0.004). Disease-free and overall survival did not significantly differ with respect to PIK3CA mutation presence and type. However, a statistically significant interaction between PIK3CA mutation status and PTEN low protein expression with regard to prognosis was identified. Conclusions The present study did not show any prognostic significance of specific PIK3CA mutations in a large group of

  7. {pi}K interaction effects on CP violation in B (right arrow) K {pi} {sup + }{pi}{ sup -} decays.

    SciTech Connect

    Loiseau, B.; El-Bennich, B.; Furman, A.; Kaminski, R.; Lesniak, L.; Moussallam, B.; Physics; LPNHE, Univ. Pierre et Marie Curie; The Henryk Niewodniczanski Inst. of Nucler Physics; IPN, CNRS ul.Bronowicka 85 /26

    2009-04-30

    The authors apply QCD factorization to the quasi two-body B {yields} (K{pi}){pi} decays where the (K{pi})-pair effective mass is limited to 1.8 GeV. Our strong interaction phases constrained by theory and {pi}K experimental data yield useful information for studies of CP violation.

  8. Pik3r1 Is Required for Glucocorticoid-Induced Perilipin 1 Phosphorylation in Lipid Droplet for Adipocyte Lipolysis.

    PubMed

    Kuo, Taiyi; Chen, Tzu-Chieh; Lee, Rebecca A; Nguyen, Nguyen Huynh Thao; Broughton, Augusta E; Zhang, Danyun; Wang, Jen-Chywan

    2017-06-01

    Glucocorticoids promote lipolysis in white adipose tissue (WAT) to adapt to energy demands under stress, whereas superfluous lipolysis causes metabolic disorders, including dyslipidemia and hepatic steatosis. Glucocorticoid-induced lipolysis requires the phosphorylation of cytosolic hormone-sensitive lipase (HSL) and perilipin 1 (Plin1) in the lipid droplet by protein kinase A (PKA). We previously identified Pik3r1 (also called p85α) as a glucocorticoid receptor target gene. Here, we found that glucocorticoids increased HSL phosphorylation, but not Plin1 phosphorylation, in adipose tissue-specific Pik3r1-null (AKO) mice. Furthermore, in lipid droplets, the phosphorylation of HSL and Plin1 and the levels of catalytic and regulatory subunits of PKA were increased by glucocorticoids in wild-type mice. However, these effects were attenuated in AKO mice. In agreement with reduced WAT lipolysis, glucocorticoid- initiated hepatic steatosis and hypertriglyceridemia were improved in AKO mice. Our data demonstrated a novel role of Pik3r1 that was independent of the regulatory function of phosphoinositide 3-kinase in mediating the metabolic action of glucocorticoids. Thus, the inhibition of Pik3r1 in adipocytes could alleviate lipid disorders caused by excess glucocorticoid exposure. © 2017 by the American Diabetes Association.

  9. A PIK3C3–Ankyrin-B–Dynactin pathway promotes axonal growth and multiorganelle transport

    PubMed Central

    Lorenzo, Damaris Nadia; Badea, Alexandra; Davis, Jonathan; Hostettler, Janell; He, Jiang; Zhong, Guisheng; Zhuang, Xiaowei

    2014-01-01

    Axon growth requires long-range transport of organelles, but how these cargoes recruit their motors and how their traffic is regulated are not fully resolved. In this paper, we identify a new pathway based on the class III PI3-kinase (PIK3C3), ankyrin-B (AnkB), and dynactin, which promotes fast axonal transport of synaptic vesicles, mitochondria, endosomes, and lysosomes. We show that dynactin associates with cargo through AnkB interactions with both the dynactin subunit p62 and phosphatidylinositol 3-phosphate (PtdIns(3)P) lipids generated by PIK3C3. AnkB knockout resulted in shortened axon tracts and marked reduction in membrane association of dynactin and dynein, whereas it did not affect the organization of spectrin–actin axonal rings imaged by 3D-STORM. Loss of AnkB or of its linkages to either p62 or PtdIns(3)P or loss of PIK3C3 all impaired organelle transport and particularly retrograde transport in hippocampal neurons. Our results establish new functional relationships between PIK3C3, dynactin, and AnkB that together promote axonal transport of organelles and are required for normal axon length. PMID:25533844

  10. Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing.

    PubMed

    Kuentz, Paul; St-Onge, Judith; Duffourd, Yannis; Courcet, Jean-Benoît; Carmignac, Virginie; Jouan, Thibaud; Sorlin, Arthur; Abasq-Thomas, Claire; Albuisson, Juliette; Amiel, Jeanne; Amram, Daniel; Arpin, Stéphanie; Attie-Bitach, Tania; Bahi-Buisson, Nadia; Barbarot, Sébastien; Baujat, Geneviève; Bessis, Didier; Boccara, Olivia; Bonnière, Maryse; Boute, Odile; Bursztejn, Anne-Claire; Chiaverini, Christine; Cormier-Daire, Valérie; Coubes, Christine; Delobel, Bruno; Edery, Patrick; Chehadeh, Salima El; Francannet, Christine; Geneviève, David; Goldenberg, Alice; Haye, Damien; Isidor, Bertrand; Jacquemont, Marie-Line; Khau Van Kien, Philippe; Lacombe, Didier; Martin, Ludovic; Martinovic, Jelena; Maruani, Annabel; Mathieu-Dramard, Michèle; Mazereeuw-Hautier, Juliette; Michot, Caroline; Mignot, Cyril; Miquel, Juliette; Morice-Picard, Fanny; Petit, Florence; Phan, Alice; Rossi, Massimiliano; Touraine, Renaud; Verloes, Alain; Vincent, Marie; Vincent-Delorme, Catherine; Whalen, Sandra; Willems, Marjolaine; Marle, Nathalie; Lehalle, Daphné; Thevenon, Julien; Thauvin-Robinet, Christel; Hadj-Rabia, Smaïl; Faivre, Laurence; Vabres, Pierre; Rivière, Jean-Baptiste

    2017-09-01

    Postzygotic activating mutations of PIK3CA cause a wide range of mosaic disorders collectively referred to as PIK3CA-related overgrowth spectrum (PROS). We describe the diagnostic yield and characteristics of PIK3CA sequencing in PROS. We performed ultradeep next-generation sequencing (NGS) of PIK3CA in various tissues from 162 patients referred to our clinical laboratory and assessed diagnostic yield by phenotype and tissue tested. We identified disease-causing mutations in 66.7% (108/162) of patients, with mutant allele levels as low as 1%. The diagnostic rate was higher (74%) in syndromic than in isolated cases (35.5%; P = 9.03 × 10(-5)). We identified 40 different mutations and found strong oncogenic mutations more frequently in patients without brain overgrowth (50.6%) than in those with brain overgrowth (15.2%; P = 0.00055). Mutant allele levels were higher in skin and overgrown tissues than in blood and buccal samples (P = 3.9 × 10(-25)), regardless of the phenotype. Our data demonstrate the value of ultradeep NGS for molecular diagnosis of PROS, highlight its substantial allelic heterogeneity, and confirm that optimal diagnosis requires fresh skin or surgical samples from affected regions. Our findings may be of value in guiding future recommendations for genetic testing in PROS and other mosaic conditions.Genet Med advance online publication 02 February 2017.

  11. Metabolomic characterisation of the effects of oncogenic PIK3CA transformation in a breast epithelial cell line.

    PubMed

    Lau, Chung-Ho E; Tredwell, Gregory D; Ellis, James K; Lam, Eric W-F; Keun, Hector C

    2017-04-10

    Somatic mutations in PIK3CA are frequently found in a number of human cancers, including breast cancer, altering cellular physiology and tumour sensitivity to chemotherapy. This renders PIK3CA an attractive molecular target for early detection and personalised therapy. Using (1)H Nuclear Magnetic Resonance spectroscopy (NMR) and Gas Chromatography - Mass Spectrometery (GC-MS) together with (13)C stable isotope-labelled glucose and glutamine as metabolic tracers, we probed the phenotypic changes in metabolism following a single copy knock-in of mutant PIK3CA (H1047R) in the MCF10A cell line, an important cell model for studying oncogenic transformation in breast tissues. We observed effects in several metabolic pathways, including a decrease in glycerophosphocholine level together with increases in glutaminolysis, de novo fatty acid synthesis and pyruvate entry into the tricarboxylic acid cycle. Our findings highlight altered glyceroplipid metabolism and lipogenesis, as key metabolic phenotypes of mutant PIK3CA transformation that are recapitulated in the MCF10A cellular model.

  12. Metabolomic characterisation of the effects of oncogenic PIK3CA transformation in a breast epithelial cell line

    PubMed Central

    Lau, Chung-Ho E.; Tredwell, Gregory D.; Ellis, James K.; Lam, Eric W.-F.; Keun, Hector C.

    2017-01-01

    Somatic mutations in PIK3CA are frequently found in a number of human cancers, including breast cancer, altering cellular physiology and tumour sensitivity to chemotherapy. This renders PIK3CA an attractive molecular target for early detection and personalised therapy. Using 1H Nuclear Magnetic Resonance spectroscopy (NMR) and Gas Chromatography – Mass Spectrometery (GC-MS) together with 13C stable isotope-labelled glucose and glutamine as metabolic tracers, we probed the phenotypic changes in metabolism following a single copy knock-in of mutant PIK3CA (H1047R) in the MCF10A cell line, an important cell model for studying oncogenic transformation in breast tissues. We observed effects in several metabolic pathways, including a decrease in glycerophosphocholine level together with increases in glutaminolysis, de novo fatty acid synthesis and pyruvate entry into the tricarboxylic acid cycle. Our findings highlight altered glyceroplipid metabolism and lipogenesis, as key metabolic phenotypes of mutant PIK3CA transformation that are recapitulated in the MCF10A cellular model. PMID:28393905

  13. Targeting Breast Cancers Featuring Activating Mutations in PIK3CA by Generating a Lethal Dose of PIP3

    DTIC Science & Technology

    2009-02-01

    AD_________________ AWARD NUMBER: W81XWH-06-1-0341 TITLE: Targeting Breast Cancers Featuring...ORGANIZATION: Dana-Farber Cancer Institute Boston, MA 02115 REPORT DATE...2006 – 31 Jan 2009 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Targeting Breast Cancers Featuring Activating Mutations in PIK3CA by Generating a

  14. Targeting Breast Cancers Featuring Activating Mutations in PIK3CA by Generating a Lethal Dose of PIP3

    DTIC Science & Technology

    2008-02-01

    2003). Frequent monoallelic deletion of PTEN and its reciprocal associatioin with PIK3CA amplification in gastric carcinoma. Int J Cancer 104, 318-327...AD_________________ Award Number: W81XWH-06-1-0341 TITLE: Targeting Breast Cancers Featuring...ORGANIZATION: Dana-Farber Cancer Institute Boston, MA 02115 REPORT DATE: February 2008 TYPE OF REPORT: Annual Summary

  15. Women in History--Mary Seacole

    ERIC Educational Resources Information Center

    Harmer, Bonnie

    2005-01-01

    Born in Jamaica in 1805, Mary Seacole (nee Grant), was the daughter of a Black Creole boarding house owner and a Scottish Army officer. Like many Creole doctress women, Seacole was taught African herbal medicine arts from her mother. In addition to understanding traditional herbal medicine, she gleaned an understanding of Western medicine from the…

  16. Mary Wollstonecraft and Catharine Macaulay on Education

    ERIC Educational Resources Information Center

    Frazer, Elizabeth

    2011-01-01

    Catharine Macaulay and Mary Wollstonecraft are linked by intellectual and political bonds; for both, education is a philosophical and political preoccupation in its own right, and also interacts with philosophical questions of morality, social power, theology, truth and human action. Macaulay's philosophical and political engagements with Hobbes,…

  17. Mary Wollstonecraft and Catharine Macaulay on Education

    ERIC Educational Resources Information Center

    Frazer, Elizabeth

    2011-01-01

    Catharine Macaulay and Mary Wollstonecraft are linked by intellectual and political bonds; for both, education is a philosophical and political preoccupation in its own right, and also interacts with philosophical questions of morality, social power, theology, truth and human action. Macaulay's philosophical and political engagements with Hobbes,…

  18. Mary Slessor (1848-1915), Pedagogue Extraordinary.

    ERIC Educational Resources Information Center

    Taylor, W. H.

    1993-01-01

    Mary Slessor was a Scottish missionary who established many schools in Nigeria and developed close relationships with Nigerian chiefs and tribal members. She championed women's rights and focused her educational endeavors on vocational training relevant to the local economy. Slessor incorporated her knowledge of Nigerian culture into her teaching…

  19. Fumarolic activity in marie byrd land, antarctica.

    PubMed

    Lemasurier, W E; Wade, F A

    1968-10-18

    Ice towers, probably formed by recent fumarolic activity, have been found around the summit calderas of two volcanoes in Marie Byrd Land. These active (?) volcanoes lie within a broad belt of Mesozoic intrusion and late Cenozoic extrusion that appears to be part of the circum-Pacific orogenic province.

  20. Women in History--Mary Seacole

    ERIC Educational Resources Information Center

    Harmer, Bonnie

    2005-01-01

    Born in Jamaica in 1805, Mary Seacole (nee Grant), was the daughter of a Black Creole boarding house owner and a Scottish Army officer. Like many Creole doctress women, Seacole was taught African herbal medicine arts from her mother. In addition to understanding traditional herbal medicine, she gleaned an understanding of Western medicine from the…

  1. Mary Bidwell Breed: The Educator as Dean.

    ERIC Educational Resources Information Center

    Fley, Jo Ann; Jaramillo, George R.

    1979-01-01

    Mary Bidwell Breed predicted that midwestern universities would probably "pass through a stage of educational development in which the liberal arts are entirely feminized, the men are entirely commercialized." We can appreciate how close she came to pinpointing trends which did not begin to be reversed until sixty years later.…

  2. Mary Budd Rowe: A Storyteller of Science

    ERIC Educational Resources Information Center

    Bianchini, Julie A.

    2008-01-01

    This article examines Mary Budd Rowe's groundbreaking and far-reaching contributions to science education. Rowe is best known for her research on wait-time: the idea that teachers can improve the quality and length of classroom discussions by waiting at least 3 s before and after student responses. Her wait-time research grew from and helped…

  3. Mary Somerville: a scientist and her ship.

    PubMed

    Fara, Patricia

    2008-09-01

    Mary Somerville enjoyed posing for busts and portraits, yet just as in her autobiography, she chose how she wished to be seen. A powerful advocate for scientific progress, Somerville gave her name to a ship that carried British products around the world, and portrayed herself as an ideal role model for women and also an exemplar of European civilisation.

  4. Mary Elizabeth Hickox Mandels, 90, bioenergy leader

    PubMed Central

    Allen, Fred; Andreotti, Raymond; Eveleigh, Douglas E; Nystrom, John

    2009-01-01

    Mary E H Mandels, who spearheaded the US Army's national bioconversion studies for four decades and was an early proponent of conversion of waste biomass to readily bioconvertible sugars for the production of chemicals and transportation fuels such as ethanol, died 17 February 2008 at Natick, MA, USA. She was 90. PMID:19723299

  5. Classroom Instruction: The Influences of Marie Clay

    ERIC Educational Resources Information Center

    McNaughton, Stuart

    2014-01-01

    Marie Clay's body of work has influenced classroom instruction in direct and indirect ways, through large overarching themes in our pedagogical content knowledge as well as specific smart practices. This paper focuses on her the contributions to our thinking about instruction which come from two broad theoretical concepts; emergent literacy…

  6. The Saint Mary's Woman: toward Intellectual Leadership.

    ERIC Educational Resources Information Center

    White, Patrick E.

    This two-year project at Saint Mary's College, a women's college in Notre Dame (Indiana), focused on building intellectual community and fostering student leadership skills. The study targeted two student groups: (1) students with much to contribute to the intellectual life of the college but alienated from traditional forms of leadership, and (2)…

  7. Classroom Instruction: The Influences of Marie Clay

    ERIC Educational Resources Information Center

    McNaughton, Stuart

    2014-01-01

    Marie Clay's body of work has influenced classroom instruction in direct and indirect ways, through large overarching themes in our pedagogical content knowledge as well as specific smart practices. This paper focuses on her the contributions to our thinking about instruction which come from two broad theoretical concepts; emergent literacy…

  8. Visions of Mary Wollstonecraft: Implications for Education.

    ERIC Educational Resources Information Center

    Manus, Alice L.

    This paper discusses the educational and social philosophy of Mary Wollstonecraft, an English writer of the 18th century. Her works included "Vindication of the Rights of Man," and her best know work, "Vindication of the Rights of Woman" which was published in 1792 and consisted of the first sustained argument for female…

  9. PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation

    PubMed Central

    Anderson, Grace R.; Wardell, Suzanne E.; Cakir, Merve; Crawford, Lorin; Leeds, Jim C.; Nussbaum, Daniel P.; Shankar, Pallavi S.; Soderquist, Ryan S.; Stein, Elizabeth M.; Tingley, Jennifer P.; Winter, Peter S.; Zieser-Misenheimer, Elizabeth K.; Alley, Holly M.; Yllanes, Alexander; Haney, Victoria; Blackwell, Kimberly L.; McCall, Shannon J.; McDonnell, Donald P.; Wood, Kris C.

    2017-01-01

    Therapies that efficiently induce apoptosis are likely to be required for durable clinical responses in patients with solid tumors. Using a pharmacological screening approach, we discovered that the combined inhibition of BCL-XL and the mTOR/4E-BP axis results in selective and synergistic induction of apoptosis in cellular and animal models of PIK3CA mutant breast cancers, including triple negative tumors. Mechanistically, inhibition of mTOR/4E-BP suppresses MCL-1 protein translation only in PIK3CA mutant tumors, creating a synthetic dependence on BCL-XL. This dual dependence on BCL-XL and MCL-1, but not on BCL-2, appears to be a fundamental property of diverse breast cancer cell lines, xenografts, and patient-derived tumors that is independent of molecular subtype or PIK3CA mutational status. Further, this dependence distinguishes breast cancers from normal breast epithelial cells, which are neither primed for apoptosis nor dependent on BCL-XL/MCL-1, suggesting a potential therapeutic window. By tilting the balance of pro- to anti-apoptotic signals in the mitochondria, dual inhibition of MCL-1 and BCL-XL also sensitizes breast cancer cells to standard of care cytotoxic and targeted chemotherapies. Together, these results suggest that patients with PIK3CA mutant breast cancers may benefit from combined treatment with inhibitors of BCL-XL and the mTOR/4E-BP axis, whereas alternative methods of inhibiting MCL-1 and BCL-XL may be effective in tumors lacking PIK3CA mutations. PMID:27974663

  10. PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation.

    PubMed

    Anderson, Grace R; Wardell, Suzanne E; Cakir, Merve; Crawford, Lorin; Leeds, Jim C; Nussbaum, Daniel P; Shankar, Pallavi S; Soderquist, Ryan S; Stein, Elizabeth M; Tingley, Jennifer P; Winter, Peter S; Zieser-Misenheimer, Elizabeth K; Alley, Holly M; Yllanes, Alexander; Haney, Victoria; Blackwell, Kimberly L; McCall, Shannon J; McDonnell, Donald P; Wood, Kris C

    2016-12-14

    Therapies that efficiently induce apoptosis are likely to be required for durable clinical responses in patients with solid tumors. Using a pharmacological screening approach, we discovered that combined inhibition of B cell lymphoma-extra large (BCL-XL) and the mammalian target of rapamycin (mTOR)/4E-BP axis results in selective and synergistic induction of apoptosis in cellular and animal models of PIK3CA mutant breast cancers, including triple-negative tumors. Mechanistically, inhibition of mTOR/4E-BP suppresses myeloid cell leukemia-1 (MCL-1) protein translation only in PIK3CA mutant tumors, creating a synthetic dependence on BCL-XL This dual dependence on BCL-XL and MCL-1, but not on BCL-2, appears to be a fundamental property of diverse breast cancer cell lines, xenografts, and patient-derived tumors that is independent of the molecular subtype or PIK3CA mutational status. Furthermore, this dependence distinguishes breast cancers from normal breast epithelial cells, which are neither primed for apoptosis nor dependent on BCL-XL/MCL-1, suggesting a potential therapeutic window. By tilting the balance of pro- to antiapoptotic signals in the mitochondria, dual inhibition of MCL-1 and BCL-XL also sensitizes breast cancer cells to standard-of-care cytotoxic and targeted chemotherapies. Together, these results suggest that patients with PIK3CA mutant breast cancers may benefit from combined treatment with inhibitors of BCL-XL and the mTOR/4E-BP axis, whereas alternative methods of inhibiting MCL-1 and BCL-XL may be effective in tumors lacking PIK3CA mutations.

  11. miR-490-5p suppresses tumour growth in renal cell carcinoma through targeting PIK3CA.

    PubMed

    Chen, Ke; Zeng, Jin; Tang, Kun; Xiao, Haibing; Hu, Junhui; Huang, Chunhua; Yao, Weimin; Yu, Gan; Xiao, Wei; Guan, Wei; Guo, Xiaolin; Xu, Hua; Ye, Zhangqun

    2016-02-01

    Dysregulated micro-RNAs have been reported in many human cancers, including renal cell carcinoma. Recent studies indicated that miR-490 is involved in tumour development and progression. However, the expression profile and function in renal cell carcinoma remains unknown. Herein, we showed that miR-490-5p was down-regulated in renal cell carcinoma tissues and cells compared with the adjacent normal tissues and normal cells. We also provided evidence that miR-490-5p acts as a tumour suppressor in renal carcinoma in a variety of in vitro and in vivo assays. Mechanistically, miR-490-5p was verified to directly bind to 3' UTR of the PIK3CA mRNA and reduce the expression of PIK3CA at both mRNA and protein levels, which further inhibits phosphatidylinositol 3-kinase/Akt signalling pathway. We further showed that knockdown of PIK3CA can block the growth inhibitory effect of miR-490-5p, and over-expression of PIK3CA can reverse the inhibitory effect of miR-490-5p on renal cancer cell tumourigenicity. Taken together, our results indicated for the first time that miR-490-5p functions as a tumour suppressor in renal carcinoma by targeting PIK3CA. Our findings suggest that miR-490-5p may be a potential gene therapy target for the treatment of renal cell carcinoma. © 2015 The Authors. Biology of the Cell published by John Wiley & Sons Ltd on behalf of Société Française des Microscopies and Société de Biologie Cellulaire de France. Published by John Wiley & Sons Ltd.

  12. Characteristics and prevalence of KRAS, BRAF, and PIK3CA mutations in colorectal cancer by high-resolution melting analysis in Taiwanese population.

    PubMed

    Hsieh, Li-Ling; Er, Tze-Kiong; Chen, Chih-Chieh; Hsieh, Jan-Sing; Chang, Jan-Gowth; Liu, Ta-Chih

    2012-10-09

    The identification of KRAS, BRAF, and PIK3CA mutations before the administration of anti-epidermal growth factor receptor therapy of colorectal cancer has become important. The aim of the present study was to investigate the occurrence of KRAS, BRAF, and PIK3CA mutations in the Taiwanese population with colorectal cancer. This study was undertaken to identify BRAF and PIK3CA mutations in patients with colorectal cancer by high-resolution melting (HRM) analysis. HRM analysis is a new gene scan tool that quickly performs the PCR and identifies sequence alterations without requiring post-PCR treatment. In the present study, DNAs were extracted from 182 cases of formalin-fixed, paraffin-embedded (FFPE) colorectal cancer samples for clinical KRAS mutational analysis by direct sequencing. All the samples were also tested for mutations within BRAF V600E and PIK3CA (exons 9 and 20) by HRM analysis. The results were confirmed by direct sequencing. The frequency of BRAF and PIK3CA mutations is 1.1%, and 7.1%, respectively. Intriguingly, we found that nine patients (4.9%) with the KRAS mutation were coexistent with the PIK3CA mutation. Four patients (2.2%) without the KRAS mutation were existent with the PIK3CA mutation. Two patients (1.1%) without the KRAS mutation were existent with the BRAF mutation. In the current study, we suppose that HRM analysis is rapid, feasible, and powerful diagnostic tool for the detection of BRAF and PIK3CA mutations in a clinical setting. Additionally, our results indicated the prevalence of KRAS, BRAF, and PIK3CA mutational status in the Taiwanese population. Copyright © 2012 Elsevier B.V. All rights reserved.

  13. Combination of COX-2 expression and PIK3CA mutation as prognostic and predictive markers for celecoxib treatment in breast cancer

    PubMed Central

    Tury, Sandrine; Becette, Véronique; Assayag, Franck; Vacher, Sophie; Benoist, Camille; Kamal, Maud; Marangoni, Elisabetta; Bièche, Ivan; Lerebours, Florence; Callens, Céline

    2016-01-01

    COX-2 expression level and prognostic value are still a matter of debate in breast cancer (BC). We addressed these points in the context of PIK3CA mutational status. Based on an interesting study of aspirin efficacy in colorectal cancer, we hypothesized that celecoxib antitumoral activity may be restricted to PIK3CA mutated BC. COX-2 mRNA expression was analyzed in 446 BC samples and in 61 BC patient-derived xenografts (PDX) using quantitative RT-PCR. The prognostic impact of COX-2 expression level was assessed independently and according to PIK3CA mutational status in our cohort and in a validation set of 817 BC. The antitumoral activity of celecoxib was tested in two triple-negative (TN) PDX with a PIK3CA wild-type (wt) or mutated genotype. COX-2 mRNA was overexpressed in 2% of BC and significantly associated with TN subtype. Metastasis-free survival (MFS) was significantly better in patients with high COX-2 expression level, the prognosis of whom was similar to patients with PIK3CA mutations. TCGA validation cohort confirmed that patients with low COX-2 expression PIK3CA wt tumors had the worse disease-free survival (DFS) compared to all other subgroups. Celecoxib had a significant antitumoral effect in PIK3CA mutated PDX only. Celecoxib antitumoral activity involved S6 ribosomal protein and AKT phosphorylation. Low expression of COX-2 has a significant negative impact on the MFS/DFS of BC patients. Antitumoral effect of celecoxib is restricted to PIK3CA mutated PDX. These results suggest that PIK3CA mutation may be a new predictive biomarker for celecoxib efficacy. PMID:27835884

  14. High-density ultracold neutron sources for the WWR-M and PIK reactors

    SciTech Connect

    Serebrov, A. P. Fomin, A. K.; Kharitonov, A. G.; Lyamkin, V. A.; Prudnikov, D. V.; Ivanov, S. A.; Erykalov, A. N.; Onegin, M. S.; Gridnev, K. A.

    2016-01-15

    It is proposed to equip the PIK and WWR-M research reactors at the Petersburg Nuclear Physics Institute (PNPI) with high-density ultracold neutron (UCN) sources, where UCNs will be obtained based on the effect of their accumulation in superfluid helium (due to the specific features of this quantum fluid). The maximum UCN storage time in superfluid helium is obtained at temperatures on the order of 1 K. These sources are expected to yield UCN densities of 10{sup 3}–10{sup 4} cm{sup –3}, i.e., approximately three orders of magnitude higher than the density from existing UCN sources throughout the world. The development of highest intensity UCN sources will make PNPI an international center of fundamental UCN research.

  15. 102({h_bar}/2{pi})k Large Area Atom Interferometers

    SciTech Connect

    Chiow, Sheng-wey; Kovachy, Tim; Chien, Hui-Chun; Kasevich, Mark A.

    2011-09-23

    We demonstrate atom interferometers utilizing a novel beam splitter based on sequential multiphoton Bragg diffractions. With this sequential Bragg large momentum transfer (SB-LMT) beam splitter, we achieve high contrast atom interferometers with momentum splittings of up to 102 photon recoil momenta (102({h_bar}/2{pi})k). To our knowledge, this is the highest momentum splitting achieved in any atom interferometer, advancing the state-of-the-art by an order of magnitude. We also demonstrate strong noise correlation between two simultaneous SB-LMT interferometers, which alleviates the need for ultralow noise lasers and ultrastable inertial environments in some future applications. Our method is intrinsically scalable and can be used to dramatically increase the sensitivity of atom interferometers in a wide range of applications, including inertial sensing, measuring the fine structure constant, and detecting gravitational waves.

  16. Somatic gain-of-function mutations in PIK3CA in patients with macrodactyly

    PubMed Central

    Rios, Jonathan J.; Paria, Nandina; Burns, Dennis K.; Israel, Bonnie A.; Cornelia, Reuel; Wise, Carol A.; Ezaki, Marybeth

    2013-01-01

    Macrodactyly is a discrete congenital anomaly consisting of enlargement of all tissues localized to the terminal portions of a limb, typically within a ‘nerve territory’. The classic terminology for this condition is ‘lipofibromatous hamartoma of nerve’ or Type I macrodactyly. The peripheral nerve, itself, is enlarged both in circumference and in length. It is not related to neurofibromatosis (NF1), nor is it associated with vascular malformations, such as in the recently reported CLOVES syndrome. The specific nerve pathophysiology in this form of macrodactyly has not been well described and a genetic etiology for this specific form of enlargement is unknown. To identify the genetic cause of macrodactyly, we used whole-exome sequencing to identify somatic mutations present in the affected nerve of a single patient. We confirmed a novel mutation in PIK3CA (R115P) present in the patient's affected nerve tissue but not in blood DNA. Sequencing PIK3CA exons identified gain-of-function mutations (E542K, H1047L or H1047R) in the affected tissue of five additional unrelated patients; mutations were absent in blood DNA available from three patients. Immunocytochemistry confirmed AKT activation in cultured cells from the nerve of a macrodactyly patient. Additionally, we found that the most abnormal structure within the involved nerve in a macrodactylous digit is the perineurium, with additional secondary effects on the axon number and size. Thus, isolated congenital macrodactyly is caused by somatic activation of the PI3K/AKT cell-signaling pathway and is genetically and biochemically related to other overgrowth syndromes. PMID:23100325

  17. Analysis of transient and catalytic desosamine-binding pockets in cytochrome P-450 PikC from Streptomyces venezuelae.

    PubMed

    Li, Shengying; Ouellet, Hugues; Sherman, David H; Podust, Larissa M

    2009-02-27

    The cytochrome P-450 PikC from Streptomyces venezuelae exhibits significant substrate tolerance and performs multiple hydroxylation reactions on structurally variant macrolides bearing the deoxyamino sugar desosamine. In previously determined co-crystal structures (Sherman, D. H., Li, S., Yermalitskaya, L. V., Kim, Y., Smith, J. A., Waterman, M. R., and Podust, L. M. (2006) J. Biol. Chem. 281, 26289-26297), the desosamine moiety of the native substrates YC-17 and narbomycin is bound in two distinct buried and surface-exposed binding pockets, mediated by specific interactions between the protonated dimethylamino group and the acidic amino acid residues Asp(50), Glu(85), and Glu(94). Although the Glu(85) and Glu(94) negative charges are essential for maximal catalytic activity of native enzyme, elimination of the surface-exposed negative charge at Asp(50) results in significantly enhanced catalytic activity. Nevertheless, the D50N substitution could not rescue catalytic activity of PikC(E94Q) based on lack of activity in the corresponding double mutant PikC(D50N/E94Q). To address the specific role for each desosamine-binding pocket, we analyzed the x-ray structures of the PikC(D50N) mutant co-crystallized with narbomycin (1.85A resolution) and YC-17 (3.2A resolution). In PikC(D50N), the desosamine moiety of both YC-17 and narbomycin was bound in a catalytically productive "buried site." This finding suggested a two-step substrate binding mechanism, whereby desosamine is recognized in the two subsites to allow the macrolide substrate to sequentially progress toward a catalytically favorable orientation. Collectively, the binding, mutagenesis, kinetic, and x-ray structural data suggest that enhancement of the catalytic activity of PikC(D50N) is due to the facilitated relocation of substrate to the buried site, which has higher binding affinity, as opposed to dissociation in solution from the transient "surface-exposed site."

  18. PIK3R1 (p85-alpha/p85α) is Somatically Mutated at High Frequency in Primary Endometrial Cancer

    PubMed Central

    Urick, Mary Ellen; Rudd, Meghan L.; Godwin, Andrew K.; Sgroi, Dennis; Merino, Maria; Bell, Daphne W.

    2011-01-01

    PI3K is an important therapeutic target. Mutations in PIK3CA, which encodes p110α, the catalytic subunit of PI3K, occur in endometrioid and non-endometrioid endometrial cancers (EECs and NEECs). The goal of this study was to determine whether PIK3R1, which encodes p85α, the inhibitory subunit of PI3K, is mutated in endometrial carcinoma. We performed exonic sequencing of PIK3R1 from 42 EECs and 66 NEECs. The pattern of PIK3R1 mutations was compared to the patterns of PIK3CA, PTEN and KRAS mutations. The biochemical effect of seven PIK3R1 mutations was examined by stable expression in U2OS cells, followed by coimmunoprecipitation analysis of p110α, and Western blotting of phospho-AKTSer473. We found that PIK3R1 was somatically mutated in 43% of EECs and 12% of NEECs. The majority of mutations (93.3%) localized to the p85α-nSH2 and -iSH2 domains. Several mutations were recurrent. PIK3R1 mutations were significantly (P=0.0015) more frequent in PIK3CA-wild type EECs (70%) than in PIK3CA-mutant EECs (18%). Introduction of wild type p85α into U2OS cells reduced the level of phospho-AKTSer473 compared to the vector control. Five p85α mutants, p85αdelH450-E451, p85αdelK459, p85αdelY463-L466, p85αdelR574-T576, and the p85αN564D positive control, were shown to bind p110α and led to increased levels of p-AKTSer473. The p85αR348X and p85αK511VfsX2 mutants did not bind p110α and showed no appreciable change in p-AKTSer473 levels. In conclusion, our study has revealed a new mode of PI3K alteration in primary endometrial tumors and warrants future studies to determine whether PIK3R1 mutations correlate with clinical outcome to targeted therapies directed against the PI3K pathway in EEC and NEEC. PMID:21478295

  19. Women who Worked with Marie Curie.

    PubMed

    Pigeard-Micault, Natalie

    2015-06-01

    Marie Curie directed a research laboratory for 28 years. Between 1906 and 1934, forty five women worked under her guidance. Some were, and are, well-known in their own countries as their first woman full professor such as Ellen Gleditsch or Margaret von Wrangel, but for twenty eight of them, who were often French, nothing has ever been written. The strong presence of women in Marie Curie's laboratory has often been highlighted and has been considered as an exception, and the result of deliberate choice. Of course, these women did not choose this workplace by accident. They knew its director was a woman, a laureate of one, and after 1911, two Nobel Prizes, who was leading a well-equipped laboratory with an important radioactive source. But how did Marie Curie selected her collaborators among the many applications she received? Was her choice influenced by gender? A prosopographical research based on genealogical researches and new sources explains this presence contextually and sheds light on several questions : where did these women come from, what were their social and geographic origins, did they occupy any specific cultural or technical area inside Curie's lab, what future did they have after the laboratory? Through their lives, we can question the existence, or not, of a one profile of the female researcher in scientific areas in France.

  20. Mary Grant Seacole: the first nurse practitioner.

    PubMed

    Messmer, P R; Parchment, Y

    1998-01-01

    Mary Grant Seacole was born in 1805, in Kingston, Jamaica, to a Jamaican doctress (medicine woman) and a Scottish naval officer. Later Seacole became a doctress, nursing British soldiers during epidemics of cholera, dysentery, and yellow fever in Jamaica, Cuba, and Panama. After refusals by both the British government and Florence Nightingale to be allowed to practice in Scutari, she financed her own way to the scene of the Crimean War and then established the British Hotel to serve both the comfort and medical needs of the wounded soldiers. At night, Seacole worked side by side with Nightingale at Scutari as a volunteer nurse. Seacole's fame grew proportionately after she was seen helping wounded soldiers on the battlefields even while the battles were still raging. Seacole died on May 14, 1881, in London. One hundred years later, many members of the London black community, a few members of the Nurses Association of Jamaica and the Friends of Mary Seacole marched to her grave, honoring her as one of the greatest women of all times. Mary Grant Seacole rose above the barriers of racial prejudice and demonstrated the determinism, compassion, and caring that have became the hallmark of nurse practitioners.

  1. Dual HER2/PIK3CA Targeting Overcomes Single-Agent Acquired Resistance in HER2-Amplified Uterine Serous Carcinoma Cell Lines In Vitro and In Vivo.

    PubMed

    Lopez, Salvatore; Cocco, Emiliano; Black, Jonathan; Bellone, Stefania; Bonazzoli, Elena; Predolini, Federica; Ferrari, Francesca; Schwab, Carlton L; English, Diana P; Ratner, Elena; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E; Terranova, Corrado; Angioli, Roberto; Santin, Alessandro D

    2015-11-01

    HER2/neu gene amplification and PIK3CA driver mutations are common in uterine serous carcinoma (USC) and may represent ideal therapeutic targets against this aggressive variant of endometrial cancer. We examined the sensitivity to neratinib, taselisib, and the combination of the two compounds in in vitro and in vivo experiments using PIK3CA-mutated and PIK3CA wild-type HER2/neu-amplified USC cell lines. Cell viability and cell-cycle distribution were assessed using flow-cytometry assays. Downstream signaling was assessed by immunoblotting. Preclinical efficacy of single versus dual inhibition was evaluated in vivo using two USC xenografts. We found both single-agent neratinib and taselisib to be active but only transiently effective in controlling the in vivo growth of USC xenografts harboring HER2/neu gene amplification with or without oncogenic PIK3CA mutations. In contrast, the combination of the two inhibitors caused a stronger and long-lasting growth inhibition in both USC xenografts when compared with single-agent therapy. Combined targeting of HER2 and PIK3CA was associated with a significant and dose-dependent increase in the percentage of cells in the G0-G1 phase of the cell cycle and a dose-dependent decline in the phosphorylation of S6. Importantly, dual inhibition therapy initiated after tumor progression in single-agent-treated mice was still remarkably effective at inducing tumor regression in both large PIK3CA and pan-ErbB inhibitor-resistant USC xenografts. Dual HER2/PIK3CA blockade may represent a novel therapeutic option for USC patients harboring tumors with HER2/neu gene amplification and mutated or wild-type PIK3CA resistant to chemotherapy.

  2. The Class II Phosphatidylinositol 3-Phosphate Kinase PIK3C2A Promotes Shigella flexneri Dissemination through Formation of Vacuole-Like Protrusions

    PubMed Central

    Dragoi, Ana-Maria

    2015-01-01

    Intracellular pathogens such as Shigella flexneri and Listeria monocytogenes achieve dissemination in the intestinal epithelium by displaying actin-based motility in the cytosol of infected cells. As they reach the cell periphery, motile bacteria form plasma membrane protrusions that resolve into vacuoles in adjacent cells, through a poorly understood mechanism. Here, we report on the role of the class II phosphatidylinositol 3-phosphate kinase PIK3C2A in S. flexneri dissemination. Time-lapse microscopy revealed that PIK3C2A was required for the resolution of protrusions into vacuoles through the formation of an intermediate membrane-bound compartment that we refer to as a vacuole-like protrusion (VLP). Genetic rescue of PIK3C2A depletion with RNA interference (RNAi)-resistant cDNA constructs demonstrated that VLP formation required the activity of PIK3C2A in primary infected cells. PIK3C2A expression was required for production of phosphatidylinositol 3-phosphate [PtdIns(3)P] at the plasma membrane surrounding protrusions. PtdIns(3)P production was not observed in the protrusions formed by L. monocytogenes, whose dissemination did not rely on PIK3C2A. PIK3C2A-mediated PtdIns(3)P production in S. flexneri protrusions was regulated by host cell tyrosine kinase signaling and relied on the integrity of the S. flexneri type 3 secretion system (T3SS). We suggest a model of S. flexneri dissemination in which the formation of VLPs is mediated by the PIK3C2A-dependent production of the signaling lipid PtdIns(3)P in the protrusion membrane, which relies on the T3SS-dependent activation of tyrosine kinase signaling in protrusions. PMID:25667265

  3. Changes in PIK3CA mutation status are not associated with recurrence, metastatic disease or progression in endocrine-treated breast cancer.

    PubMed

    Arthur, L M; Turnbull, A K; Renshaw, L; Keys, J; Thomas, J S; Wilson, T R; Lackner, M R; Sims, A H; Dixon, J M

    2014-08-01

    The phosphatidylinositol-3-kinase pathway plays an important role in proliferation, migration and survival in breast cancer and may play a role in resistance to endocrine therapy. Pathway activation occurs as a result of mutations in PIK3CA or loss of functional PTEN. Matched primary and recurrent samples from 120 breast cancer patients treated with endocrine therapy were profiled with a qPCR-based mutation assay covering eight mutational hotspots in PIK3CA. PTEN was assayed by immunohistochemistry. Samples were well characterized with respect to anatomic location of recurrence (metastatic nodal or local recurrence as opposed to contralateral or ipsilateral new primary cancers). In total, 43 % of patients had at least one PIK3CA mutation at diagnosis, and 41 % had a mutation at the time of recurrence. Only 8 % of patients with local recurrence, metastatic disease or progression on primary endocrine treatment changed their PIK3CA mutation status (four gains, two losses, total 76). The most common changes in PIK3CA mutation status were seen in patients who developed a new cancer either in the treated or contralateral breast (64 %, three gains, four losses, total 11). PIK3CA mutation status does not change in the majority of patients with breast cancer and the acquisition of mutations in PIK3CA is not responsible for the development of endocrine resistance. PTEN loss at diagnosis is associated with a significantly shorter time to progression compared with tumours in which PTEN was retained. These are the most comprehensive data currently available correlating PIK3CA status, site of recurrence and endocrine resistance.

  4. An integrative analysis of PIK3CA mutation, PTEN, and INPP4B expression in terms of trastuzumab efficacy in HER2-positive breast cancer.

    PubMed

    Sueta, Aiko; Yamamoto, Yutaka; Yamamoto-Ibusuki, Mutsuko; Hayashi, Mitsuhiro; Takeshita, Takashi; Yamamoto, Satoko; Iwase, Hirotaka

    2014-01-01

    The phosphoinositide-3-kinase (PI3K) pathway is commonly deregulated in breast cancer through several mechanisms, including PIK3CA mutation and loss of phosphatase and tensin homolog (PTEN) and inositol polyphosphate 4-phosphatase-II (INPP4B). We aimed to evaluate the predictive relevance of these biomarkers to trastuzumab efficacy in HER2-positive disease. We evaluated the effect of trastuzumab in 43 breast cancer patients with HER2-overexpression who received neoadjuvant treatment. PIK3CA mutation was examined by direct sequencing and digital PCR assay, and PIK3CA copy number was assessed by digital PCR assay of pretreatment tissues. PTEN, pAkt, and INPP4B were assessed by immunohistochemistry. Direct sequencing detected mutant DNA in 21% of all patients, but the incidence increased to 49% using digital PCR. The pathological complete response (pCR) rate in patients with PIK3CA mutations was 29% compared with 67% for those without PIK3CA mutations (P = 0.093), when the mutation was defined as positive if the mutant proportion was more than 10% of total genetic content by digital PCR. Low PTEN expression was associated with less pCR compared to high expression (33% versus 72%, P = 0.034). There were no significant associations of PIK3CA copy number, pAKt, or INPP4B with trastuzumab efficacy. In multivariate analysis, activation of the PI3K pathway due to either PIK3CA mutation or low PTEN were related to poorer response to trastuzumab (OR of predictive pCR was 0.11, 95%CI; 0.03-0.48). In conclusion, activating the PI3K pathway is associated with low pCR to trastuzumab-based treatment in HER2-positive breast cancer. Combined analysis of PIK3CA mutation and PTEN expression may serve as critical indicators to identify patients unlikely to respond to trastuzumab.

  5. Physiological Levels of Pik3caH1047R Mutation in the Mouse Mammary Gland Results in Ductal Hyperplasia and Formation of ERα-Positive Tumors

    PubMed Central

    Tikoo, Anjali; Roh, Vincent; Montgomery, Karen G.; Ivetac, Ivan; Waring, Paul; Pelzer, Rebecca; Hare, Lauren; Shackleton, Mark; Humbert, Patrick; Phillips, Wayne A.

    2012-01-01

    PIK3CA, the gene coding for the p110α subunit of phosphoinositide 3-kinase, is frequently mutated in a variety of human tumors including breast cancers. To better understand the role of mutant PIK3CA in the initiation and/or progression of breast cancer, we have generated mice with a conditional knock-in of the common activating mutation, Pik3caH1047R, into one allele of the endogenous gene in the mammary gland. These mice developed a ductal anaplasia and hyperplasia by 6 weeks of age characterized by multi-layering of the epithelial lining of the mammary ducts and expansion of the luminal progenitor (Lin−; CD29lo; CD24+; CD61+) cell population. The Pik3caH1047R expressing mice eventually develop mammary tumors with 100% penetrance but with a long latency (>12 months). This is significantly longer than has been reported for transgenic models where expression of the mutant Pik3ca is driven by an exogenous promoter. Histological analysis of the tumors formed revealed predominantly ERα-positive fibroadenomas, carcinosarcomas and sarcomas. In vitro induction of Pik3caH1047R in immortalized mammary epithelial cells also resulted in tumor formation when injected into the mammary fat pad of immunodeficient recipient mice. This novel model, which reproduces the scenario of a heterozygous somatic mutation occurring in the endogenous PIK3CA gene, will thus be a valuable tool for investigating the role of Pik3caH1047R mutation in mammary tumorigenesis both in vivo and in vitro. PMID:22666336

  6. Impact of regular aspirin use on overall and cancer-specific survival in patients with colorectal cancer harboring a PIK3CA mutation

    PubMed Central

    KOTHARI, NISHI; KIM, RICHARD; JORISSEN, ROBERT N.; DESAI, JAYESH; TIE, JEANNE; WONG, HUI-LI; FARRAGHER, IAN; JONES, IAN; DAY, FIONA L.; LI, SHAN; SAKTHINANDESWAREN, ANURATHA; PALMIERI, MICHELLE; LIPTON, LARA; SCHELL, MICHAEL; TEER, JAMIE K.; SHIBATA, DAVID; YEATMAN, TIMOTHY; SIEBER, OLIVER M.; GIBBS, PETER; TRAN, BEN

    2016-01-01

    Background Recent data have suggested that regular aspirin use improves overall and cancer-specific survival in the subset of colorectal cancer (CRC) patients harboring PIK3CA mutations. However, the number of PIK3CA-mutated CRC patients examined in these studies was modest. Our collaborative study aims to validate the association between regular aspirin use and survival in patients with PIK3CA-mutated CRC. Patients and methods Patients with PIK3CA-mutated CRC were identified at Moffitt Cancer Center (MCC) in the United States and Royal Melbourne Hospital (RMH) in Australia. Prospective clinicopathological data and survival data were available. At MCC, PIK3CA mutations were identified by targeted exome sequencing using the Illumina GAIIx Next Generation Sequencing platform. At RMH, Sanger sequencing was utilized. Multivariate survival analyses were conducted using Cox logistic regression. Results From a cohort of 1487 CRC patients, 185 patients harbored a PIK3CA mutation. Median age of patients with PIK3CA-mutated tumors was 72 years (range: 34 – 92) and median follow up was 54 months. Forty-nine (26%) patients used aspirin regularly. Regular aspirin use was not associated with improved overall survival (multivariate HR 0.96, p = 0.86). There was a trend towards improved cancer-specific survival (multivariate HR 0.60, p = 0.14), but this was not significant. Conclusions Despite examining a large number of patients, we did not confirm that regular aspirin use was associated with statistically significant improvements in survival in PIK3CA-mutated CRC patients. Prospective evaluation of this relationship is warranted. PMID:25549537

  7. KIT over-expression by p55PIK-PI3K leads to Imatinib-resistance in patients with gastrointestinal stromal tumors

    PubMed Central

    Cao, Xiaonian; Luo, Xuelai; Wang, Guoping; Xia, Xianmin; Hu, Junbo; Wang, Jing

    2016-01-01

    Imatinib is the first-line drug for gastrointestinal stromal tumors (GISTs), as mutated KIT is closely associated with the occurrence of GIST. However, Imatinib resistance (IMA-resistance) occurs inevitably in most GIST patients. Although the over-expression of KIT in GIST is one of the major factors contributing to IMA-resistance, the underlying mechanism is still unclear. In this study, we demonstrate that p55PIK, an isoform of phosphoinositide 3-kinase (PI3K), increases KIT expression, leading to IMA-resistance in GISTs by activating NF-κB signaling pathway. Furthermore, down-regulation of p55PIK significantly decreases KIT expression and re-sensitizes IMA-resistance-GIST cells to Imatinib in vitro and in vivo. Interestingly, the expression of both p55PIK and KIT proteins is significantly increased in tumor samples from IMA-resistance-GIST patients, suggesting that p55PIK up-regulation may be important for IMA-resistance in the clinical setting. Altogether, our data provide evidence that p55PIK-PI3K signaling can contribute to IMA-resistance in GIST by increasing KIT expression. Moreover, p55PIK may be a novel potential drug target for treating tumors that develop IMA-resistance. PMID:26587973

  8. Deguelin Potentiates Apoptotic Activity of an EGFR Tyrosine Kinase Inhibitor (AG1478) in PIK3CA-Mutated Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Baba, Yuh; Maeda, Toyonobu; Suzuki, Atsuko; Takada, Satoshi; Fujii, Masato; Kato, Yasumasa

    2017-01-01

    Head and neck squamous cell carcinoma (HNSCC) is known to be intrinsically resistant to inhibitors for epidermal growth factor receptor (EGFR). Until now, clinical outcomes for HNSCC using EGFR inhibitors as single agents have yielded disappointing results. Here, we aimed to study whether combinatorial treatment using AG1478 (EGFR tyrosine kinase inhibitor) and deguelin, which is a rotenoid isolated from the African plant Mundulea sericea, could enhance the anti-tumor effects of AG1478 in HNSCC. For Ca9-22 cells with EGFR, KRAS, and PIK3CA wild types, AG1478 alone suppressed both phosphorylated levels of ERK and AKT and induced apoptosis. On the contrary, for HSC-4 cells with EGFR and KRAS wild types, and a PIK3CA mutant, AG1478 alone did not suppress the phosphorylated level of AKT nor induce apoptosis, while it suppressed ERK phosphorylation. Forced expression of constitutively active PIK3CA (G1633A mutation) significantly reduced the apoptotic effect of AG1478 on the PIK3CA wild-type Ca9-22 cells. When HSC-4 cells with the PIK3CA G1633A mutation were treated with a combination of AG1478 and deguelin, combination effects on apoptosis induction were observed through the inhibition of the AKT pathway. These results suggest that the combination of EGFR tyrosine kinase inhibitor with deguelin is a potential therapeutic approach to treat PIK3CA-mutated HNSCC. PMID:28134774

  9. Conditional activation of Pik3caH1047R in a knock-in mouse model promotes mammary tumorigenesis and emergence of mutations

    PubMed Central

    Yuan, W; Stawiski, E; Janakiraman, V; Chan, E; Durinck, S; Edgar, K A; Kljavin, N M; Rivers, C S; Gnad, F; Roose-Girma, M; Haverty, P M; Fedorowicz, G; Heldens, S; Soriano, R H; Zhang, Z; Wallin, J J; Johnson, L; Merchant, M; Modrusan, Z; Stern, H M; Seshagiri, S

    2013-01-01

    Oncogenic mutations in PIK3CA, which encodes the phosphoinositide-3-kinase (PI3K) catalytic subunit p110α, occur in ∼25% of human breast cancers. In this study, we report the development of a knock-in mouse model for breast cancer where the endogenous Pik3ca allele was modified to allow tissue-specific conditional expression of a frequently found Pik3caH1047R (Pik3cae20H1047R) mutant allele. We found that activation of the latent Pik3caH1047R allele resulted in breast tumors with multiple histological types. Whole-exome analysis of the Pik3caH1047R-driven mammary tumors identified multiple mutations, including Trp53 mutations that appeared spontaneously during the development of adenocarinoma and spindle cell tumors. Further, we used this model to test the efficacy of GDC-0941, a PI3K inhibitor, in clinical development, and showed that the tumors respond to PI3K inhibition. PMID:22370636

  10. PIK3CA Mutations Are Associated With Decreased Benefit to Neoadjuvant Human Epidermal Growth Factor Receptor 2–Targeted Therapies in Breast Cancer

    PubMed Central

    Majewski, Ian J.; Nuciforo, Paolo; Mittempergher, Lorenza; Bosma, Astrid J.; Eidtmann, Holger; Holmes, Eileen; Sotiriou, Christos; Fumagalli, Debora; Jimenez, Jose; Aura, Claudia; Prudkin, Ludmila; Díaz-Delgado, Maria Carmen; de la Peña, Lorena; Loi, Sherene; Ellis, Catherine; Schultz, Nikolaus; de Azambuja, Evandro; Harbeck, Nadia; Piccart-Gebhart, Martine; Bernards, René; Baselga, José

    2015-01-01

    Purpose We investigated whether mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) correlates with response to neoadjuvant human epidermal growth factor receptor 2 (HER2) –targeted therapies in patients with breast cancer. Patients and Methods Baseline tissue biopsies were available from patients with HER2-positive early breast cancer who were enrolled onto the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (NeoALTTO). Activating mutations in PIK3CA were identified using mass spectrometry–based genotyping. Results PIK3CA mutations were identified in 23% of HER2-positive breast tumors, and these mutations were associated with poorer outcome in all of the treatment arms. Patients treated with a combination of trastuzumab and lapatinib who had wild-type PIK3CA obtained a total pathologic complete response (pCR) rate of 53.1%, which decreased to 28.6% in patients with tumors that carried PIK3CA activating mutations (P = .012). Conclusion Activating mutations in PIK3CA predicted poor pCR in patients with HER2-positive breast cancer treated with neoadjuvant therapies that target HER2. Consequently, the combination of anti-HER2 agents and PI3K inhibitors is being investigated. PMID:25559818

  11. MiR-422a acts as a tumor suppressor in glioblastoma by targeting PIK3CA

    PubMed Central

    Liang, Haiqian; Wang, Renjie; Jin, Ying; Li, Jianwei; Zhang, Sai

    2016-01-01

    Although surgical treatment, chemotherapy, and radiotherapy have improved the overall survival rate in glioblastoma multiforme (GBM), further intensive research of GBM’s molecular mechanism is still needed. In this study, we observed that miR-422a was downregulated in GBM tissues and cell lines by quantitative real-time polymerase chain reaction (PCR) and primer extension assay. Overexpression of miR-422a significantly reduced the cell proliferation, migration, and invasion of GBM cells. Functional study indicated that miR-422a inhibited cell proliferation, invasion, and migration by targeting PIK3CA, an important member of PI3K/Akt signal pathway. These results demonstrate that the miR-422a/PIK3CA axis may constitute a potential target for GBM therapy. PMID:27648359

  12. A missense mutation in PIK3R5 gene in a family with ataxia and oculomotor apraxia.

    PubMed

    Al Tassan, Nada; Khalil, Dania; Shinwari, Jameela; Al Sharif, Latifa; Bavi, Prashant; Abduljaleel, Zainularifeen; Abu Dhaim, Nada; Magrashi, Amna; Bobis, Steve; Ahmed, Hala; Alahmed, Samaher; Bohlega, Saeed

    2012-02-01

    Autosomal recessive ataxias are heterogeneous group of disorders characterized by cerebellar atrophy and peripheral sensorimotor neuropathy. Molecular characterization of this group of disorders identified a number of genes contributing to these overlapping phenotypes. Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive form of ataxia caused by mutations in the SETX gene. We report on a consanguineous family with autosomal recessive inheritance and clinical characteristics of AOA2, and no mutations in the SETX gene. We mapped the AOA locus in this family to chromosome 17p12-p13. Sequencing of all genes in the refined region identified a homozygous missense mutation in PIK3R5 that was absent in 477 normal controls. Our characterization of the PIK3R5 protein and findings suggest that it may play a role in the development of the cerebellum and vermis.

  13. NASA and Mary J. Blige Encourage Exciting Careers For Women

    NASA Image and Video Library

    NASA is collaborating with award-winning recording artist Mary J. Blige to encourage young women to pursue exciting experiences and career choices through studying science, technology, engineering ...

  14. Somatic mutations in PIK3CA and activation of AKT in intraductal tubulopapillary neoplasms of the pancreas.

    PubMed

    Yamaguchi, Hiroshi; Kuboki, Yuko; Hatori, Takashi; Yamamoto, Masakazu; Shiratori, Keiko; Kawamura, Shunji; Kobayashi, Makio; Shimizu, Michio; Ban, Shinichi; Koyama, Isamu; Higashi, Morihiro; Shin, Nobuhiro; Ishida, Kazuyuki; Morikawa, Takanori; Motoi, Fuyuhiko; Unno, Michiaki; Kanno, Atsushi; Satoh, Kennichi; Shimosegawa, Tooru; Orikasa, Hideki; Watanabe, Tomoo; Nishimura, Kazuhiko; Harada, Youji; Furukawa, Toru

    2011-12-01

    Intraductal tubulopapillary neoplasm (ITPN) is a recently recognized rare variant of intraductal neoplasms of the pancreas. Molecular aberrations underlying the neoplasm remain unknown. We investigated somatic mutations in PIK3CA, PTEN, AKT1, KRAS, and BRAF. We also investigated aberrant expressions of phosphorylated AKT, phosphatase and tensin homolog (PTEN), tumor protein 53 (TP53), SMAD4, and CTNNB1 in 11 cases of ITPNs and compared these data with those of 50 cases of intraductal papillary mucinous neoplasm (IPMN), another distinct variant of pancreatic intraductal neoplasms. Mutations in PIK3CA were found in 3 of 11 ITPNs but not in IPMNs (P = 0.005; Fisher exact test). In contrast, mutations in KRAS were found in none of the ITPNs but were found in 26 of the 50 IPMNs (P = 0.001; Fisher exact test). PIK3CA mutations were associated with strong expression of phosphorylated AKT (P < 0.001; the Mann-Whitney U test). Moreover, the expression of phosphorylated AKT was apparent in most ITPNs but only in a few IPMNs (P < 0.001; the Mann-Whitney U test). Aberrant expressions of TP53, SMAD4, and CTNNB1 were not statistically different between these neoplasms. Mutations in PIK3CA and the expression of phosphorylated AKT were not associated with age, sex, tissue invasion, and patients' prognosis in ITPNs. These results indicate that activation of the phosphatidylinositol 3-kinase pathway may play a crucial role in ITPNs but not in IPMNs. In contrast, the mutation in KRAS seems to play a major role in IPMNs but not in ITPNs. The activated phosphatidylinositol 3-kinase pathway may be a potential target for molecular diagnosis and therapy of ITPNs.

  15. Concordant analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression between primary colorectal cancer and matched metastases

    PubMed Central

    Mao, Chen; Wu, Xin-Yin; Yang, Zu-Yao; Threapleton, Diane Erin; Yuan, Jin-Qiu; Yu, Yuan-Yuan; Tang, Jin-Ling

    2015-01-01

    Current data on the concordance of KRAS, BRAF, PIK3CA mutation status or PTEN expression status between primary tumors and metastases in colorectal cancer (CRC) are conflicting. We conducted a systematic review and meta-analysis to examine concordance and discordance of the status of these four biomarkers between primary tumors and corresponding metastases in CRC patients. The biomarker status in primary tumors was used as the reference standard. Concordance data for KRAS, BRAF, PIK3CA and PTEN were provided by 43, 16, 9 and 7 studies, respectively. The pooled concordance rate was 92.0% (95% CI: 89.7%–93.9%) for KRAS, 96.8% (95% CI: 94.8%–98.0%) for BRAF, 93.9% (95% CI: 89.7%–96.5%) for PIK3CA and 71.7% (95% CI: 57.6%–82.5%) for PTEN. The pooled false positive and false negative rates for KRAS were 9.0% (95% CI: 6.5%–12.4%) and 11.3% (95% CI: 8.0%–15.8%), respectively. KRAS, BRAF and PIK3CA mutations are highly concordant between primary tumors and corresponding metastases in CRC, but PTEN loss is not. Nine percent of patients with wild-type KRAS in primary tumors who received anti-EGFR treatment had mutant KRAS in metastases, while 11.3% patients with mutant KRAS primary tumors had wild-type KRAS in the metastases. These 11.3% patients currently do not receive potentially beneficial anti-EGFR treatment. PMID:25639985

  16. Clinicopathological features and prognostic roles of KRAS, BRAF, PIK3CA and NRAS mutations in advanced gastric cancer

    PubMed Central

    2014-01-01

    Background RAS-RAF-MEK-ERK and PI3K-AKT pathways form a significant cascade for potential molecular target therapy in advanced cancer. The clinical significance of mutations in these genes in advanced gastric cancer (AGC) is uncertain. Methods We collected formalin-fixed, paraffin-embedded and fresh frozen tumor samples from AGC patients and analyzed the KRAS, NRAS, BRAF and PIK3CA mutations by direct-sequencing. We retrospectively investigated the clinicopathological features of these mutations in AGC patients, and selected patients with metastatic gastric cancer. Results Among 167 AGC patients, mutations of KRAS codons 12/13 (N = 8/164, 4.9%), PIK3CA (N = 9/163, 5.5%), and NRAS codon 12/13(N = 3/159, 1.9%) were detected. Comparison of the clinicopathological features of the mutated KRAS, PIK3CA, NRAS genes with an all-wild type of these genes showed that the frequency of the intestinal type was significantly higher in patients whose tumor tissue contained KRAS mutations (P = 0.014). Among 125 patients with metastatic gastric cancer, patients with NRAS codon 12/13 mutations in their tumors had shorter overall survival compared with NRAS wild-type patients (MST: 14.7 vs 8.8 months, P = 0.011). By multivariate analyses, NRAS codon 12/13 mutation was an indicator for poor prognosis in patients with metastatic gastric cancer (adjusted HR 5.607, 95% CI: 1.637-19.203). Conclusions Our study indicated that mutations of KRAS, PIK3CA and NRAS were rare in AGC. NRAS mutations were likely to associate with poor prognosis in metastatic state of AGC patients, but further validation of other research is required. PMID:24774510

  17. PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation.

    PubMed

    Keppler-Noreuil, Kim M; Rios, Jonathan J; Parker, Victoria E R; Semple, Robert K; Lindhurst, Marjorie J; Sapp, Julie C; Alomari, Ahmad; Ezaki, Marybeth; Dobyns, William; Biesecker, Leslie G

    2015-02-01

    Somatic activating mutations in the phosphatidylinositol-3-kinase/AKT/mTOR pathway underlie heterogeneous segmental overgrowth phenotypes. Because of the extreme differences among patients, we sought to characterize the phenotypic spectrum associated with different genotypes and mutation burdens, including a better understanding of associated complications and natural history. Historically, the clinical diagnoses in patients with PIK3CA activating mutations have included Fibroadipose hyperplasia or Overgrowth (FAO), Hemihyperplasia Multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal (CLOVES) syndrome, macrodactyly, Fibroadipose Infiltrating Lipomatosis, and the related megalencephaly syndromes, Megalencephaly-Capillary Malformation (MCAP or M-CM) and Dysplastic Megalencephaly (DMEG). A workshop was convened at the National Institutes of Health (NIH) to discuss and develop a consensus document regarding diagnosis and treatment of patients with PIK3CA-associated somatic overgrowth disorders. Participants in the workshop included a group of researchers from several institutions who have been studying these disorders and have published their findings, as well as representatives from patient-advocacy and support groups. The umbrella term of "PIK3CA-Related Overgrowth Spectrum (PROS)" was agreed upon to encompass both the known and emerging clinical entities associated with somatic PIK3CA mutations including, macrodactyly, FAO, HHML, CLOVES, and related megalencephaly conditions. Key clinical diagnostic features and criteria for testing were proposed, and testing approaches summarized. Preliminary recommendations for a uniform approach to assessment of overgrowth and molecular diagnostic testing were determined. Future areas to address include the surgical management of overgrowth tissue and vascular anomalies, the optimal approach to thrombosis risk, and the testing of potential

  18. MicroRNA-363-3p inhibits papillary thyroid carcinoma progression by targeting PIK3CA

    PubMed Central

    Liu, Jia; Li, Qun; Li, Rui; Ren, Peiyou; Dong, Su

    2017-01-01

    MicroRNA-363-3p (miR-363-3p) reportedly plays crucial roles in tumor development and progression in many types of cancers. However, its role in papillary thyroid carcinoma (PTC) remain largely unclear. We therefore investigated the function and underlying mechanism of miR-363-3p in PTC. Here, we found that miR-363-3p was significantly downregulated in human PTC tissue samples and cell lines, and that miR-363-3p levels are negatively correlated with advanced clinical stage and lymph node metastasis. In addition to suppressing tumor growth in vivo, restoration of miR-363-3p in TPC-1 cells significantly inhibits proliferation, migration, and invasion and induced apoptosis in vitro. Mechanistically, miR-363-3p was verified to directly bind to 3’UTR of the phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) mRNA, and reduce its expression at both mRNA and protein levels, which further inhibits phosphatidylinositol 3-kinase/Akt signaling pathway. PIK3CA expression was also found to be increased in human PTC tissues, and were inversely correlated with miR-363-3p. Furthermore, restoration of PIK3CA partially rescued the miR-363-3p-induced inhibition effect on TPC-1 cell proliferation, migration and invasion. Taken together, these findings indicated for the first time that miR-363-3p functions as a tumor suppressor in PTC, and its suppressive effect is mediated by repressing PIK3CA. PMID:28123856

  19. Mutations in PIK3CD Can Cause Hyper IgM Syndrome (HIGM) Associated with Increased Cancer Susceptibility

    PubMed Central

    Crank, M. C.; Grossman, J. K.; Moir, S.; Pittaluga, S.; Buckner, C. M.; Kardava, L.; Agharahimi, A.; Meuwissen, H.; Stoddard, J.; Niemela, J.; Kuehn, H.

    2014-01-01

    Autosomal dominant gain of function mutations in the gene encoding PI3K p110δ were recently associated with a novel combined immune deficiency characterized by recurrent sinopulmonary infections, CD4 lymphopenia, reduced class-switched memory B cells, lymphadenopathy, CMV and/or EBV viremia and EBV-related lymphoma. A subset of affected patients also had elevated serum IgM. Here we describe three patients in two families who were diagnosed with HIGM at a young age and were recently found to carry heterozygous mutations in PIK3CD. These patients had an abnormal circulating B cell distribution featuring a preponderance of early transitional (T1) B cells and plasmablasts. When stimulated in vitro, PIK3CD mutated B cells were able to secrete class-switched immunoglobulins. This finding implies that the patients’ elevated serum IgM levels were unlikely a product of an intrinsic B cell functional inability to class switch. All three patients developed malignant lymphoproliferative syndromes that were not associated with EBV. Thus, we identified a novel subset of patients with PIK3CD mutations associated with HIGM, despite indications of preserved in vitro B cell class switch recombination, as well as susceptibility to non-EBV-associated malignancies. PMID:24610295

  20. Prenatal Diagnosis of CLOVES Syndrome Confirmed by Detection of a Mosaic PIK3CA Mutation in Cultured Amniocytes

    PubMed Central

    Emrick, Lisa T.; Murphy, Lauren; Shamshirsaz, Alireza A.; Ruano, Rodrigo; Cassady, Christopher I.; Liu, Liu; Chang, Fengqi; Sutton, V. Reid; Li, Marilyn; Van den Veyver, Ignatia B.

    2015-01-01

    Congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies (CLOVES) syndrome, a segmental overgrowth syndrome, is caused by post zygotic somatic mutations in PIK3CA, a gene involved in the receptor tyrosine kinase phosphatidylinositol 3-kinase (PI3)-AKT growth-signaling pathway. Prenatal ultrasound findings of lymphovascular malformations, segmental overgrowth and skeletal defects can raise suspicion for CLOVES syndrome, but molecular confirmation of PIK3CA mutations on prenatally obtained samples is challenging because of somatic mosaicism. We detected a mosaic disease-causing mutation in PIK3CA by sequencing of DNA extracted from cultured amniotic cells, but not from DNA directly prepared from an amniotic fluid sample in a fetus with prenatally suspected CLOVES syndrome. The infant was born prematurely and displayed severe lymphovascular malformations and segmental overgrowth consistent with a clinical diagnosis of CLOVES syndrome; he passed away at 29 days of life. We discuss the complexities and limitations of genetic testing for somatic mosaic mutations in the prenatal period and highlight the potential need for multiple approaches to arrive at a molecular diagnosis. PMID:25044986

  1. Phosphoproteomic comparison of Pik3ca and Pten signalling identifies the nucleotidase NT5C as a novel AKT substrate

    PubMed Central

    Moniz, Larissa S.; Surinova, Silvia; Ghazaly, Essam; Velasco, Lorena Gonzalez; Haider, Syed; Rodríguez-Prados, Juan Carlos; Berenjeno, Inma M.; Chelala, Claude; Vanhaesebroeck, Bart

    2017-01-01

    To identify novel effectors and processes regulated by PI3K pathway activation, we performed an unbiased phosphoproteomic screen comparing two common events of PI3K deregulation in cancer: oncogenic Pik3ca mutation (Pik3caH1047R) and deletion of Pten. Using mouse embryonic fibroblast (MEF) models that generate inducible, low-level pathway activation as observed in cancer, we quantified 7566 unique phosphopeptides from 3279 proteins. A number of proteins were found to be differentially-regulated by Pik3caH1047R and Pten loss, suggesting unique roles for these two events in processes such as vesicular trafficking, DNA damage repair and RNA splicing. We also identified novel PI3K effectors that were commonly-regulated, including putative AKT substrates. Validation of one of these hits, confirmed NT5C (5′,3′-Nucleotidase, Cytosolic) as a novel AKT substrate, with an unexpected role in actin cytoskeleton regulation via an interaction with the ARP2/3 complex. This study has produced a comprehensive data resource and identified a new link between PI3K pathway activation and actin regulation. PMID:28059163

  2. Somatic mosaicism of the PIK3CA gene identified in a Hungarian girl with macrodactyly and syndactyly.

    PubMed

    Tripolszki, Kornélia; Knox, Rachel; Parker, Victoria; Semple, Robert; Farkas, Katalin; Sulák, Adrien; Horváth, Emese; Széll, Márta; Nagy, Nikoletta

    2016-04-01

    Isolated macrodactyly (OMIM 155500) belongs to a heterogeneous group of overgrowth syndromes. It is a congenital anomaly resulting in enlargement of all tissues localized to the terminal portions of a limb and caused by somatic mutations in the phosphatidylinositol 3-kinase catalytic alpha (PIK3CA, OMIM 171834) gene. Here we report a Hungarian girl with macrodactyly and syndactyly. Genetic screening at hotspots in the PIK3CA gene identified a mosaic mutation (c.1624G > A, p.Glu542Lys) in the affected tissue, but not in the peripheral blood. To date, this somatic mutation has been reported in eight patients affected by different forms of segmental overgrowth syndromes. Detailed analysis of the Hungarian child and previously reported cases suggests high phenotypic diversity associated with the p.Glu542Lys somatic mutation. The identification of the mutation provides a novel therapeutic modality for the affected patients: those who carry somatic mutations in the PIK3CA gene are potential recipients of a novel "repurposing" approach of rapamycin treatment.

  3. Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: towards recommendation for molecular testing and management.

    PubMed

    Avila, Magali; Dyment, David A; Sagen, Jørn V; St-Onge, Judith; Moog, Ute; Chung, Brian H Y; Mansour, Sahar; Albanese, Assunta; Garcia, Sixto; Ortiz Martin, David; Lopez, Ainhoa Abad; Claudi, Tor; König, Rainer; White, Susan M; Sawyer, Sarah L; Bernstein, Jon A; Slattery, Leah; Jobling, Rebekah K; Yoon, Grace; Curry, Cynthia J; Le Merrer, Martine; Le Luyer, Bernard; Héron, Delphine; Mathieu-Dramard, Michèle; Bitoun, Pierre; Odent, Sylvie; Amiel, Jeanne; Kuentz, Paul; Thevenon, Julien; Laville, Martine; Reznik, Yves; Fagour, Cédric; Nunes, Marie-Laure; Delesalle, Dorothée; Manouvrier, Sylvie; Lascols, Olivier; Huet, Frédéric; Binquet, Christine; Faivre, Laurence; Rivière, Jean-Baptiste; Vigouroux, Corinne; Njølstad, Pål Rasmus; Innes, A Micheil; Thauvin-Robinet, Christel

    2015-10-24

    SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had 4 or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included IUGR < 10(th) percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended.

  4. Inhibitors of STAT3, β-catenin, and IGF-1R sensitize mouse PIK3CA-mutant breast cancer to PI3K inhibitors.

    PubMed

    Merino, Vanessa F; Cho, Soonweng; Liang, Xiaohui; Park, Sunju; Jin, Kideok; Chen, Qian; Pan, Duojia; Zahnow, Cynthia A; Rein, Alan R; Sukumar, Saraswati

    2017-03-15

    Although mutations in the phosphoinositide 3-kinase catalytic subunit (PIK3CA) are common in breast cancer, PI3K inhibitors alone have shown modest efficacy. We sought to identify additional pathways altered in PIK3CA-mutant tumors that might be targeted in combination with PI3K inhibitors. We generated two transgenic mouse models expressing the human PIK3CA-H1047R- and the -E545K hotspot-mutant genes in the mammary gland and evaluated their effects on development and tumor formation. Molecular analysis identified pathways altered in these mutant tumors, which were also targeted in multiple cell lines derived from the PIK3CA tumors. Finally, public databases were analyzed to determine whether novel pathways identified in the mouse tumors were altered in human tumors harboring mutant PIK3CA. Mutant mice showed increased branching and delayed involution of the mammary gland compared to parental FVB/N mice. Mammary tumors arose in 30% of the MMTV-PIK3CA-H1047R and in 13% of -E545K mice. Compared to MMTV-Her-2 transgenic mouse mammary tumors, H1047R tumors showed increased upregulation of Wnt/β-catenin/Axin2, hepatocyte growth factor (Hgf)/Stat3, insulin-like growth factor 2 (Igf-2), and Igf-1R pathways. Inhibitors of STAT3, β-catenin, and IGF-1R sensitized H1047R-derived mouse tumor cells and PIK3CA-H1047R overexpressing human HS578T breast cancer cells to the cytotoxic effects of PI3K inhibitors. Analysis of The Cancer Genome Atlas database showed that, unlike primary PIK3CA-wild-type and HER-2(+) breast carcinomas, PIK3CA-mutant tumors display increased expression of AXIN2, HGF, STAT3, IGF-1, and IGF-2 mRNA and activation of AKT, IGF1-MTOR, and WNT canonical signaling pathways. Drugs targeting additional pathways that are altered in PIK3CA-mutant tumors may improve treatment regimens using PI3K inhibitors alone.

  5. Possible resolution of the B{yields}{pi}{pi}, {pi}K puzzles

    SciTech Connect

    Li Hsiangnan; Mishima, Satoshi

    2011-02-01

    We show that there exist uncanceled soft divergences in the k{sub T} factorization for nonfactorizable amplitudes of two-body nonleptonic B meson decays, similar to those identified in hadron hadroproduction. These divergences can be grouped into a soft factor using the eikonal approximation, which is then treated as an additional nonperturbative input in the perturbative QCD formalism. Viewing the special role of the pion as a qq bound state and as a pseudo Nambu-Goldstone boson, we postulate that the soft effect associated with it is significant. This soft factor enhances the nonfactorizable color-suppressed tree amplitudes, such that the branching ratios B({pi}{sup 0}{pi}{sup 0}) and B({pi}{sup 0}{rho}{sup 0}) are increased under the constraint of the B({rho}{sup 0}{rho}{sup 0}) data, the difference between the direct CP asymmetries A{sub CP}({pi}{sup {+-}}K{sup {+-}}) and A{sub CP}({pi}{sup 0}K{sup {+-}}) is enlarged, and the mixing-induced CP asymmetry S{sub {pi}}{sup 0}{sub K{sub S}} is reduced. Namely, the known {pi}{pi} and {pi}K puzzles can be resolved simultaneously.

  6. Reexamining B{yields}{pi}{pi}, {pi}K decays in QCD factorization approach

    SciTech Connect

    Li Xinqiang; Yang Yadong

    2005-10-01

    Motivated by the recent experimental data, we have revisited the B{yields}{pi}K,{pi}{pi} decays in the framework of QCD factorization, with inclusion of the important strong penguin corrections of order {alpha}{sub s}{sup 2} induced by b{yields}Dg*g* (D=d or s and g* denotes an off-shell gluon) transitions. We find that these higher order strong penguin contributions can provide {approx}30% enhancement to the penguin-dominated B{yields}{pi}K decay rates, and such an enhancement can improve the consistency between the theoretical predictions and the experimental data significantly, while for the tree-dominated B{yields}{pi}{pi} decays, these higher order contributions play only a minor role. When these strong penguin contributions are summed, only a small strong phase remains and the direct CP asymmetries get small corrections. We also find that patterns of the ratios between the CP-averaged branching fractions remain nearly unaffected even after including these higher order corrections and the {pi}K puzzle still persists. Our results may indicate that to resolve the puzzle one would have to resort to new physics contributions in the electroweak penguin sector as found by Buras et al.

  7. Measurement of glacier velocity at Pik Lenin, Tajikistan, by feature tracking

    NASA Astrophysics Data System (ADS)

    Kumari, S.; Ghosh, S. K.; Buchroithner, M. F.

    2014-11-01

    Glaciers, especially in mountain area are sensitive indicators of climate fluctuations and also contribute to present rates of sea level rise. In Central Asia, these glaciers are the primary resource for fresh water. Understanding the seasonal behavior of these glaciers would help to make efficient use of the available water reservoir. Different methods have been employed to study glacier displacements in past. The conventional survey techniques are very cost-intensive and highly depend on accessibility to high mountain glaciers also directs us to look for new ways to study these areas. Here remote sensing comes in handy with freely available data and a good coverage with high spatial and temporal resolution. Optical satellite imagery, available free can be effectively used for research purpose. The glacier in this region fed lake Karakul (380 km2), the largest Lake in Tajikistan. The objective is to study the displacement tendency of the Glacier in Pik Lenin area using Landsat 7 dataset. Normalized cross correlation algorithm has been implemented via CIAS to estimate the motion of glacier surface. A number of combination of reference block and search area size were tested for 30 m resolution dataset. As a result the specifications: reference block size of 15 pixels and search area size of 10 pixels was found out as the best set of parameters and considered for further processing. The study derives a reliable set of data depicting the velocities in the glacier which after post processing shows peak velocity of 121 m/y of the glacier.

  8. STS-101 Crew Interview / Mary Ellen Weber

    NASA Technical Reports Server (NTRS)

    2000-01-01

    Live footage of a preflight interview with Mission Specialist Mary Ellen Weber is seen. The interview addresses many different questions including why Weber became an astronaut, the events that led to her interest in chemistry and sky diving. Other interesting information that this one-on-one interview discusses is the reaction and reasons for the change of the mission objectives. Weber also mentions the scheduled space-walk, docking with the International Space Station (ISS), the repairs of equipment and change of the batteries, and the installation of handrails. Weber also discusses her responsibilities during the space-walk, and docking of the spacecraft.

  9. Marie Curie's contribution to Medical Physics.

    PubMed

    Jean-Claude, Rosenwald; Nüsslin, Fridtjof

    2013-09-01

    On occasion of its 50th anniversary, the International Organization for Medical Physics (IOMP) from now on is going to celebrate annually an International Day of Medical Physics for which the 7th November, the birthday of Marie Sklodowska Curie, a most exceptional character in science at all and a pioneer of medical physics, has been chosen. This article briefly outlines her outstanding personality, sketches her fundamental discovery of radioactivity and emphasizes the impact of her various achievements on the development of medical physics at large. © 2013 Published by Elsevier Ltd on behalf of Associazione Italiana di Fisica Medica.

  10. Gifts from Mary Ainsworth and John Bowlby.

    PubMed

    Crittenden, Patricia M

    2017-07-01

    Attachment theory has developed over many decades - and continues to develop. Its roots lie in several seminal publications of John Bowlby (the basis of attachment theory) and Mary D. S. Ainsworth (the notion of individual differences in attachment). This paper identifies the prescient contributions of these early publications and two processes (a long-term dialogue and reflection on discrepancy) that underlay emergent theory. Because I was a student of Ainsworth when both attachment theory and individual differences in attachment organization were becoming better known, I offer some of my recollections of that period, suggesting how that period may have affected current work in attachment.

  11. Mary Budd Rowe: a storyteller of science

    NASA Astrophysics Data System (ADS)

    Bianchini, Julie A.

    2008-12-01

    This article examines Mary Budd Rowe's groundbreaking and far-reaching contributions to science education. Rowe is best known for her research on wait-time: the idea that teachers can improve the quality and length of classroom discussions by waiting at least 3 s before and after student responses. Her wait-time research grew from and helped inform her staunch advocacy of science education as inquiry; Rowe saw wonder and excitement as central to the teaching and learning of science. She spent much of her professional life designing professional development experiences and innovative curriculum materials to help teachers, particularly elementary school teachers, enact inquiry in their classrooms.

  12. Pediatric Charcot-Marie-Tooth disease.

    PubMed

    Jani-Acsadi, Agnes; Ounpuu, Sylvia; Pierz, Kristan; Acsadi, Gyula

    2015-06-01

    Heritable diseases of the peripheral nerves (Charcot-Marie-Tooth disease [CMT]) affect the motor units and sensory nerves, and they are among the most prevalent genetic conditions in the pediatric patient population. The typical clinical presentation includes distal muscle weakness and atrophy, but the severity and progression are largely variable. Improvements in supportive treatment have led to better preservation of patients' motor functions. More than 80 genes have been associated with CMT. These genetic discoveries, along with the developments of cellular and transgenic disease models, have allowed clinicians to better understand the disease mechanisms, which should lead to more specific treatments.

  13. Jean-Marie Mariotti Center for Interferometry

    NASA Astrophysics Data System (ADS)

    Chelli, Alain; Duvert, Gilles; Bonneau, Daniel; Perrin, Guy S.; Thiebaut, Eric M.; Mourard, Denis; Petrov, Romain G.; Cruzalebes, Pierre; Lopez, Bruno; Malbet, Fabien; Daigne, Gerard; Ollivier, Marc

    2003-02-01

    The Jean-Marie Mariotti Center is a network of 11 French Institutes, Laboratories or Observatories, appointed by CNRS in 2000. It coordinates the efforts of the member institutes to offer all the potential users of interferometric facilities the best operational environment, providing software, academic formation and stimulating the prospective on new interferometric developments. At present, besides academic formation, the major effort is focused on the development of the software to prepare the observations, to reduce the data and to interpret the results in terms of models or reconstructed images. In this contribution, we describe the achievements and the future plans of the Mariotti Center.

  14. Water resources of St. Mary Parish, Louisiana

    USGS Publications Warehouse

    Prakken, Lawrence B.; White, Vincent E.; Lovelace, John K.

    2014-01-01

    Information concerning the availability, use, and quality of water in St. Mary Parish, Louisiana, is critical for proper water-supply management. The purpose of this fact sheet is to present information that can be used by water managers, parish residents, and others for management of this vital resource. Information on the availability, past and current use, use trends, and water quality from groundwater and surface-water sources in the parish is presented. Previously published reports and data stored in the U.S. Geological Survey’s National Water Information System (http://waterdata.usgs.gov/nwis) are the primary sources of the information presented here.

  15. 33 CFR 117.329 - St. Marys River.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 33 Navigation and Navigable Waters 1 2011-07-01 2011-07-01 false St. Marys River. 117.329 Section 117.329 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Florida § 117.329 St. Marys River. The draws of US17...

  16. Genetics Home Reference: Charcot-Marie-Tooth disease

    MedlinePlus

    ... Roussy-Lévy syndrome Genetic Testing Registry: X-linked hereditary motor and sensory neuropathy Other Diagnosis and Management Resources (16 links) GeneReview: Charcot-Marie-Tooth Hereditary Neuropathy Overview GeneReview: Charcot-Marie-Tooth Neuropathy Type ...

  17. 33 CFR 117.653 - St. Mary's Falls Canal.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false St. Mary's Falls Canal. 117.653 Section 117.653 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Michigan § 117.653 St. Mary's Falls Canal. The draw...

  18. Marie and Pierre Curie and radium: history, mystery, and discovery.

    PubMed

    Mould, R F

    1999-09-01

    Commencing with Marie Curie's early life in Poland and the discovery of radium in the rue l'Homond "shed" in Paris in 1898, this paper includes some little known facts. It ends with some unusual uses of and claims for radium, and finally, because Medical Physics is an American journal, details are included of Marie Curie's two visits to the USA.

  19. Exploration of the Mars Radiation Environment Using MARIE

    NASA Technical Reports Server (NTRS)

    Cucinotta, F.; Badhwar, G.; Zeitlin, C.; Cleghorn, T.; Bahr, J.; Beyer, T.; Chambellan, C.; Delaune, P.; Dunn, R.; Flanders, J.

    2002-01-01

    One of three science instruments onboard Mars Odyssey is the Mars Radiation Environment Experiment (MARIE), which is described here. MARIE is an energetic particle spectrometer which will characterize the space radiation environment of Mars and determine its risk to human exploration. Additional information is contained in the original extended abstract.

  20. PIK3CA missense mutation is associated with unfavorable outcome in grade 3 endometrioid carcinoma but not in serous endometrial carcinoma.

    PubMed

    McIntyre, John B; Nelson, Gregg S; Ghatage, Prafull; Morris, Don; Duggan, Máire A; Lee, Cheng-Han; Doll, Corinne M; Köbel, Martin

    2014-01-01

    To evaluate the outcome association of PIK3CA mutational status within histological types of rigorously classified high-grade endometrial carcinomas. We assessed PIK3CA mutational status in exon 9 and exon 20 hot spots by Sanger sequencing of DNA derived from formalin fixed paraffin embedded tissue of 57 grade 3 endometrioid, 26 serous, 11 clear cell and 5 dedifferentiated carcinomas. We correlated PIK3CA mutation status with clinicopathological and other molecular parameters. Univariate and multivariate disease specific survival analysis was performed using Kaplan-Meier and Cox regression analyses. PIK3CA exon 9 or exon 20 missense mutations were identified in 20 of 99 (20%) high-grade endometrial carcinomas without significant difference across histological types (p=0.22). Presence of PIK3CA exon 9 or exon 20 missense mutations was associated with shorter disease specific survival within grade 3 endometrioid (p=0.0029) but not endometrial serous (p=0.57) carcinoma based on univariate analysis. Within grade 3 endometrioid carcinoma, PIK3CA exon 9 or exon 20 missense mutations were more commonly observed in cases that were deficient for mismatch repair protein expression (p=0.0058) and showed loss of ARID1A expression (p=0.037). PIK3CA exon 9 or exon 20 missense mutations are present across all histological types of high-grade endometrial carcinomas but a significant outcome association is only seen in grade 3 endometrioid carcinoma, suggesting a greater biological importance in this tumor type. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Conditional loss of ErbB3 delays mammary gland hyperplasia induced by mutant PIK3CA without affecting mammary tumor latency, gene expression, or signaling.

    PubMed

    Young, Christian D; Pfefferle, Adam D; Owens, Philip; Kuba, María G; Rexer, Brent N; Balko, Justin M; Sánchez, Violeta; Cheng, Hailing; Perou, Charles M; Zhao, Jean J; Cook, Rebecca S; Arteaga, Carlos L

    2013-07-01

    Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K), have been shown to transform mammary epithelial cells (MEC). Studies suggest this transforming activity requires binding of mutant p110α via p85 to phosphorylated YXXM motifs in activated receptor tyrosine kinases (RTK) or adaptors. Using transgenic mice, we examined if ErbB3, a potent activator of PI3K, is required for mutant PIK3CA-mediated transformation of MECs. Conditional loss of ErbB3 in mammary epithelium resulted in a delay of PIK3CA(H1047R)-dependent mammary gland hyperplasia, but tumor latency, gene expression, and PI3K signaling were unaffected. In ErbB3-deficient tumors, mutant PI3K remained associated with several tyrosyl phosphoproteins, potentially explaining the dispensability of ErbB3 for tumorigenicity and PI3K activity. Similarly, inhibition of ErbB RTKs with lapatinib did not affect PI3K signaling in PIK3CA(H1047R)-expressing tumors. However, the p110α-specific inhibitor BYL719 in combination with lapatinib impaired mammary tumor growth and PI3K signaling more potently than BYL719 alone. Furthermore, coinhibition of p110α and ErbB3 potently suppressed proliferation and PI3K signaling in human breast cancer cells harboring PIK3CA(H1047R). These data suggest that PIK3CA(H1047R)-driven tumor growth and PI3K signaling can occur independently of ErbB RTKs. However, simultaneous blockade of p110α and ErbB RTKs results in superior inhibition of PI3K and mammary tumor growth, suggesting a rational therapeutic combination against breast cancers harboring PIK3CA activating mutations.

  2. Results from the Martian Radiation Environment Experiment MARIE

    NASA Technical Reports Server (NTRS)

    Zeitlin, C.; Cleghorn, T.; Cucinotta, F.; Saganti, P.; Andersen, V.; Lee, K.; Pinsky, L.; Atwell, W.; Turner, R.

    2003-01-01

    One of the three science instruments aboard the 2001 Mars Odyssey spacecraft is the Martian Radiation Environment Experiment, MARIE. MARIE consists of a stack of silicon detectors, augmented by a Cerenkov detector. MARIE is designed to measure a portion of the particle spectrum of the Galactic Cosmic Rays (GCR), as well as the high fluxes of low-energy protons (energies less than about 100 MeV) that are intermittently produced by active regions on the sun in Solar Particle Events (SPE). MARIE is providing the first detailed information about the radiation environment near Mars.measurements. MARIE has been operating successfully for nearly a year. Solar particle events of considerable interest have been observed, and data have been obtained that will yield GCR spectra from a novel observation point in the solar system.

  3. Roadmap to MaRIE March 2015

    SciTech Connect

    Barnes, Cris William

    2015-03-30

    Los Alamos National Laboratory’s proposed MaRIE facility is slated to introduce the world’s highest energy hard x-ray free electron laser (XFEL). As the light source for the Matter-Radiation Interactions in Extremes experimental facility (MaRIE), the 42-keV XFEL, with bursts of x-ray pulses at gigahertz repetition for studying fast dynamical processes, will help accelerate discovery and design of the advanced materials needed to meet 21st-century national security and energy security challenges. Yet the science of free-electron lasers has a long and distinguished history at Los Alamos National Laboratory (LANL), where for nearly four decades Los Alamos scientists have been performing research, design, development, and collaboration work in FEL science. The work at Los Alamos has evolved from low-gain amplifier and oscillator FEL development to highbrightness photoinjector development, and later, self-amplified spontaneous emission (SASE) and high-gain amplifier FEL development.

  4. MicroRNA-126 affects rheumatoid arthritis synovial fibroblast proliferation and apoptosis by targeting PIK3R2 and regulating PI3K-AKT signal pathway

    PubMed Central

    Deng, Jia-Xin; Zhang, Yu-Ping; Liang, Wan-Yi; Jiang, Zhen-Lan; Yu, Qing-Hong; Li, Juan

    2016-01-01

    Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes inflammation and destruction of the joints as well as an increased risk of cardiovascular disease. RA synovial fibroblasts (RASFs) are involved in the progression of RA and release pro-inflammatory cytokines. On the other hand, microRNAs (miRs) may help control the inflammatory response of immune and non-immune cells. Therefore, our study used lentiviral expression vectors to test the effects of miR-126 overexpression on RASF proliferation and apoptosis. Luciferase experiments verified the targeting relationship between miR-126 and PIK3R2 gene. The co-transfection of anti-miR-126 and PIK3R2 siRNA to RASFs were used to identify whether PIK3R2 was directly involved in proliferation and apoptosis of miR-126-induced RASFs. Real-time polymerase chain reaction (PCR) was used to detect miR-126 and PIK3R2 expressions. MTT assay was used to detect cell proliferation. Flow cytometry was used to detect cell apoptosis and cell cycle. Western blotting was used to detect PIK3R2, PI3K, AKT and p-AKT proteins. After Lv-miR-126 infected RASFs, the relative expression of miR-126 was significantly enhanced. MiR-126 promoted RASF proliferation and inhibited apoptosis. Levels of PIK3R2 decreased while total PI3K and p-AKT levels increased in RASFs overexpressing miR-126. Co-transfection of anti-miR-126 and PIK3R2 siRNA also increased PI3K and p-AKT levels as well as RASF proliferation and reduced apoptosis, as compared to anti-miR-126 treatment alone. Finally, luciferase reporter assays showed that miR-126 targeted PIK3R2. Our data indicate that miR-126 overexpression in RASFs inhibits PIK3R2 expression and promotes proliferation while inhibiting apoptosis. This suggests inhibiting miR-126 may yield therapeutic benefits in the treatment of RA. PMID:27729613

  5. Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer.

    PubMed

    Domingo, Enric; Church, David N; Sieber, Oliver; Ramamoorthy, Rajarajan; Yanagisawa, Yoko; Johnstone, Elaine; Davidson, Brian; Kerr, David J; Tomlinson, Ian P M; Midgley, Rachel

    2013-12-01

    Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer (CRC) and are associated with reduced disease recurrence and improved outcome after primary treatment. However, toxicities of NSAIDs have limited their use as antineoplastic therapy. Recent data have suggested that the benefit of aspirin after CRC diagnosis is limited to patients with PIK3CA-mutant cancers. We sought to determine the predictive utility of PIK3CA mutation for benefit from both cyclooxygenase-2 inhibition and aspirin. We performed molecular analysis of tumors from 896 participants in the Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime (VICTOR) trial, a large randomized trial comparing rofecoxib with placebo after primary CRC resection. We compared relapse-free survival and overall survival between rofecoxib therapy and placebo and between the use and nonuse of low-dose aspirin, according to tumor PIK3CA mutation status. We found no evidence of a greater benefit from rofecoxib treatment compared with placebo in patients whose tumors had PIK3CA mutations (multivariate adjusted hazard ratio [HR], 1.2; 95% CI, 0.53 to 2.72; P = .66; (P)INTERACTION = .47) compared with patients with PIK3CA wild-type cancers (HR, 0.87; 95% CI, 0.64 to 1.16; P = .34). In contrast, regular aspirin use after CRC diagnosis was associated with a reduced rate of CRC recurrence in patients with PIK3CA-mutant cancers (HR, 0.11; 95% CI, 0.001 to 0.832; P = .027; (P)INTERACTION = .024) but not in patients lacking tumor PIK3CA mutation (HR, 0.92; 95% CI, 0.60 to 1.42; P = .71). Although tumor PIK3CA mutation does not predict benefit from rofecoxib treatment, it merits further evaluation as a predictive biomarker for aspirin therapy. Our findings are concordant with recent data and support the prospective investigation of adjuvant aspirin in PIK3CA-mutant CRC.

  6. More antitumor efficacy of the PI3K inhibitor GDC-0941 in breast cancer with PIK3CA mutation or HER2 amplification status in vitro.

    PubMed

    Zheng, Jie; Wang, Huan; Yao, Jia; Zou, Xianjin

    2014-01-01

    PIK3CA is probably the most commonly mutated kinase in several malignant tumors. Activation of class I phosphatidylinositol 3' kinase (PI3K) regulates tumor proliferation, survival, etc. This study sought to identify whether the pan-inhibitor has more antitumor efficacy in breast cancer cells with PIK3CA Mutation or HER2 amplification than basal-like cancer cells. The proliferation of breast cancer cells was measured by MTT assay in the presence of GDC-0941. Afterwards, we determined the visible changes in signaling in the PI3K/AKT/mTOR pathway. Finally, we examined GDC-0941 effects on cell cycle, apoptosis and motility. GDC-0941 exhibited excellent inhibition on three cell lines with PIK3CA mutation or HER2 amplification. In addition, GDC-0941 resulted in decreased Akt activity. GDC-0941 downregulated the key components of the cell cycle machinery, such as cyclin D1, upregulated the apoptotic markers and inhibited cell motility on three cell lines with PIK3CA Mutation or HER2 amplification. Antitumor activity of GDC-0941 treatment amongst tumor cell lines with PIK3CA mutation and HER2 amplification may have clinical utility in patients with these oncogenic alterations.

  7. Sensitive genotyping of somatic mutations in the EGFR, KRAS, PIK3CA, BRAF genes from NSCLC patients using hydrogel biochips.

    PubMed

    Emelyanova, Marina; Arkhipova, Ksenia; Mazurenko, Natalia; Chudinov, Alexander; Demidova, Irina; Zborovskaya, Irina; Lyubchenko, Lyudmila; Zasedatelev, Alexander; Nasedkina, Tatiana

    2015-04-01

    Targeted inhibitors of the epidermal growth factor receptor (EGFR) are used for the treatment of non-small cell lung cancer (NSCLC). Somatic mutations in the EGFR gene and key effectors of the EGFR-signaling pathway (KRAS, BRAF, PIK3CA) are associated with sensitivity to these drugs. We developed a highly sensitive LUNG CANCER (LC)-biochip approach for the detection of the most common EGFR, KRAS, PIK3CA, and BRAF gene mutations. The locked nucleic acid clamp PCR technique was used to increase the sensitivity of the assay, then allele-specific hybridization of a fluorescently labeled target on a biochip was performed. To prove the feasibility of the approach, clinical samples from 112 patients with NSCLC were analyzed. A total of 14 EGFR (12.5%) mutations, 21 (18.8%) KRAS mutations, 12 (10.7%) PIK3CA mutations, and 1 BRAF mutation (0.9%) were found. We compared the results with those from direct sequencing. We detected 50 different mutations by the LC-biochip assay and only 33 of them were found by direct sequencing. To demonstrate that the LC-biochip assay did not give false-positive results, the 17 specimens with discordant results were subjected to locked nucleic acid clamp PCR followed by sequencing. The results of this analysis were identical to the results obtained by the LC-biochip assay indicating that the biochip-based assay was both accurate and reliable. This approach was able to detect approximately 0.5% of mutated alleles in wild-type DNA background. The biochip-based assay is a reliable and inexpensive method for the identification of NSCLC patients, who may respond to a specific targeted therapy.

  8. Role of E542 and E545 missense mutations of PIK3CA in breast cancer: a comparative computational approach.

    PubMed

    Thirumal Kumar, D; George Priya Doss, C

    2017-09-01

    Recent statistics describe breast cancer as the leading cause of death among women across the world with varied causes and reasons. Lifestyle, diet, genetic and environmental factors introduce their generous contributions towards breast cancer, among which genetic factors have lately become one of the most important aspects in understanding the mechanism. Although various genes have already been reported in causing breast cancer, PIK3CA stands second on the list. Mutations observed in this gene have the ability to trigger the different activities of the cell, thereby bypassing the regular cellular cycle. Among the mutations in PIK3CA, three hotspot mutations were commonly reported, one in the catalytic domain (position HIS1047) and other two in the helical domain (position GLU542 and GLU545). In the helical domain of PIK3CA, the lysine substitution at 542-545 positions was significantly studied in causing breast cancer. To compare the deleterious effect of these mutations, in silico prediction tools along with molecular dynamics simulations and molecular docking approach was initiated to analyse the change in binding landscape upon mutation. In this comparative analysis, we report that the mere existence of mutant E545K can trigger the function of the protein but may not be as harmful as H1047R. Among the two mutations E542K and E545K, the latter shows the most deleterious effect that correlates with the previous reported experimental studies. We assume the results observed in this combinatorial computational study might further pave a better way for providing better treatment procedures.

  9. Discovery of Colorectal Cancer PIK3CA Mutation as Potential Predictive Biomarker: Power and Promise of Molecular Pathological Epidemiology

    PubMed Central

    Ogino, Shuji; Lochhead, Paul; Giovannucci, Edward; Meyerhardt, Jeffrey A; Fuchs, Charles S; Chan, Andrew T

    2013-01-01

    Regular use of aspirin reduces incidence and mortality of various cancers, including colorectal cancer. Anti-cancer effect of aspirin represents one of the “Provocative Questions” in cancer research. Experimental and clinical studies support a carcinogenic role for PTGS2 (cyclooxygenase-2), which is an important enzymatic mediator of inflammation, and a target of aspirin. Recent “Molecular Pathological Epidemiology” (MPE) research has shown that aspirin use is associated with better prognosis and clinical outcome in PIK3CA-mutated colorectal carcinoma, suggesting somatic PIK3CA mutation as a molecular biomarker that predicts response to aspirin therapy. The PI3K enzyme plays a pivotal role in the PI3K-AKT signaling pathway. Activating PIK3CA oncogene mutations are observed in various malignancies including breast cancer, ovarian cancer, brain tumor, hepatocellular carcinoma, lung cancer and colon cancer. The prevalence of PIK3CA mutations increases continuously from rectal to cecal cancers, supporting the “colorectal continuum” paradigm, and an important interplay of gut microbiota and host immune/inflammatory reaction. MPE represents an interdisciplinary integrative science, conceptually defined as “epidemiology of molecular heterogeneity of disease”. Because exposome and interactome vary from person to person and influence disease process, each disease process is unique (the unique disease principle). Hence, MPE concept and paradigm can extend to non-neoplastic diseases including diabetes mellitus, cardiovascular diseases, metabolic diseases, etc. MPE research opportunities are currently limited by paucity of tumor molecular data in existing large-scale population-based studies. However, genomic, epigenomic, and molecular pathology testing (e.g., analyses for microsatellite instability, MLH1 promoter CpG island methylation, and KRAS and BRAF mutations in colorectal tumors) is becoming routine clinical practice. In order for integrative molecular

  10. Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker: power and promise of molecular pathological epidemiology.

    PubMed

    Ogino, S; Lochhead, P; Giovannucci, E; Meyerhardt, J A; Fuchs, C S; Chan, A T

    2014-06-05

    Regular use of aspirin reduces incidence and mortality of various cancers, including colorectal cancer. Anticancer effect of aspirin represents one of the 'Provocative Questions' in cancer research. Experimental and clinical studies support a carcinogenic role for PTGS2 (cyclooxygenase-2), which is an important enzymatic mediator of inflammation, and a target of aspirin. Recent 'molecular pathological epidemiology' (MPE) research has shown that aspirin use is associated with better prognosis and clinical outcome in PIK3CA-mutated colorectal carcinoma, suggesting somatic PIK3CA mutation as a molecular biomarker that predicts response to aspirin therapy. The PI3K (phosphatidylinositol-4,5-bisphosphonate 3-kinase) enzyme has a pivotal role in the PI3K-AKT signaling pathway. Activating PIK3CA oncogene mutations are observed in various malignancies including breast cancer, ovarian cancer, brain tumor, hepatocellular carcinoma, lung cancer and colon cancer. The prevalence of PIK3CA mutations increases continuously from rectal to cecal cancers, supporting the 'colorectal continuum' paradigm, and an important interplay of gut microbiota and host immune/inflammatory reaction. MPE represents an interdisciplinary integrative science, conceptually defined as 'epidemiology of molecular heterogeneity of disease'. As exposome and interactome vary from person to person and influence disease process, each disease process is unique (the unique disease principle). Therefore, MPE concept and paradigm can extend to non-neoplastic diseases including diabetes mellitus, cardiovascular diseases, metabolic diseases, and so on. MPE research opportunities are currently limited by paucity of tumor molecular data in the existing large-scale population-based studies. However, genomic, epigenomic and molecular pathology testings (for example, analyses for microsatellite instability, MLH1 promoter CpG island methylation, and KRAS and BRAF mutations in colorectal tumors) are becoming routine

  11. Asymmetric real-time PCR and multiplex melting curve analysis with TaqMan probes for detecting PIK3CA mutations.

    PubMed

    Botezatu, Irina V; Nechaeva, Irina O; Stroganova, Аnna М; Senderovich, Anastasia I; Kondratova, Valentina N; Shelepov, Valery P; Lichtenstein, Anatoly V

    2015-12-01

    The data in this article are related to the research article entitled "Optimization of melting analysis with TaqMan probes for detection of KRAS, NRAS, and BRAF mutations" Botezatu et al. [1]. Somatic mutations in the PIK3CA gene ("hot spots" in exons 9 and 20) are found in many human cancers, and their presence can determine prognosis and a treatment strategy. An effective method of mutation scanning PIK3CA in clinical laboratories is DNA Melting Analysis (DMA) (Vorkas et al., 2010; Simi et al., 2008) [2], [3]. It was demonstrated recently that the TaqMan probes which have been long used in Real Time PCR may also be utilized in DMA (Huang et al., 2011) [4]. After optimization of this method Botezatu et al. [1], it was used for multiplex scanning PIK3CA hotspot mutations in formalin-fixed paraffin-embedded (FFPE) samples from patients with colorectal and lung cancer.

  12. Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer

    PubMed Central

    Roper, Jatin; Sinnamon, Mark J.; Coffee, Erin M.; Belmont, Peter; Keung, Lily; Georgeon-Richard, Larissa; Wang, Wei Vivian; Faber, Anthony C.; Yun, Jihye; Yilmaz, Omer H.; Bronson, Roderick T.; Martin, Eric S.; Tsichlis, Philip N.; Hung, Kenneth E.

    2014-01-01

    PI3K inhibition in combination with other agents has not been studied in the context of PIK3CA wild-type, KRAS mutant cancer. In a screen of phospho-kinases, PI3K inhibition of KRAS mutant colorectal cancer cells activated the MAPK pathway. Combination PI3K/MEK inhibition with NVP-BKM120 and PD-0325901 induced tumor regression in a mouse model of PIK3CA wild-type, KRAS mutant colorectal cancer, which was mediated by inhibition of mTORC1, inhibition of MCL-1, and activation of BIM. These findings implicate mitochondrial-dependent apoptotic mechanisms as determinants for the efficacy of PI3K/MEK inhibition in the treatment of PIK3CA wild-type, KRAS mutant cancer. PMID:24576621

  13. Diagnosis of Charcot-Marie-Tooth Disease

    PubMed Central

    Banchs, Isabel; Casasnovas, Carlos; Albertí, Antonia; De Jorge, Laura; Povedano, Mónica; Montero, Jordi; Martínez-Matos, Juan Antonio; Volpini, Victor

    2009-01-01

    Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN) is a genetically heterogeneous group of conditions that affect the peripheral nervous system. The disease is characterized by degeneration or abnormal development of peripheral nerves and exhibits a range of patterns of genetic transmission. In the majority of cases, CMT first appears in infancy, and its manifestations include clumsiness of gait, predominantly distal muscular atrophy of the limbs, and deformity of the feet in the form of foot drop. It can be classified according to the pattern of transmission (autosomal dominant, autosomal recessive, or X linked), according to electrophysiological findings (demyelinating or axonal), or according to the causative mutant gene. The classification of CMT is complex and undergoes constant revision as new genes and mutations are discovered. In this paper, we review the most efficient diagnostic algorithms for the molecular diagnosis of CMT, which are based on clinical and electrophysiological data. PMID:19826499

  14. The life and legacy of Marie Curie.

    PubMed Central

    Rockwell, Sara

    2003-01-01

    Marie Curie was a remarkable woman whose discoveries broke new ground in physics and chemistry and also opened the door for advances in engineering, biology, and medicine. She broke new ground for women in science: she was, for example, the first woman to receive a doctor of science degree in France, the first woman to win Nobel Prize, the first woman to lecture at the Sorbonne, the first person to win two Nobel Prizes, and the first Nobel Laureate whose child also won a Nobel Prize. Her life offers insights into the changing role of women in science and academia over the past century. It also offers examples of many ways in which scientists can, and should, work to improve the educational programs and career opportunities available to those who follow in their footsteps. Images Figure 1 Figure 2 Figure 3 PMID:15482656

  15. The life and legacy of Marie Curie.

    PubMed

    Rockwell, Sara

    2003-01-01

    Marie Curie was a remarkable woman whose discoveries broke new ground in physics and chemistry and also opened the door for advances in engineering, biology, and medicine. She broke new ground for women in science: she was, for example, the first woman to receive a doctor of science degree in France, the first woman to win Nobel Prize, the first woman to lecture at the Sorbonne, the first person to win two Nobel Prizes, and the first Nobel Laureate whose child also won a Nobel Prize. Her life offers insights into the changing role of women in science and academia over the past century. It also offers examples of many ways in which scientists can, and should, work to improve the educational programs and career opportunities available to those who follow in their footsteps.

  16. Update on Charcot-Marie-Tooth Disease

    PubMed Central

    Patzkó, Ágnes; Shy, Michael E.

    2011-01-01

    Charcot-Marie-Tooth disease (CMT) disease encompasses a genetically heterogeneous group of inherited neuropathies, also known as hereditary motor and sensory neuropathies. CMT results from mutations in more than 40 genes expressed in Schwann cells and neurons causing overlapping phenotypes. The classic CMT phenotype reflects length-dependent axonal degeneration characterized by distal sensory loss and weakness, deep tendon reflex abnormalities, and skeletal deformities. Recent articles have provided insight into the molecular pathogenesis of CMT, which, for the first time, suggest potential therapeutic targets. Although there are currently no effective medications for CMT, multiple clinical trials are ongoing or being planned. This review will focus on the underlying pathomechanisms and diagnostic approaches of CMT and discuss the emerging therapeutic strategies. PMID:21080241

  17. Mary Anning: the fossilist as exegete.

    PubMed

    Goodhue, Thomas W

    2005-03-01

    The fossil hunter Mary Anning began collecting her 'curiosities' at a time when the age and nature of these relics from the past were little understood. Her spectacular discoveries of prehistoric marine reptiles, fossilized fish and a pterosaur touched off a geology-mania around the world. Two documents that have escaped previous analysis cast light on the religious journey of this remarkable woman. An eight-page manuscript at the Natural History Museum in London indicates a fascination with Benjamin West's painting 'Christ Rejected' and sophistication in Biblical interpretation; and a commonplace book at the Dorset County Museum in Dorchester tracks the shift in her Christian denomination from dissent to the Established Church, providing further indication of her spiritual depth - a piety that furthered, rather than hindered, her scientific progress.

  18. Copy number gain of PIK3CA and MET is associated with poor prognosis in head and neck squamous cell carcinoma.

    PubMed

    Brauswetter, Diána; Dános, Kornél; Gurbi, Bianka; Félegyházi, Éva Fruzsina; Birtalan, Ede; Meggyesházi, Nóra; Krenács, Tibor; Tamás, László; Peták, István

    2016-05-01

    The incidence of head and neck squamous cell carcinomas is still growing, and the long-term prognosis of advanced disease remains poor. Only a fraction of head and neck cancers are sensitive to the EGFR-inhibitor cetuximab, which is the only registered targeted therapy available today. In several cancers, gene copy number alterations of MET and PIK3CA have been found to be prognostic and predictive for therapy response. The aim of this study was to systematically analyze in head and neck cancers the pathological characteristics and prognostic significance of copy number changes of MET and PIK3CA genes. MET and PIK3CA copy numbers were analyzed by fluorescence in situ hybridization in tumor samples of 152 patients. Expression of EGFR, p16, and Ki67 was studied by immunohistochemistry. High polysomy of PIK3CA (chromosome 3) was found in 20 % of cases and amplification in 4.5 %. Regarding MET, 35 % of cases showed low or high polysomy of the gene (chromosome 7), while no intra-chromosomal amplification of MET was detected. PIK3CA copy number gain (high polysomy or amplification) was significantly associated with shorter disease-specific survival, larger tumor volume, and lower p16 expression. MET copy number gain (low or high polysomy) in tumors was significantly associated with shorter disease-specific survival and lower level of EGFR. PIK3CA and MET may play an important role in oncogenesis of certain specific subtypes of head and neck cancer. There is an urgent need for the development of novel targeted therapies against these tumors associated with poor prognosis.

  19. PIK3CA, BRAF, and PTEN status and benefit from cetuximab in the treatment of advanced colorectal cancer--results from NCIC CTG/AGITG CO.17.

    PubMed

    Karapetis, Christos S; Jonker, Derek; Daneshmand, Manijeh; Hanson, Jennifer E; O'Callaghan, Christopher J; Marginean, Celia; Zalcberg, John R; Simes, John; Moore, Malcolm J; Tebbutt, Niall C; Price, Timothy J; Shapiro, Jeremy D; Pavlakis, Nick; Gibbs, Peter; Van Hazel, Guy A; Lee, Ursula; Haq, Rashida; Virk, Shakeel; Tu, Dongsheng; Lorimer, Ian A J

    2014-02-01

    Cetuximab improves survival in patients with K-ras wild-type advanced colorectal cancer. We examined the predictive and prognostic significance of additional biomarkers in this setting, in particular BRAF, PIK3CA, and PTEN. Available colorectal tumor samples were analyzed from the CO.17 study. BRAF mutations were identified in tumor-derived DNA by direct sequencing and PIK3CA mutations were identified using a high-resolution melting screen with confirmation by sequencing. PTEN expression by immunohistochemistry (IHC) was performed on tissue microarrays. For each biomarker, prognostic and predictive effects were examined using a Cox model with tests for treatment-biomarker interaction. A total of 572 patients with pretreated colorectal cancer were randomly assigned to receive cetuximab or best supportive care (BSC). Of 401 patients assessed for BRAF status, 13 (3.2%) had mutations. Of 407 patients assessed for PIK3CA status, 61 (15%) had mutations. Of 205 patients assessed for PTEN, 148 (72%) were negative for IHC expression. None of BRAF, PIK3CA, or PTEN was prognostic for overall or progression-free survival in the BSC arm. None was predictive of benefit from cetuximab, either in the whole study population or the K-ras wild-type subset. In the K-ras wild-type subgroup, the overall survival adjusted HR according to BRAF mutation status was 1.39 (interaction P = 0.69), PIK3CA mutation status HR = 0.79 (interaction P = 0.63), and PTEN expression HR = 0.75 (interaction P = 0.61). In chemotherapy-refractory colorectal cancer, neither PIK3CA mutation status nor PTEN expression were prognostic, nor were they predictive of benefit from cetuximab. Evaluation of predictive significance of BRAF mutations requires a larger sample size. ©2013 AACR.

  20. Non-Invasive Imaging of Phosphoinositide-3-Kinase-Catalytic-Subunit-Alpha (PIK3CA) Promoter Modulation in Small Animal Models

    PubMed Central

    Gaikwad, Snehal M.; Gunjal, Lata; Junutula, Anitha R.; Astanehe, Arezoo; Gambhir, Sanjiv Sam; Ray, Pritha

    2013-01-01

    Activation of the PI3K/Akt pathway, a critical step for survival in cancer cells is often associated with decreased sensitivity to several chemotherapeutic drugs. PIK3CA gene amplification is observed in 16–24% of epithelial ovarian cancer (EOC) patients in conjunction with p53 mutations. A 900 bp long PIK3CA promoter is shown to be negatively regulated by p53 in ovarian surface epithelial cells but the consequence of chemotherapeutic drug treatments on this promoter in ovarian cancer cells is largely unknown. We aim to study the modulation of this promoter by cisplatin using an improved fusion reporter in ovarian cancer cells and tumor xenografts by non-invasive imaging approach. A PIK3CA sensor was developed using a bi-fusion reporter from a newly constructed library of bi- and tri-fusion vectors comprising of two mutant far red fluorescent proteins (mcherry/mch and tdTomato/tdt), a mutant firefly luciferase (fluc2), and a PET reporter protein (ttk). In vivo imaging of mice implanted with 293T cells transiently expressing these bi- and tri-fusion reporters along with respective controls revealed comparable activity of each reporter in the fusion background and fluc2-tdt as the most sensitive one. Repression of the PIK3CA sensor by drugs was inversely proportional to cellular p53 level in a germline (PA1) and in an EOC (A2780) cell line but not in a p53 deficient EOC (SKOV3) cell line. Bioluminescence imaging of tumor xenografts stably expressing the PIK3CA sensor in PA1 and A2780 cells exhibited attenuating activity without any change in SKOV3 tumors expressing the PIK3CA sensor after cisplatin treatment. Sequential mutation at p53 binding sites showed gradual increase in promoter activity and decreased effects of the drugs. These newly developed PIK3CA-fluc2-tdt and the mutant reporter sensors thus would be extremely useful for screening new drugs and for functional assessment of PIK3CA expression from intact cells to living subjects. PMID:23393606

  1. Effects of TP53 and PIK3CA mutations in early breast cancer: a matter of co-mutation and tumor-infiltrating lymphocytes.

    PubMed

    Kotoula, Vassiliki; Karavasilis, Vasilios; Zagouri, Flora; Kouvatseas, George; Giannoulatou, Eleni; Gogas, Helen; Lakis, Sotiris; Pentheroudakis, George; Bobos, Mattheos; Papadopoulou, Kyriaki; Tsolaki, Eleftheria; Pectasides, Dimitrios; Lazaridis, Georgios; Koutras, Angelos; Aravantinos, Gerasimos; Christodoulou, Christos; Papakostas, Pavlos; Markopoulos, Christos; Zografos, George; Papandreou, Christos; Fountzilas, George

    2016-07-01

    The purpose of this study is to investigate whether the outcome of breast cancer (BC) patients treated with adjuvant chemotherapy is affected by co-mutated TP53 and PIK3CA according to stromal tumor-infiltrating lymphocytes (TILs). Paraffin tumors of all clinical subtypes from 1661 patients with operable breast cancer who were treated within 4 adjuvant trials with anthracycline-taxanes chemotherapy were informative for TP53 and PIK3CA mutation status (semiconductor sequencing genotyping) and for stromal TILs density. Disease-free survival (DFS) was examined. TP53 mutations were associated with higher (p < 0.001) and PIK3CA with lower (p = 0.004) TILs in an ER /PgR-specific manner (p < 0.001). Mutations did not affect the favorable DFS of patients with lymphocyte-predominant (LP) BC. Within non-LPBC, PIK3CA-only mutations conferred best, while TP53-PIK3CA co-mutations (6 % of all tumors) conferred worst DFS (HR 0.59; 95 % CI 0.44-0.79; p = 0.001 for PIK3CA-only). TP53-only mutations were unfavorable in patients with lower TILs, while patients with lower TILs performed worse if their tumors carried TP53-only mutations (interaction p = 0.046). Multivariate analysis revealed favorable PIK3CA-only mutations in non-LPBC (HR 0.64; 95 % CI 0.47-0.88; p = 0.007), and unfavorable TP53 mutations in ER/PgRpos/HER2neg (HR 1.55; 95 % CI 1.07-2.24; p = 0.021). Mutations did not interact with TILs in non-LP triple-negative and HER2-positive patients. TP53 and PIK3CA mutations appear to have diverse effects on the outcome of early BC patients, according to whether these genes are co-mutated or not, and for TP53 according to TILs density and ER/PgR-status. These findings need to be considered when evaluating the effect of these two most frequently mutated genes in the context of large clinical trials.

  2. Exploring the Universe with John Milton and Mary Shelley.

    ERIC Educational Resources Information Center

    Poston, David

    1989-01-01

    Presents an approach to teaching John Milton's "Paradise Lost" in conjunction with Mary Shelley's "Frankenstein." Notes that a study of these works stimulates vigorous discussions on theological and moral issues, human nature, and the cultural past and future. (MM)

  3. 4. VIEW OF SILVER BRIDGE (ST. MARY'S BRIDGE), CARRYING COUNTY ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    4. VIEW OF SILVER BRIDGE (ST. MARY'S BRIDGE), CARRYING COUNTY ROAD OVER SOURIS RIVER NEAR SOUTH END OF REFUGE, LOOKING NORTHEAST - Upper Souris National Wildlife Refuge Dams, Souris River Basin, Foxholm, Surrey (England), ND

  4. Deployment of Autonomous GPS Stations in Marie Byrd Land, Antartica

    NASA Technical Reports Server (NTRS)

    Donnellan, A.; Luyendyk, B.; Smith, M.; Dace, G.

    1999-01-01

    During the 1998-1999 Antarctic field season, we installed three autonomous GPS stations in Marie Byrd Land, West Antarctica to measure glacio-isostatic rebound and rates of spreading across the West Antartic Rift System.

  5. Marie Curie's Doctoral Thesis: Prelude to a Nobel Prize.

    ERIC Educational Resources Information Center

    Wolke, Robert L.

    1988-01-01

    Traces the life and research techniques of Marie Curie's doctoral dissertation leading to the discovery and purification of radium from ore. Reexamines the discoveries of other scientists that helped lead to this separation. (ML)

  6. Exploring the Universe with John Milton and Mary Shelley.

    ERIC Educational Resources Information Center

    Poston, David

    1989-01-01

    Presents an approach to teaching John Milton's "Paradise Lost" in conjunction with Mary Shelley's "Frankenstein." Notes that a study of these works stimulates vigorous discussions on theological and moral issues, human nature, and the cultural past and future. (MM)

  7. 10. Historic American Buildings Survey W. N. Manning, Photographer, Mary ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    10. Historic American Buildings Survey W. N. Manning, Photographer, Mary 17, 1935 FIREPLACE IN LIVING ROOM, N.E. ROOM - Lewis Llewellyn Cato House, 823 West Barbour Street, Eufaula, Barbour County, AL

  8. Students Speak With Vacuum Chamber Project Manager Mary Cerimele

    NASA Image and Video Library

    From the International Space Station Flight Control Room at NASA's Johnson Space Center, Vacuum Chamber A Project Manager Mary Cerimele participates in a Digital Learning Network (DLN) event with s...

  9. Mary Carpenter: 19th Century English Correctional Education Hero.

    ERIC Educational Resources Information Center

    Gehring, Thom; Bowers, Fredalene B.

    2003-01-01

    Describes Mary Carpenter's (1807-1877) work in prison reform and correctional education. Provides biographical information and selections from her writings. (Contains 11 references and a chronology of her work.) (JOW)

  10. Mary Carpenter: 19th Century English Correctional Education Hero.

    ERIC Educational Resources Information Center

    Gehring, Thom; Bowers, Fredalene B.

    2003-01-01

    Describes Mary Carpenter's (1807-1877) work in prison reform and correctional education. Provides biographical information and selections from her writings. (Contains 11 references and a chronology of her work.) (JOW)

  11. 3. Photocopy of photograph (location of original unknown) Mary Mather, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    3. Photocopy of photograph (location of original unknown) Mary Mather, photographer, ca. 1920 PARTIAL EAST ELEVATION, OBSCURED BY FOLIAGE - Bagatelle Plantation, East River Road (moved to Iberville Parish), Donaldsonville, Ascension Parish, LA

  12. 2. Photocopy of photograph (location of original unknown) Mary Mather, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    2. Photocopy of photograph (location of original unknown) Mary Mather, photographer, ca. 1920 GENERAL VIEW OF WEST (LEFT) AND SOUTH (RIGHT) FACADES, TAKEN FROM LEVEE - Bagatelle Plantation, East River Road (moved to Iberville Parish), Donaldsonville, Ascension Parish, LA

  13. Marie Curie's Doctoral Thesis: Prelude to a Nobel Prize.

    ERIC Educational Resources Information Center

    Wolke, Robert L.

    1988-01-01

    Traces the life and research techniques of Marie Curie's doctoral dissertation leading to the discovery and purification of radium from ore. Reexamines the discoveries of other scientists that helped lead to this separation. (ML)

  14. Martian Radiation Environment: Model Calculations and Recent Measurements with "MARIE"

    NASA Technical Reports Server (NTRS)

    Saganti, P. B.; Cucinotta, F. A.; zeitlin, C. J.; Cleghorn, T. F.

    2004-01-01

    The Galactic Cosmic Ray spectra in Mars orbit were generated with the recently expanded HZETRN (High Z and Energy Transport) and QMSFRG (Quantum Multiple-Scattering theory of nuclear Fragmentation) model calculations. These model calculations are compared with the first eighteen months of measured data from the MARIE (Martian Radiation Environment Experiment) instrument onboard the 2001 Mars Odyssey spacecraft that is currently in Martian orbit. The dose rates observed by the MARIE instrument are within 10% of the model calculated predictions. Model calculations are compared with the MARIE measurements of dose, dose-equivalent values, along with the available particle flux distribution. Model calculated particle flux includes GCR elemental composition of atomic number, Z = 1-28 and mass number, A = 1-58. Particle flux calculations specific for the current MARIE mapping period are reviewed and presented.

  15. MACKINAW UNDERWAY ON MARCH 21, 1994, FROM SAULTE SAINTE MARIE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    MACKINAW UNDERWAY ON MARCH 21, 1994, FROM SAULTE SAINTE MARIE TO WHITEFISH BAY AND BACK; LOOKING AFT FROM BRIDGE WING, FIRST DAY OF BREAK UP OF SHIPPING CHANNEL - U.S. Coast Guard Icebreaker Mackinaw, Cheboygan, Cheboygan County, MI

  16. Mary Tyler Moore Helps Launch NIH MedlinePlus Magazine

    MedlinePlus

    ... Issues Mary Tyler Moore Helps Launch NIH MedlinePlus Magazine Past Issues / Winter 2007 Table of Contents For ... Javascript on. Among those attending the NIH MedlinePlus magazine launch on Capitol Hill were (l-r) NIH ...

  17. Oral sildenafil as a treatment option for lymphatic malformations in PIK3CA-related tissue overgrowth syndromes.

    PubMed

    Horbach, Sophie E R; Jolink, Folkert; van der Horst, Chantal M A M

    2016-11-01

    Patients with extensive lymphatic malformations associated with tissue overgrowth syndromes (such as Klippel-Trenaunay syndrome and CLOVES) often pose a therapeutic challenge for physicians. In recent years, it has been suggested that oral sildenafil therapy might be used to treat congenital lymphatic malformations. However, this possible new therapy has not yet been used in patients with lymphatic malformations associated with tissue overgrowth syndromes. A 30-year-old man with extensive capillary-lymphatic malformations of the right leg and thorax, and a tissue overgrowth syndrome caused by a somatic mutation in the PIK3CA gene, was treated with oral sildenafil due to symptoms of pain, dyspnea, and functional impairment. Several weeks after the start of the treatment, the patient reported softening of the lymphatic malformation and a significant improvement of his symptoms and physical condition. So far, sildenafil is still considered a last resort in the treatment of complex treatment-resistant lymphatic malformations. With this case report, we demonstrate that sildenafil could also be an alternative treatment option for lymphatic malformations in patients with syndromes belonging to the PIK3CA-related overgrowth spectrum. © 2016 Wiley Periodicals, Inc.

  18. Exome sequencing identifies a novel mutation in PIK3R1 as the cause of SHORT syndrome

    PubMed Central

    2014-01-01

    Background SHORT syndrome is a rare autosomal dominant condition whose name is the acronym of short stature, hyperextensibility of joints, ocular depression, Rieger anomaly and teething delay (MIM 269880). Additionally, the patients usually present a low birth weight and height, lipodystrophy, delayed bone age, hernias, low body mass index and a progeroid appearance. Case presentation In this study, we used whole-exome sequencing approaches in two patients with clinical features of SHORT syndrome. We report the finding of a novel mutation in PIK3R1 (c.1929_1933delTGGCA; p.Asp643Aspfs*8), as well as a recurrent mutation c.1945C > T (p.Arg649Trp) in this gene. Conclusions We found a novel frameshift mutation in PIK3R1 (c.1929_1933delTGGCA; p.Asp643Aspfs*8) which consists of a deletion right before the site of substrate recognition. As a consequence, the protein lacks the position that interacts with the phosphotyrosine residue of the substrate, resulting in the development of SHORT syndrome. PMID:24886349

  19. Characterization of Atg38 and NRBF2, a fifth subunit of the autophagic Vps34/PIK3C3 complex

    PubMed Central

    Ohashi, Yohei; Soler, Nicolas; García Ortegón, Miguel; Zhang, Lufei; Kirsten, Marie L.; Perisic, Olga; Masson, Glenn R.; Burke, John E.; Jakobi, Arjen J.; Apostolakis, Apostolos A.; Johnson, Christopher M.; Ohashi, Maki; Ktistakis, Nicholas T.; Sachse, Carsten; Williams, Roger L.

    2016-01-01

    ABSTRACT The phosphatidylinositol 3-kinase Vps34 is part of several protein complexes. The structural organization of heterotetrameric complexes is starting to emerge, but little is known about organization of additional accessory subunits that interact with these assemblies. Combining hydrogen-deuterium exchange mass spectrometry (HDX-MS), X-ray crystallography and electron microscopy (EM), we have characterized Atg38 and its human ortholog NRBF2, accessory components of complex I consisting of Vps15-Vps34-Vps30/Atg6-Atg14 (yeast) and PIK3R4/VPS15-PIK3C3/VPS34-BECN1/Beclin 1-ATG14 (human). HDX-MS shows that Atg38 binds the Vps30-Atg14 subcomplex of complex I, using mainly its N-terminal MIT domain and bridges the coiled-coil I regions of Atg14 and Vps30 in the base of complex I. The Atg38 C-terminal domain is important for localization to the phagophore assembly site (PAS) and homodimerization. Our 2.2 Å resolution crystal structure of the Atg38 C-terminal homodimerization domain shows 2 segments of α-helices assembling into a mushroom-like asymmetric homodimer with a 4-helix cap and a parallel coiled-coil stalk. One Atg38 homodimer engages a single complex I. This is in sharp contrast to human NRBF2, which also forms a homodimer, but this homodimer can bridge 2 complex I assemblies. PMID:27630019

  20. Molecular Identification of a Dietzia maris Hip Prosthesis Infection Isolate

    PubMed Central

    Pidoux, O.; Argenson, J.-N.; Jacomo, V.; Drancourt, M.

    2001-01-01

    Dietzia maris, an environmental actinomycete, has been implicated only once in human disease. We herein report the first D. maris isolate from a bone biopsy specimen in a patient hospitalized for a total hip prosthesis replacement. Cell wall fatty acid analysis and 16S ribosomal DNA gene sequencing were utilized to achieve its definite identification. This case report illustrates the usefulness of such methods for the accurate identification of actinomycetes. PMID:11427581

  1. Dietary restriction-resistant human tumors harboring the PIK3CA-activating mutation H1047R are sensitive to metformin

    PubMed Central

    Cufí, Sílvia; Corominas-Faja, Bruna; Lopez-Bonet, Eugeni; Bonavia, Rosa; Pernas, Sonia; López, Isabel álvarez; Dorca, Joan; Martínez, Susana; López, Norberto Batista; Fernández, Severina Domínguez; Cuyàs, Elisabet; Visa, Joana; Rodríguez-Gallego, Esther; Quirantes-Piné, Rosa; Segura-Carretero, Antonio; Joven, Jorge; Martin-Castillo, Begoña; Menendez, Javier A.

    2013-01-01

    Cancer cells expressing constitutively active phosphatidylinositol-3 kinase (PI3K) are proliferative regardless of the absence of insulin, and they form dietary restriction (DR)-resistant tumors in vivo. Because the binding of insulin to its receptors activates the PI3K/AKT/mammalian target of rapamycin (mTOR) signaling cascade, activating mutations in the PIK3CA oncogene may determine tumor response to DR-like pharmacological strategies targeting the insulin and mTOR pathways. The anti-diabetic drug metformin is a stereotypical DR mimetic that exerts its anti-cancer activity through a dual mechanism involving insulin-related (systemic) and mTOR-related (cell-autonomous) effects. However, it remains unclear whether PIK3CA-activating mutations might preclude the anti-cancer activity of metformin in vivo. To model the oncogenic PIK3CA-driven early stages of cancer, we used the clonal breast cancer cell line MCF10DCIS.com, which harbors the gain-of-function H1047R hot-spot mutation in the catalytic domain of the PI3KCA gene and has been shown to form DR-refractory xenotumors. To model PIK3CA-activating mutations in late stages of cancer, we took advantage of the isogenic conversion of a PIK3CA-wild-type tumor into a PIK3CA H1047R-mutated tumor using the highly metastatic colorectal cancer cell line SW48. MCF10DCIS.com xenotumors, although only modestly affected by treatment with oral metformin (approximately 40% tumor growth inhibition), were highly sensitive to the intraperitoneal (i.p.) administration of metformin, the anti-cancer activity of which increased in a time-dependent manner and reached >80% tumor growth inhibition by the end of the treatment. Metformin treatment via the i.p. route significantly reduced the proliferation factor mitotic activity index (MAI) and decreased tumor cellularity in MCF10DCIS.com cancer tissues. Whereas SW48-wild-type (PIK3CA+/+) cells rapidly formed metformin-refractory xenotumors in mice, ad libitum access to water containing

  2. Monte Carlo Simulations of the Response of the MARIE Instrument

    NASA Technical Reports Server (NTRS)

    Andersen, V.; Lee, K.; Pinsky, L.; Atwell, W.; Cleghorn, T.; Cucinotta, F.; Saganti, P.; Turner, R.; Zeitlin, C.

    2003-01-01

    The MARIE instrument aboard Mars Odyssey functions as a telescope for the detection of charged, energetic, nuclei. The directionality that leads to the telescope description is achieved by requiring coincident signals in two designated detectors in MARIE s silicon detector stack for the instrument to trigger. Because of this, MARIE is actually a bi directional telescope. Triggering particles can enter the detector stack by passing through the lightly shielded front of the instrument, but can also enter the back of the instrument by passing through the bulk of Odyssey. Because of this, understanding how to relate the signals recorded by MARIE to astrophysically important quantities such as particle fluxes or spectra exterior to the spacecraft clearly requires detailed modeling of the physical interactions that occur as the particles pass through the spacecraft and the instrument itself. In order to facilitate in the calibration of the MARIE data, we have begun a program to simulate the response of MARIE using the FLUKA [1] [2] Monte Carlo radiation transport code.

  3. Monte Carlo Simulations of the Response of the MARIE Instrument

    NASA Technical Reports Server (NTRS)

    Andersen, V.; Lee, K.; Pinsky, L.; Atwell, W.; Cleghorn, T.; Cucinotta, F.; Saganti, P.; Turner, R.; Zeitlin, C.

    2003-01-01

    The MARIE instrument aboard Mars Odyssey functions as a telescope for the detection of charged, energetic, nuclei. The directionality that leads to the telescope description is achieved by requiring coincident signals in two designated detectors in MARIE s silicon detector stack for the instrument to trigger. Because of this, MARIE is actually a bi directional telescope. Triggering particles can enter the detector stack by passing through the lightly shielded front of the instrument, but can also enter the back of the instrument by passing through the bulk of Odyssey. Because of this, understanding how to relate the signals recorded by MARIE to astrophysically important quantities such as particle fluxes or spectra exterior to the spacecraft clearly requires detailed modeling of the physical interactions that occur as the particles pass through the spacecraft and the instrument itself. In order to facilitate in the calibration of the MARIE data, we have begun a program to simulate the response of MARIE using the FLUKA [1] [2] Monte Carlo radiation transport code.

  4. MaRIE theory, modeling and computation roadmap executive summary

    SciTech Connect

    Lookman, Turab

    2010-01-01

    The confluence of MaRIE (Matter-Radiation Interactions in Extreme) and extreme (exascale) computing timelines offers a unique opportunity in co-designing the elements of materials discovery, with theory and high performance computing, itself co-designed by constrained optimization of hardware and software, and experiments. MaRIE's theory, modeling, and computation (TMC) roadmap efforts have paralleled 'MaRIE First Experiments' science activities in the areas of materials dynamics, irradiated materials and complex functional materials in extreme conditions. The documents that follow this executive summary describe in detail for each of these areas the current state of the art, the gaps that exist and the road map to MaRIE and beyond. Here we integrate the various elements to articulate an overarching theme related to the role and consequences of heterogeneities which manifest as competing states in a complex energy landscape. MaRIE experiments will locate, measure and follow the dynamical evolution of these heterogeneities. Our TMC vision spans the various pillar science and highlights the key theoretical and experimental challenges. We also present a theory, modeling and computation roadmap of the path to and beyond MaRIE in each of the science areas.

  5. Referrals to the Marie Curie nursing service in North Yorkshire.

    PubMed

    Hanratty, B; Feather, J; Ward, C

    2000-01-01

    District and Marie Curie nurses participated in a small-scale study to describe referrals to a Marie Curie service in one English health district over a 3-month period. The number of new patients referred was small; they were geographically clustered and had widely differing life expectancies. Anecdotal reports of difficulties with the 'Nurselink' referral system were not confirmed, and in situations where the system was in operation, Marie Curie nurses were more likely to speak directly to the referring nurse. The most frequently cited reason for referral was general nursing needs; however, Marie Curie nurses felt that they were most often involved to provide family support. These findings suggest that there may not be a shared understanding of the Marie Curie nurse's role, and that equity in community palliative nursing care merits examination. Defining and publicizing the role of the Marie Curie nurse, providing guidance for referrals and prioritizing communication between professionals are proposed not only to enhance the service locally but to ensure that the service is available to all. This article illustrates the value of research to identify ways to improve service delivery.

  6. SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells.

    PubMed

    Pasquier, Benoit

    2015-04-03

    Autophagy plays an important role in cancer and it has been suggested that it functions not only as a tumor suppressor pathway to prevent tumor initiation, but also as a prosurvival pathway that helps tumor cells endure metabolic stress and resist death triggered by chemotherapeutic agents. We recently described the discovery of inhibitors of PIK3C3/Vps34 (phosphatidylinositol 3-kinase, catalytic subunit type 3), the lipid kinase component of the class III phosphatidylinositol 3-kinase (PtdIns3K). This PtdIns3K isoform has attracted significant attention in recent years because of its role in autophagy. Following chemical optimization we identified SAR405, a low molecular mass kinase inhibitor of PIK3C3, highly potent and selective with regard to other lipid and protein kinases. We demonstrated that inhibiting the catalytic activity of PIK3C3 disrupts vesicle trafficking from late endosomes to lysosomes. SAR405 treatment also inhibits autophagy induced either by starvation or by MTOR (mechanistic target of rapamycin) inhibition. Finally our results show that combining SAR405 with everolimus, the FDA-approved MTOR inhibitor, results in a significant synergy on the reduction of cell proliferation using renal tumor cells. This result indicates a potential therapeutic application for PIK3C3 inhibitors in cancer.

  7. Deletion of autophagy-related 5 (Atg5) and Pik3c3 genes in the lens causes cataract independent of programmed organelle degradation.

    PubMed

    Morishita, Hideaki; Eguchi, Satoshi; Kimura, Hirotaka; Sasaki, Junko; Sakamaki, Yuriko; Robinson, Michael L; Sasaki, Takehiko; Mizushima, Noboru

    2013-04-19

    The lens of the eye is composed of fiber cells, which differentiate from epithelial cells and undergo programmed organelle degradation during terminal differentiation. Although autophagy, a major intracellular degradation system, is constitutively active in these cells, its physiological role has remained unclear. We have previously shown that Atg5-dependent macroautophagy is not necessary for lens organelle degradation, at least during the embryonic period. Here, we generated lens-specific Atg5 knock-out mice and showed that Atg5 is not required for lens organelle degradation at any period of life. However, deletion of Atg5 in the lens results in age-related cataract, which is accompanied by accumulation of polyubiquitinated and oxidized proteins, p62, and insoluble crystallins, suggesting a defect in intracellular quality control. We also produced lens-specific Pik3c3 knock-out mice to elucidate the possible involvement of Atg5-independent alternative autophagy, which is proposed to be dependent on Pik3c3 (also known as Vps34), in lens organelle degradation. Deletion of Pik3c3 in the lens does not affect lens organelle degradation, but it leads to congenital cataract and a defect in lens development after birth likely due to an impairment of the endocytic pathway. Taken together, these results suggest that clearance of lens organelles is independent of macroautophagy. These findings also clarify the physiological role of Atg5 and Pik3c3 in quality control and development of the lens, respectively.

  8. Deciphering the impact of somatic mutations in exon 20 and exon 9 of PIK3CA gene in breast tumors among Indian women through molecular dynamics approach.

    PubMed

    Sudhakar, N; Priya Doss, C George; Thirumal Kumar, D; Chakraborty, Chiranjib; Anand, Kushi; Suresh, M

    2016-01-01

    We examined 25 breast tumor samples for somatic mutations in exon 20 and exon 9 of PIK3CA gene in South Indian population. Genomic DNA was isolated and amplified for PIK3CA gene, followed by direct sequencing of purified polymerase chain reaction products. We identified PI3K3CA mutations in 5 of 25 (20%), including four of the mutations in p.H1047R and one in p.H1047L. Nucleotide base substitution A to G (c.3140A > G) and A to T (c.3140A > T) results in p.H1047R and p.H1047L mutation in exon 20 of PIK3CA gene. We did not observe any mutation in exon 9 of PIK3CA gene. Furthermore, we investigated the effect of mutations on protein structure and function by the combination of sequence and structure-based in silico prediction methods. This determined the underlying relationship between the mutation and its phenotypic effects. Next step, we complemented by molecular dynamics simulation analysis (30 ns) of native and mutant structures that measured the effect of mutation on protein structure. The obtained results support that the application of computational methods helps predict the biological significance of mutations.

  9. The clinical value of HER-2 overexpression and PIK3CA mutations in the older breast cancer population: a FOCUS study analysis.

    PubMed

    Engels, Charla C; Kiderlen, Mandy; Bastiaannet, Esther; van Eijk, Ronald; Mooyaart, Antien; Smit, Vincent T H B M; de Craen, Anton J M; Kuppen, Peter J K; Kroep, Judith R; van de Velde, Cornelis J H; Liefers, Gerrit Jan

    2016-04-01

    Studies to confirm the effect of acknowledged prognostic markers in older breast cancer patients are scarce. The aim of this study was to evaluate the prognostic value of HER-2 overexpression and PIK3CA mutations in older breast cancer patients. Female breast cancer patients aged 65 years or older, diagnosed between 1997 and 2004 in a geographical region in The Netherlands, with an invasive, non-metastatic tumour and tumour material available, were included in the study. The primary endpoint was relapse-free period and secondary endpoint was relative survival. Determinants were immunochemical HER-2 scores (0/1+, 2+ or 3+) and PIK3CA as a binary measure. Overall, 1698 patients were included, and 103 had a HER-2 score of 3+. HER-2 overexpression was associated with a higher recurrence risk (5 years recurrence risk 34 % vs. 12 %, adjusted p = 0.005), and a worse relative survival (10 years relative survival 48 % vs. 84 % for HER-2 negative; p = 0.004). PIK3CA mutations had no significant prognostic effect. We showed, in older breast cancer patients, that HER-2 overexpression was significantly associated with a worse outcome, but PIK3CA mutations had no prognostic effect. These results imply that older patients with HER-2 overexpressing breast cancer might benefit from additional targeted anti-HER-2 therapy.

  10. Update on Charcot-Marie-Tooth disease.

    PubMed

    Gutmann, Laurie; Shy, Michael

    2015-10-01

    Charcot-Marie-Tooth disease (CMT) is the common terminology used to describe the hereditary neuropathies. This update reviews advances in the past year in our understanding of these diseases, including some important earlier references. In the past year, advances in next-generation sequencing continued to increase the number of genes associated with CMT. The connection between genotype and phenotype has become more complicated. New insights into the pathogenesis of the diseases are reviewed. Treatment and clinical trial updates coming from these new insights, as well as use of high-throughput screening to match potential treatments with targets, are moving the field forward. There is a discussion of potential next steps, including the use of patient-derived induced pluripotent stem cells, to enhance our understanding of individual genotypes and phenotypes. The use of high-throughput screens, and techniques such as RNAi and induced pluripotent stem cell continue to push forward other therapies for specific genetic forms of CMT and are potentially more generalizable to peripheral neuropathies. These developments, along with the development of improved outcome measures and longitudinal natural history data, advance CMT, making the future for finding treatments and/or cures closer than it has ever been.

  11. [Pathology of Charcot-Marie-Tooth Disease].

    PubMed

    Oka, Nobuyuki

    2016-01-01

    Although genetic testing is available, nerve biopsy is useful in selected patients for the diagnosis of Charcot-Marie-Tooth disease (CMT). These are sporadic cases of hereditary neuropathy, or familial cases in which genetic testing is negative. CMT is caused by mutations of various genes. The pathological features of CMT have mostly been investigated using nerve biopsy, which may shed light on the presumed functions of mutated gene products. PMP22 duplication in CMT1A induces numerous large onion bulb lesions (OB). Compared to chronic inflammatory demyelinating polyradiculoneuropathy, the differential features of CMT1A are patchy distribution of OB and non-inflammatory lesions. CMT1B also manifests as OB, but presents abnormal compaction of myelin sheaths caused by uncompacted myelin or excessive myelin folding. CMT2 includes axonal neuropathies and many causative genes have been found. CMT2A (MFN2 mutation) shows abnormal mitochondria with a spherical morphology instead of tubular in the longitudinal direction. CMT4 consists of autosomal recessive forms with demyelinating pathology. Most subtypes have mutations of genes relating to myelin maintenance, and pathologically, they show abnormal folding of the myelin structure.

  12. Astronaut Mary Ellen Weber with BDS

    NASA Image and Video Library

    1995-08-08

    STS070-301-025 (13-22 July 1995) --- Astronaut Mary Ellen Weber works with a syringe related to the Bioreactor Development System (BDS). The almost weightless state of space travel provides life science researchers with the opportunity to grow cells into three-dimensional tissue pieces that are not achievable using conventional tissue culture methods on Earth. At specified times during the STS-70 mission, crew members injected color producing substances to document fluid movement in the reactor, and various-sized beads to estimate the tissue size that could be supported in the Bioreactor. The photo was among NASA's first release of still photography from the STS-70 mission. The mission was launched from the Kennedy Space Center (KSC) on July 13, 1995, and ended when Discovery landed on Runway 33 there on July 22, 1995. The crew members were astronauts Terence T. (Tom) Henricks, commander; Kevin R. Kregel, pilot; and Donald A. Thomas, Nancy J. Currie and Weber, all mission specialists.

  13. [Clinical and genetic analysis for activated PI3K-δ syndrome by PIK3CD gene mutation].

    PubMed

    Liu, H; Tang, X L; Liu, J R; Li, H M; Zhao, S Y

    2016-09-01

    To analyze clinical and genetic features of activated PI3K-δ syndrome (APDS), a new form of immunodeficiency disease caused by PIK3CD gene mutation. Data of two patients diagnosed as APDS at Second Department of Respiratory Medicine of Beijing Children's Hospital Affiliated to Capital Medical University in 2015 were retrospectively reviewed. Pathogenetic genes were screened by whole exome sequencing, and identified by first generation sequencing. The identified pathogenetic genes were further verified in patients' parents. Then the gene sequencing results were analyzed. Both patients were females, aged 2 years and 4 months and 5 years respectively. The main clinical features of both cases were recurrent respiratory infections, enlargement of lymph node, hepatosplenomegaly, cytomegalovirus (CMV) or Epstein-Barr virus (EBV) viremia, decreased number of native CD4(+) T cell, inverted CD4(+) /CD8(+) T cell ratio and increased IgM. Patient 1 has decreased IgA and IgG. Patient 2 showed wide follicular hyperplasia of the airway mucosa. Both patients had de novo mutation in c. 3061G>A(E1021K)of PIK3CD gene, which was homozygous in patient 1 and heterozygous in patient 2. Both were treated with 500 mg/kg dose of gamma globulin intravenously at 4-weeks interval. Patient 1 started oral rapamycin therapy at the dose of 1 mg/(m(2)·d) and discontinued the treatment after 2 weeks. Patient 2 was given low dose of oral prednisone. The two patients were followed up for 2 months. The number of respiratory infection in both patients was decreased. Hepatosplenomegaly was subsided, while respiratory tract damage was not improved in patient 2. The clinical manifestations of APDS include recurrent respiratory tract infection, enlargement of lymph nodes, hepatosplenomegaly, and CMV or EBV infection. The immunophenotype is decreased native CD4(+) T cell, inverted CD4(+) /CD8(+) T cell ratio, increased IgM and decreased IgA/IgG for some patients. c. 3061G>A(E1021K)of PIK3CD gene is a

  14. Prevalence and coexistence of KRAS, BRAF, PIK3CA, NRAS, TP53, and APC mutations in Indian colorectal cancer patients: Next-generation sequencing-based cohort study.

    PubMed

    Jauhri, Mayank; Bhatnagar, Akanksha; Gupta, Satish; Bp, Manasa; Minhas, Sachin; Shokeen, Yogender; Aggarwal, Shyam

    2017-02-01

    Colorectal cancer incidences are on a rise in India. In this study, we have analyzed the mutation frequencies of six potential biomarkers, their coexistence, association with clinicopathological characteristics, and tumor location in Indian colorectal cancer patients. Next-generation sequencing was performed to identify mutations in the six potential biomarker genes using formalin-fixed paraffin-embedded tissue blocks of 112 colorectal cancer patients. The mutation frequency observed in KRAS, BRAF, PIK3CA, NRAS, TP53, and APC was 35.7%, 7.1%, 16.1%, 6.3%, 39.3%, and 29.5%, respectively. The significant associations of mutations were KRAS with age less than 60 years (p = 0.041), PIK3CA with males (p = 0.032), tumor stage I-II (p = 0.013), lack of metastasis in lymph nodes (p = 0.040), NRAS with rectum (p = 0.002), and APC with T2 stage of tumor growth (p = 0.013). No single patient harbored mutations in these six genes or any five genes simultaneously. Significance was noted in coexistence of KRAS with APC (p = 0.024) and mutual exclusion of KRAS with BRAF (p = 0.029). PIK3CA exon 9 was observed to be more frequently associated with KRAS mutations than PIK3CA exon 20 (p = 0.072). NRAS mutations were mutually exclusive with BRAF and PIK3CA mutations. As per our knowledge, this is the first next-generation sequencing-based biomarker study in Indian colorectal cancer patients. Frequent coexistence of gene mutations in pairs and triplets suggests that synergistic effect of overlapping mutations might further trigger the disease. In addition, infrequent coexistence of multiple gene mutations hints toward different signaling pathways for colorectal cancer tumorigenesis.

  15. Ernst Julius Öpik's (1916) note on the theory of explosion cratering on the Moon's surface—The complex case of a long-overlooked benchmark paper

    NASA Astrophysics Data System (ADS)

    Racki, Grzegorz; Koeberl, Christian; Viik, Tõnu; Jagt-Yazykova, Elena A.; Jagt, John W. M.

    2014-10-01

    High-velocity impact as a common phenomenon in planetary evolution was ignored until well into the twentieth century, mostly because of inadequate understanding of cratering processes. An eight-page note, published in Russian by the young Ernst Julius Öpik, a great Estonian astronomer, was among the key selenological papers, but due to the language barrier, it was barely known and mostly incorrectly cited. This particular paper is here intended to serve as an explanatory supplement to an English translation of Öpik's article, but also to document an early stage in our understanding of cratering. First, we outline the historical-biographical background of this benchmark paper, and second, a comprehensive discussion of its merits is presented, from past and present perspectives alike. In his theoretical research, Öpik analyzed the explosive formation of craters numerically, albeit in a very simple way. For the first time, he approximated relationships among minimal meteorite size, impact energy, and crater diameter; this scaling focused solely on the gravitational energy of excavating the crater (a "useful" working approach). This initial physical model, with a rational mechanical basis, was developed in a series of papers up to 1961. Öpik should certainly be viewed as the founder of the numerical simulation approach in planetary sciences. In addition, the present note also briefly describes Nikolai A. Morozov as a remarkable man, a forgotten Russian scientist and, surprisingly, the true initiator of Öpik's explosive impact theory. In fact, already between 1909 and 1911, Morozov probably was the first to consider conclusively that explosion craters would be circular, bowl-shaped depressions even when formed under different impact angles.

  16. Combined inhibition of PI3K and PARP is effective in the treatment of ovarian cancer cells with wild-type PIK3CA genes

    PubMed Central

    Wang, Dong; Li, Chengbo; Zhang, Yuan; Wang, Min; Jiang, Nan; Xiang, Lin; Li, Ting; Roberts, Thomas M.; Zhao, Jean J.; Cheng, Hailing; Liu, Pixu

    2017-01-01

    Objective Combined inhibition of PI3K and PARP has been shown to be effective in the treatment of preclinical models of breast cancer and prostate cancer independent of BRCA or PIK3CA mutational status. However, the knowledge about this combination treatment in ovarian cancer is limited. The aim of this study was to evaluate the therapeutic effect of PI3K inhibitor BKM120 and PARP inhibitor Olaparib on ovarian cancer cell lines bearing wild-type PIK3CA genes. Methods We exposed three wild-type PIK3CA ovarian cancer cell lines to a PI3K inhibitor BKM120 and /or a PARP inhibitor Olaparib. The effect of BKM120 as a single-agent or in combination with Olaparib was evaluated by Cell Count Kit (CCK8) assay, immunoblotting, comet assay, flow cytometry and immunofluorescence staining assay. The combination indexes for synergistic effect on cell viability were calculated with the Chou-Talalay method. Ex vivo cultured ovarian cancer tissues from patients were analyzed by histological and immunohistochemical analyses. Results Combined inhibition of PI3K and PARP effectively synergized to block the growth of three wild-type PIK3CA ovarian cancer cell lines and explants of a primary ovarian tumor specimen. Mechanistically, dual blockade of PI3K and PARP in these ovarian cancer cell lines resulted in substantially attenuated PI3K/AKT/mTOR signaling, impaired DNA damage response and deficient homologous recombination repair, with remarkable BRCA downregulation. Conclusions The combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib may be effective in ovarian cancers with a broader spectrum of cancer-associated genetic alterations but not limited to those with mutant PIK3CA or BRCA genes. BRCA downregulation may be a potential biomarker for the effective response to the proposed combination treatment. PMID:27426307

  17. On the possibility of placing a universal neutron diffractometer in an inclined channel of the PIK reactor

    SciTech Connect

    Elyutin, N. O.; Lvov, D. V.; Tyulyusov, A. N.

    2011-12-15

    The possibility of placing a universal neutron diffractometer, which is designed for working with perfect crystals, in one of the inclined channels of the PIK reactor is discussed. It is proposed to use a double monochromator block (DMB) in the vertical plane and mounting crystals in the antiparallel position with reflection at a Bragg angle of 15 Degree-Sign . In this configuration, a set of well-known monochromator crystals (pyrolytic graphite, SiO{sub 2}, Si, Ge, Cu, and Pb) provides transmission bands of quasi-monochromatic neutrons in the range of 1-1.8 Angstrom-Sign . The angular and energy distributions of neutrons transmitted through the DMB are calculated. A scheme of the block for filtering radiations is proposed, and its parameters are calculated. The principles of instrument operation in a physical room (beyond the DMB) are determined.

  18. Saint Mary of Nazareth Hospital Center. Chicago, Illinois.

    PubMed

    1985-01-01

    Saint Mary of Nazareth Hospital has been serving the ethnic community on Chicago's near-northwest side since 1894. The city's first Polish hospital, it was founded by the Sisters of the Holy Family of Nazareth to care for many Polish immigrants who settled in the area. Although the surrounding neighborhood is now predominantly comprised of 56% hispanic, 9% black and 37% white ethnic residents, the hospital retains strong ties to the Polish community, as witnessed by a visit to Saint Marys by Cardinal Karol Wojtyla shortly before his election as Pope John Paul II. The hospital's first site was a vacant three-story brick apartment building which the Sisters remodeled into a 24-bed hospital. This facility was quickly outgrown, even after purchase of the two-story frame house next door which increased Saint Marys capacity to 44 beds. Eight years after its founding, a brand new hospital was built. Over the years, Saint Marys continued to experience steady growth requiring the periodic addition of new buildings and wings. By the early 1970s, the need for another brand-new facility was evident. In 1975, a new hospital opened, based on some of the Friesen supply concepts. Today, Saint Marys operates a nearby family practice center, a home health care service, a satellite lab and an intensive care emergency helicopter serving patients in a 120 mile radius.

  19. Auditory function in children with Charcot-Marie-Tooth disease.

    PubMed

    Rance, Gary; Ryan, Monique M; Bayliss, Kristen; Gill, Kathryn; O'Sullivan, Caitlin; Whitechurch, Marny

    2012-05-01

    The peripheral manifestations of the inherited neuropathies are increasingly well characterized, but their effects upon cranial nerve function are not well understood. Hearing loss is recognized in a minority of children with this condition, but has not previously been systemically studied. A clear understanding of the prevalence and degree of auditory difficulties in this population is important as hearing impairment can impact upon speech/language development, social interaction ability and educational progress. The aim of this study was to investigate auditory pathway function, speech perception ability and everyday listening and communication in a group of school-aged children with inherited neuropathies. Twenty-six children with Charcot-Marie-Tooth disease confirmed by genetic testing and physical examination participated. Eighteen had demyelinating neuropathies (Charcot-Marie-Tooth type 1) and eight had the axonal form (Charcot-Marie-Tooth type 2). While each subject had normal or near-normal sound detection, individuals in both disease groups showed electrophysiological evidence of auditory neuropathy with delayed or low amplitude auditory brainstem responses. Auditory perception was also affected, with >60% of subjects with Charcot-Marie-Tooth type 1 and >85% of Charcot-Marie-Tooth type 2 suffering impaired processing of auditory temporal (timing) cues and/or abnormal speech understanding in everyday listening conditions.

  20. Recent advances in Charcot-Marie-Tooth disease.

    PubMed

    Baets, Jonathan; De Jonghe, Peter; Timmerman, Vincent

    2014-10-01

    This article focuses on recent advances in Charcot-Marie-Tooth disease, in particular additions to the genetic spectrum, novel paradigms in molecular techniques and an update on therapeutic strategies. Several new Charcot-Marie-Tooth disease-causing genes have been recently identified, further enlarging the genetic diversity and phenotypic variability, including: SBF1, DHTKD1, TFG, MARS, HARS, HINT1, TRIM1, AIFM1, PDK3 and GNB4. The increasing availability and affordability of next-generation sequencing technologies has ramped up gene discovery and drastically changed genetic screening strategies. All large-scale trials studying the effect of ascorbic acid in Charcot-Marie-Tooth 1A have now been completed and were negative. Efforts have been made to design more robust outcome-measures for clinical trials. Promising results with lonaprisan, curcumin and histone deacetylase 6 inhibitors have been obtained in animal models. Charcot-Marie-Tooth is the most common form of inherited peripheral neuropathy and represents the most prevalent hereditary neuromuscular disorder. The genetic spectrum spans more than 70 genes. Gene discovery has been revolutionized recently by new high-throughput molecular technologies. In addition, the phenotypic diversity has grown tremendously. This is a major challenge for geneticists and neurologists. No effective therapy is available for Charcot-Marie-Tooth. Several large trials with ascorbic acid were negative but research into novel compounds continues.

  1. Investigating the Structure and Dynamics of the PIK3CA Wild-Type and H1047R Oncogenic Mutant

    PubMed Central

    Pavlaki, Maria; Lazani, Vasiliki; Christoforidis, Savvas; Agianian, Bogos; Cournia, Zoe

    2014-01-01

    The PIK3CA gene is one of the most frequently mutated oncogenes in human cancers. It encodes p110α, the catalytic subunit of phosphatidylinositol 3-kinase alpha (PI3Kα), which activates signaling cascades leading to cell proliferation, survival, and cell growth. The most frequent mutation in PIK3CA is H1047R, which results in enzymatic overactivation. Understanding how the H1047R mutation causes the enhanced activity of the protein in atomic detail is central to developing mutant-specific therapeutics for cancer. To this end, Surface Plasmon Resonance (SPR) experiments and Molecular Dynamics (MD) simulations were carried out for both wild-type (WT) and H1047R mutant proteins. An expanded positive charge distribution on the membrane binding regions of the mutant with respect to the WT protein is observed through MD simulations, which justifies the increased ability of the mutated protein variant to bind to membranes rich in anionic lipids in our SPR experiments. Our results further support an auto-inhibitory role of the C-terminal tail in the WT protein, which is abolished in the mutant protein due to loss of crucial intermolecular interactions. Moreover, Functional Mode Analysis reveals that the H1047R mutation alters the twisting motion of the N-lobe of the kinase domain with respect to the C-lobe and shifts the position of the conserved P-loop residues in the vicinity of the active site. These findings demonstrate the dynamical and structural differences of the two proteins in atomic detail and propose a mechanism of overactivation for the mutant protein. The results may be further utilized for the design of mutant-specific PI3Kα inhibitors that exploit the altered mutant conformation. PMID:25340423

  2. Soils of Marie Byrd Land, West Antarctica

    NASA Astrophysics Data System (ADS)

    Lupachev, A. V.; Abakumov, E. V.

    2013-10-01

    Soils of Marie Byrd Land-one of the remotest and difficultly accessible regions of Antarctica-were investigated in the area of the mothballed Russkaya station located to the south of 74° S. Despite the extremely severe wind regime (the average wind velocity is 13 m/s, and the maximum wind velocity is up to 60 m/s), the projective cover of vegetation in the area of the station averages 25-40% and reaches 60-80% in some places. The phenomena of physical weathering of the bedrock-exfoliation, stone pavements, residual rocks exposed by wind (hoodoos), and others-are clearly manifested. In most of the described soils, normal organic and organomineral horizons are absent. The soil profiles represent the mixture of the residues of mosses and lichens and the gravelly eluvium. The fine earth material is blown out of the surface horizons by strong winds; its residual accumulation takes place in the middle and lower parts of the profiles. The classification position of these soils is open to argument; they are close to Petrozems and Lithozems. Most of the profiles are underlain by the massive or slightly disintegrated bedrock with dry permafrost at a depth of 20 to 50 cm. Soils with dry permafrost comprise about 75% of the surveyed area. In separate loci in the depressions of the local mesorelief and on gentle slopes, the soils with clearly expressed cryoturbation features are developed; their profiles are underlain by the ice-rich permafrost and compose about 15% of the surveyed area. Anthropogenically disturbed soils and soils polluted with petroleum hydrocarbons, heavy metals, and other pollutants occupy about 10% of the surveyed area.

  3. 78 FR 14653 - Amendment of Class E Airspace; Sault Ste Marie, ON

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-07

    ... control zone over Sault Ste Marie Airport. The FAA is taking this action to enhance the safety and... Airport, Sault Ste Marie, ON, to coincide with that portion of the control zone in Canadian airspace....

  4. 105. Catalog OPark Structure/Construction & Maintenance, 23 Marys Rock Tunnel, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    105. Catalog O-Park Structure/Construction & Maintenance, 23 Marys Rock Tunnel, Negative No. 6306 ca. late 1930s MARYS ROCK TUNNEL, SOUTH PORTAL. - Skyline Drive, From Front Royal, VA to Rockfish Gap, VA , Luray, Page County, VA

  5. 77 FR 25013 - Requested Administrative Waiver of the Coastwise Trade Laws: Vessel MARIE ELENA; Invitation for...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-26

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF TRANSPORTATION Maritime Administration Requested Administrative Waiver of the Coastwise Trade Laws: Vessel MARIE ELENA... the vessel MARIE ELENA is: Intended Commercial Use of Vessel: ``Sailboat passenger charter...

  6. AmeriFlux US-MRf Mary's River (Fir) site

    DOE Data Explorer

    Law, Bev [Oregon State University

    2016-01-01

    This is the AmeriFlux version of the carbon flux data for the site US-MRf Mary's River (Fir) site. Site Description - The Marys River Fir site is part of the "Synthesis of Remote Sensing and Field Observations to Model and Understand Disturbance and Climate Effects on the Carbon Balance of Oregon and Northern California (ORCA)". Located in the western region of Oregon the Marys River site represents the western extent of the climate gradient that spans eastward into the semi-arid basin of central Oregon. The sites that make up the eastern extent of the ORCA climate gradient is the Metolius site network (US-Me1, US-ME2, US-ME4, US-Me5) all of which are part of the TERRA PNW project at Oregon State University.

  7. MARIE Dose and Flux Measurements in Mars Orbit

    NASA Technical Reports Server (NTRS)

    Zeitlin, C.; Cleghorn, T.; Cucinotta, F. A.; Saganti, P.; Andersen, V.; Lee, K. T.; Pinsky, L. S.; Turner, R.; Atwell, W.

    2004-01-01

    We present results from the Martian Radiation Environment Experiment (MARIE), aboard the 2001 Mars Odyssey spacecraft in orbit around Mars. MARIE operated successfully from March 2002 through October 2003. At the time of this writing, the instrument is off due to a loss of communications during an extremely intense Solar Particle Event. Efforts to revive MARIE are planned for Spring 2004, when Odyssey's role as a communications relay for the MER rovers is completed. During the period of successful operation, MARIE returned the first detailed energetic charged particle data from Mars. Due to limitations of the instrument, normalizing MARIE data to flux or dose is not straightforward - several large corrections are needed. Thus normalized results (like dose or flux) have large uncertainties and/or significant model-dependence. The problems in normalization are mainly due to inefficiency in detecting high-energy protons (signal-to-noise problems force the trigger threshold to be higher than optimal), to the excessively high gains employed in the signal processing electronics (many ions deposit energy sufficient to saturate the electronics, and dE/dx information is lost), and to artifacts associated with the two trigger detectors (incomplete registration of dE/dx). Despite these problems, MARIE is efficient for detecting helium ions with kinetic energies above about 30 MeV/nucleon, and for detecting high-energy ions (energies above about 400 MeV/nucleon) with charges from 5 to 10. Fluxes of these heavier ions can be compared to fluxes obtained from the ACE/CRIS instrument, providing at least one area of direct comparison between data obtained at Earth and at Mars; this analysis will be presented as a work in progress. We will also present dose-rate data, with a detailed explanation of the many sources of uncertainty in normalization. The results for both flux and dose will be compared to predictions of the HZETRN model of the GCR.

  8. MARIE Dose and Flux Measurements in Mars Orbit

    NASA Astrophysics Data System (ADS)

    Zeitlin, C.; Cleghorn, T.; Cucinotta, F.; Saganti, P.; Andersen, V.; Lee, K.; Pinsky, L.; Turner, R.; Atwell, W.

    We present results from the Martian Radiation Environment Experiment (MARIE), aboard the 2001 Mars Odyssey spacecraft in orbit around Mars. MARIE operated successfully from March 2002 through October 2003. At the time of this writing, the instrument is off due to a loss of communications during an extremely intense Solar Particle Event. Efforts to revive MARIE are planned for Spring 2004, when Odyssey's role as a communications relay for the MER rovers is completed. During the period of successful operation, MARIE returned the first detailed energetic charged particle data from Mars. Due to limitations of the instrument, normalizing MARIE data to flux or dose is not straightforward - several large corrections are needed. Thus normalized results (like dose or flux) have large uncertainties and/or significant model-dependence. The problems in normalization are mainly due to inefficiency in detecting high-energy protons (signal-to-noise problems force the trigger threshold to be higher than optimal), to the excessively high gains employed in the signal processing electronics (many ions deposit energy sufficient to saturate the electronics, and dE/dx information is lost), and to artifacts associated with the two trigger detectors (incomplete registration of dE/dx). Despite these problems, MARIE is efficient for detecting helium ions with kinetic energies above about 30 MeV/nucleon, and for detecting high-energy ions (energies above about 400 MeV/nucleon) with charges from 5 to 10. Fluxes of these heavier ions can be compared to fluxes obtained from the ACE/CRIS instrument, providing at least one area of direct comparison between data obtained at Earth and at Mars; this analysis will be presented as a work in progress. We will also present dose-rate data, with a detailed explanation of the many sources of uncertainty in normalization. The results for both flux and dose will be compared to predictions of the HZETRN model of the GCR environment.

  9. 33 CFR 207.441 - St. Marys Falls Canal and Locks, Mich.; security.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false St. Marys Falls Canal and Locks... OF THE ARMY, DEPARTMENT OF DEFENSE NAVIGATION REGULATIONS § 207.441 St. Marys Falls Canal and Locks... the conduct of crew and passengers while transiting St. Marys Falls Canal and Locks and for...

  10. 33 CFR 207.440 - St. Marys Falls Canal and Locks, Mich.; use, administration, and navigation.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false St. Marys Falls Canal and Locks.... Marys Falls Canal and Locks, Mich.; use, administration, and navigation. (a) The use, administration... by radiotelephone to the Corps of Engineers Chief Lockmaster at St. Marys Falls Canal dispatch...

  11. 75 FR 51945 - Safety Zone; Potomac River, St. Mary's River, St. Inigoes, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-24

    ... SECURITY Coast Guard 33 CFR Part 165 RIN 1625-AA00 Safety Zone; Potomac River, St. Mary's River, St... establishing a temporary safety zone upon specified waters of the St. Mary's River, a tributary of the Potomac... certain waters of the St. Mary's River, near its confluence with the Potomac River, within a one nautical...

  12. An algorithm for generating an m-ary summation tree

    NASA Technical Reports Server (NTRS)

    Sievers, M.

    1978-01-01

    An algorithm is presented for generating an m-ary summation tree. The algorithm is completely general and may be applied to any length input string. For an N length sequence summed in groups of m sub l at each level l a maximum of 3L - 2 storage is required. A special case of the general m-ary tree where all m sub l are equal is used to smooth data in a radio frequency interference experiment. The maximum storage required when m l sub l = m for all l reduces to the closed form 3 log m N - 2.

  13. ANESTHESIA FOR CHARCOT-MARIE-TOOTH DISEASE: CASE REPORT.

    PubMed

    Alzaben, Khalid R; Samarah, Omar Q; Obeidat, Salameh S; Halhouli, Oday; Al Kharabsheh, Murad

    2016-06-01

    Charcot-Marie-Tooth disease comprises a group of disorders characterized by progressive muscle weakness and wasting. Reviewing the anaesthetic literature produced conflicting reports about the best anaesthetic options for patients with CMTD; as they are at increased risk of prolonged response to muscle relaxants, malignant hyperthermia and risks of regional anaesthesia. We present a case of the successful use of total intravenous anaesthesia with dexmedetomidine and propofol combined with caudal block using bupivacaine mixed with dexmedetomidine without any complications, for a 17 year old male patient with Charcot Marie-Tooth disease who underwent a lower limb orthopedic surgery.

  14. [Charcot-Marie-Tooth disease and bilateral vitritis].

    PubMed

    Anaya-Pava, E J; Cárdenas-Hernández, R I

    2015-04-01

    We describe a patient diagnosed with Charcot-Marie-Tooth disease, with a 4 months history of bilateral decreased visual acuity and floaters. On examination, he had severe bilateral vitreous opacity and sectoral diffuse vascular sheathing. It could not be linked to some underlying aetiology and did not respond to oral steroids. Publications relating to ocular findings in patients with Charcot-Marie-Tooth disease exclude bilateral vitritis. In this case we were unable to test the association with another disease as the cause of vitritis. Copyright © 2013 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.

  15. Effectors of epidermal growth factor receptor pathway: the genetic profiling ofKRAS, BRAF, PIK3CA, NRAS mutations in colorectal cancer characteristics and personalized medicine.

    PubMed

    Shen, Yinchen; Wang, Jianfei; Han, Xiaohong; Yang, Hongying; Wang, Shuai; Lin, Dongmei; Shi, Yuankai

    2013-01-01

    Mutations in KRAS oncogene are recognized biomarkers that predict lack of response to anti- epidermal growth factor receptor (EGFR) antibody therapies. However, some patients with KRAS wild-type tumors still do not respond, so other downstream mutations in BRAF, PIK3CA and NRAS should be investigated. Herein we used direct sequencing to analyze mutation status for 676 patients in KRAS (codons 12, 13 and 61), BRAF (exon 11 and exon 15), PIK3CA (exon 9 and exon 20) and NRAS (codons12, 13 and 61). Clinicopathological characteristics associations were analyzed together with overall survival (OS) of metastatic colorectal cancer patients (mCRC). We found 35.9% (242/674) tumors harbored a KRAS mutation, 6.96% (47/675) harbored a BRAF mutation, 9.9% (62/625) harbored a PIK3CA mutation and 4.19% (26/621) harbored a NRAS mutation. KRAS mutation coexisted with BRAF, PIK3CA and NRAS mutation, PIK3CA exon9 mutation appeared more frequently in KRAS mutant tumors (P = 0.027) while NRAS mutation almost existed in KRAS wild-types (P<0.001). Female patients and older group harbored a higher KRAS mutation (P = 0.018 and P = 0.031, respectively); BRAF (V600E) mutation showed a higher frequency in colon cancer and poor differentiation tumors (P = 0.020 and P = 0.030, respectively); proximal tumors appeared a higher PIK3CA mutation (P<0.001) and distant metastatic tumors shared a higher NRAS mutation (P = 0.010). However, in this study no significant result was found between OS and gene mutation in mCRC group. To our knowledge, the first large-scale retrospective study on comprehensive genetic profile which associated with anti-EGFR MoAbs treatment selection in East Asian CRC population, appeared a specific genotype distribution picture, and the results provided a better understanding between clinicopathological characteristics and gene mutations in CRC patients.

  16. Simultaneous identification of 36 mutations in KRAS codons 61and 146, BRAF, NRAS, and PIK3CA in a single reaction by multiplex assay kit

    PubMed Central

    2013-01-01

    Background Retrospective analyses in the West suggest that mutations in KRAS codons 61 and 146, BRAF, NRAS, and PIK3CA are negative predictive factors for cetuximab treatment in colorectal cancer patients. We developed a novel multiplex kit detecting 36 mutations in KRAS codons 61 and 146, BRAF, NRAS, and PIK3CA using Luminex (xMAP) assay in a single reaction. Methods Tumor samples and clinical data from Asian colorectal cancer patients treated with cetuximab were collected. We investigated KRAS, BRAF, NRAS, and PIK3CA mutations using both the multiplex kit and direct sequencing methods, and evaluated the concordance between the 2 methods. Objective response, progression-free survival (PFS), and overall survival (OS) were also evaluated according to mutational status. Results In total, 82 of 83 samples (78 surgically resected specimens and 5 biopsy specimens) were analyzed using both methods. All multiplex assays were performed using 50 ng of template DNA. The concordance rate between the methods was 100%. Overall, 49 (59.8%) patients had all wild-type tumors, 21 (25.6%) had tumors harboring KRAS codon 12 or 13 mutations, and 12 (14.6%) had tumors harboring KRAS codon 61, KRAS codon 146, BRAF, NRAS, or PIK3CA mutations. The response rates in these patient groups were 38.8%, 4.8%, and 0%, respectively. Median PFS in these groups was 6.1 months (95% confidence interval (CI): 3.1–9.2), 2.7 months (1.2–4.2), and 1.6 months (1.5–1.7); median OS was 13.8 months (9.2–18.4), 8.2 months (5.7–10.7), and 6.3 months (1.3–11.3), respectively. Statistically significant differences in both PFS and OS were found between patients with all wild-type tumors and those with KRAS codon 61, KRAS codon 146, BRAF, NRAS, or PIK3CA mutations (PFS: 95% CI, 0.11–0.44; P < 0.0001; OS: 95% CI, 0.15–0.61; P < 0.0001). Conclusions Our newly developed multiplex kit is practical and feasible for investigation of a range of sample types. Moreover, mutations in KRAS

  17. Impact of concurrent PIK3CA mutations on response to EGFR tyrosine kinase inhibition in EGFR-mutant lung cancers and on prognosis in oncogene-driven lung adenocarcinomas

    PubMed Central

    Eng, Juliana; Woo, Kaitlin M.; Sima, Camelia S.; Plodkowski, Andrew; Hellmann, Matthew D.; Chaft, Jamie; Kris, Mark G.; Arcila, Maria E.; Ladanyi, Marc; Drilon, Alexander

    2016-01-01

    INTRODUCTION In patients with EGFR or KRAS-mutant lung adenocarcinomas, the prognostic impact of a concurrent PIK3CA mutation remains unclear. Although preclinical data suggest that sensitivity to EGFR tyrosine kinase inhibition (TKI) is decreased in EGFR-mutant lung cancers also harboring a PIK3CA mutation, this interaction has not been explored clinically. METHODS Patients with lung adenocarcinomas harboring a PIK3CA mutation concurrent with a separate driver mutation were identified via mutational hotspot testing, multiplex sizing assays, and FISH. Overall survival (OS) and outcomes with EGFR TKI monotherapy (EGFR-mutant) were estimated using Kaplan-Meier methods and compared between double mutant (EGFR or KRAS-mutant, concurrent PIK3C-mutant) and single mutant patients (EGFR or KRAS-mutant, PI3KCA wild-type) using log-rank tests. RESULTS In EGFR and KRAS-mutant lung cancers, a concurrent PIK3CA mutation was associated with a decrease in median OS: 18 vs 33 months (EGFR double n=10 vs single n=43 mutant, p=0.006), and 9 vs 16 months (KRAS double n=16 vs single n=47 mutant, p=0.020). In EGFR-mutant lung cancers, a concurrent PIK3CA mutation did not impact benefit from EGFR TKI monotherapy. Single vs double mutant: objective response rate 83% (n=29) vs 62% (n=6, p=0.80), median time to progression 11 (n=29) vs 8 months (n=6, p=0.84), and median duration of TKI therapy 15 (n=32) vs 15 months (n=10, p=0.65). CONCLUSION A concurrent PIK3CA mutation is a poor prognostic factor in patients with advanced EGFR- or KRAS-mutant lung adenocarcinomas. There was no evidence that clinical benefit from EGFR TKI monotherapy is affected by a concurrent PIK3CA mutation in EGFR-mutant lung cancers. PMID:26334752

  18. The predictive and prognostic role of phosphatase phosphoinositol-3 (PI3) kinase (PIK3CA) mutation in HER2-positive breast cancer receiving HER2-targeted therapy: a meta-analysis.

    PubMed

    Ibrahim, Ezzeldin M; Kazkaz, Ghieth A; Al-Mansour, Mubarak M; Al-Foheidi, Meteb E

    2015-08-01

    The association between PIK3CA mutation and resistance to anti-HER2 therapy (AHT) is not precisely defined. This meta-analysis intended to explore the clinical utility of PIK3CA mutation in HER2-positive breast cancer treated with AHT. Literature search identified 19 eligible studies. There were 1720 patients with advanced, 828 with early and 1290 patients treated in the neoadjuvant setting. In metastatic breast cancer, AHT showed no differential objective response benefit between the wild type (WT) and the mutated type (MT) PIK3CA subgroups (odds ratio [OR] = 1.09; 95 % CI 0.60-2.00; P = 0.78). AHT favorable affected progression-free survival (PFS) irrespective of PIK3CA mutation. There was no PFS difference between WT and MT regardless of the offered therapy. In early breast cancer, trastuzumab combined with the same chemotherapy conferred consistent relapse-free survival benefit in WT and MT subgroups (WT: HR = 0.59; 95 % CI 0.44-0.80; P < 0.001 vs. MT: HR = 0.42; 95 % CI 0.24-0.74; P < 0.001). In the neoadjuvant setting, AHT-based therapy produced a 72 % higher pathologic complete response (pCR) rate in WT as compared with that in MT PIK3CA tumors (OR = 1.72; 95 % CI 1.29-2.13; P < 0.001). In that setting, there was no disease-free or overall survival difference based on PIK3CA mutational status. In this meta-analysis, AHT did not achieve differential benefit according to PIK3CA mutation in HER2-positive metastatic or early breast cancer; however, in the neoadjuvant setting, patients harboring WT PIK3CA tumors attained a higher pCR rate.

  19. Molecular cloning, cDNA sequence, and chromosomal localization of the human phosphatidylinositol 3-kinase p110{alpha} (PIK3CA) gene

    SciTech Connect

    Volinia, S.; Hiles, I.; Waterfield, M.D.

    1994-12-01

    Phosphatidylinositol (PI) 3-kinase is a heterodimeric enzyme comprising a 110-kDa catalytic subunit and an 85-kDa regulatory subunit that binds to tyrosine phosphopeptide sites linked directly or indirectly to receptors serving diverse signal functions. Knowledge of the structure and function of PI 3-kinase was greatly advanced by the purification, cDNA cloning, and subsequent expression of the bovine enzyme. Here the cloning of the cDNA for the human p110{alpha}subunit of PI 3-kinase (PIK3CA), encoding a protein 99% identical to the bovine p110, and of its gene in YAC is described. The chromosomal localization of the gene for PIK3CA is shown to be at 3q21-qter as determined using somatic cell hybrids. In situ hybridization performed using Alu-PCR from the YAC DNA located the gene in 3q26.3. 30 refs., 3 figs., 1 tab.

  20. Characterization of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next generation sequencing study

    PubMed Central

    Mirzaa, Ghayda; Conti, Valerio; Timms, Andrew E.; Smyser, Christopher D.; Ahmed, Sarah; Carter, Melissa; Barnett, Sarah; Hufnagel, Robert B.; Goldstein, Amy; Narumi-Kishimoto, Yoko; Olds, Carissa; Collins, Sarah; Johnston, Kathreen; Deleuze, Jean-François; Nitschké, Patrick; Friend, Kathryn; Harris, Catharine; Goetsch, Allison; Martin, Beth; Boyle, Evan August; Parrini, Elena; Mei, Davide; Tattini, Lorenzo; Slavotinek, Anne; Blair, Ed; Barnett, Christopher; Shendure, Jay; Chelly, Jamel; Dobyns, William B.; Guerrini, Renzo

    2015-01-01

    SUMMARY Background Bilateral perisylvian polymicrogyria (BPP), the most common form of regional polymicrogyria, causes the congenital bilateral perisylvian syndrome, featuring oromotor dysfunction, cognitive impairment and epilepsy. BPP is etiologically heterogeneous, but only a few genetic causes have been reported. The aim of this study was to identify additional genetic etiologies of BPP and delineate their frequency in this patient population. Methods We performed child-parent (trio)-based whole exome sequencing (WES) on eight children with BPP. Following the identification of mosaic PIK3R2 mutations in two of these eight children, we performed targeted screening of PIK3R2 in a cohort of 118 children with BPP who were ascertained from 1980 until 2015 using two methods. First, we performed targeted sequencing of the entire PIK3R2 gene by single molecule molecular inversion probes (smMIPs) on 38 patients with BPP with normal-large head size. Second, we performed amplicon sequencing of the recurrent PIK3R2 mutation (p.Gly373Arg) on 80 children with various types of polymicrogyria including BPP. One additional patient underwent clinical WES independently, and was included in this study given the phenotypic similarity to our cohort. All patients included in this study were children (< 18 years of age) with polymicrogyria enrolled in our research program. Findings Using WES, we identified a mosaic mutation (p.Gly373Arg) in the regulatory subunit of the PI3K-AKT-MTOR pathway, PIK3R2, in two children with BPP. Of the 38 patients with BPP and normal-large head size who underwent targeted next generation sequencing by smMIPs, we identified constitutional and mosaic PIK3R2 mutations in 17 additional children. In parallel, one patient was found to have the recurrent PIK3R2 mutation by clinical WES. Seven patients had BPP alone, and 13 had BPP in association with features of the megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH). Nineteen patients had

  1. 77 FR 33094 - Safety Zone; International Bridge 50th Anniversary Celebration Fireworks, St. Mary's River, U.S...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-05

    ... Celebration Fireworks, St. Mary's River, U.S. Army Corps of Engineers Locks, Sault Sainte Marie, MI AGENCY..., Sault Sainte Marie, MI; in the Federal Register (77 FR 21893). We received 1 public submission... Locks, Sault Sainte Marie, MI; in the Federal Register (76 FR 22064). We received 1 public...

  2. Mary Edwards Walker: the soul ahead of her time.

    PubMed

    Rehman, Atiq; Rahman, Naba G; Harris, Sharon M; Cheema, Faisal H

    2015-02-01

    Mary Edwards Walker was a gallant woman who stood for women's rights, embodied the true American spirit, and served the Union Army in the Civil War as a surgeon. She later became the first and only woman in United States history to be awarded the Congressional Medal of Honor.

  3. Mary Petroline Lovato: Courage and Compassion Conquer Cancer.

    ERIC Educational Resources Information Center

    Yuhas, Stephanie

    1998-01-01

    A survivor of leukemia, Mary Lovato has used support groups, fundraising, and workshops to educate Pueblo and other Native people about treatment and management of cancer and has made significant progress in breaking the silence that surrounds the disease among her people. (SAS)

  4. Stirring the Waters: The Influence of Marie Clay.

    ERIC Educational Resources Information Center

    Gaffney, Janet S., Ed.; Askew, Billie J., Ed.

    Celebrating Marie Clay as a major theorist of child literacy acquisition, this book presents 15 essays by distinguished scholars that reflect on her contributions to the field of early literacy; early childhood, bilingual, and special education; developmental, cognitive, and school psychology; assessment; teacher education; professional…

  5. Mary E. Hall: Dawn of the Professional School Librarian

    ERIC Educational Resources Information Center

    Alto, Teresa

    2012-01-01

    A century ago, a woman named Mary E. Hall convinced school leaders of the need for the professional school librarian--a librarian who cultivated a love of reading, academic achievement, and independent learning skills. After graduating from New York City's Pratt Institute Library School in 1895, Hall developed her vision for the high school…

  6. Mary Lyon and Mount Holyoke. Opening the Gates.

    ERIC Educational Resources Information Center

    Green, Elizabeth Alden

    The efforts of Mary Lyon, virtually singlehandedly, to raise money, recruit students, and plan the academic development of Mount Holyoke Female Seminary, founded in 1837, are detailed in this book. The founder sought to educate women through rigorous application of the intellect, which she believed to lead to salvation. In doing so she…

  7. Mary's Story: A Curriculum for Teaching Medical Terminology.

    ERIC Educational Resources Information Center

    Pennsylvania State Univ., University Park. Inst. for the Study of Adult Literacy.

    This packet of materials for a class on medical terminology consists of a collection of stories with highlighted vocabulary, teacher's guide, and student's guide. The materials teach medical terms in a series of stories about a woman named Mary Consola. Each story begins with a list of word parts that will be learned; after the story, new word…

  8. Case Study of a College that Closed: Saint Mary's College

    ERIC Educational Resources Information Center

    Brown, Alice W.

    2011-01-01

    Few colleges choose to close. One that did was Saint Mary's College in Raleigh, North Carolina. Although trustees resisted for a decade, they ultimately made the decision before an anticipated denial of accreditation, allowing the college to control its final days in ways not possible for those who wait until an outside agency forces closure. This…

  9. 6. Photo copy of photograph, (original owned by Mary Gaudineer, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    6. Photo copy of photograph, (original owned by Mary Gaudineer, Beckley, WV, copy at National Forest Office, Elkins, WV), Don Gaudineer, 1934. CONSTRUCTION OF FERNOW EXPERIMENTAL FOREST BUNKHOUSE AND GARAGE. (see also historic photograph WV-237-13) - Parsons Nursery, Fernow Experimental Forest Residence, South side of U.S. Route 219, Parsons, Tucker County, WV

  10. A Day in the Life of Mary Cassatt.

    ERIC Educational Resources Information Center

    Stoppel, Julie

    2002-01-01

    Offers a way to present art history to classroom students where the art teacher pretends to be an artist. Focuses on a lesson where the teacher pretended to be Mary Cassatt. States that the students used pastels when drawing their artwork, in conjunction with the art history lesson. (CMK)

  11. Collection Development Policy: Academic Library, St. Mary's University. Revised.

    ERIC Educational Resources Information Center

    Sylvia, Margaret

    This guide spells out the collection development policy of the library of St. Mary's University in San Antonio, Texas. The guide is divided into the following five topic areas: (1) introduction to the community served, parameters of the collection, cooperation in collection development, and priorities of the collection; (2) considerations in…

  12. 39. Photographic copy of photographs (orignals in possession of Mary ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    39. Photographic copy of photographs (orignals in possession of Mary A. Vreeland), photographer not stated UPPER LEFT AND RIGHT: DINING ROOM AND PARLOR DECORATED FOR CHRISTMAS, CIRCA 1979 LOWER LEFT: VIEW SOUTHEAST, REAR DOOR, CIRCA 1930s LOWER RIGHT: VIEW NORTHWEST, FRONT ELEVATION, CIRCA 1930s - Cadmus House, 159 Fairfield Avenue, West Caldwell, Essex County, NJ

  13. Diaphragm weakness in Charcot-Marie-Tooth disease.

    PubMed Central

    Laroche, C M; Carroll, N; Moxham, J; Stanley, N N; Evans, R J; Green, M

    1988-01-01

    Two patients are described with Charcot-Marie-Tooth disease and chronic peripheral neuropathy. Both had dyspnoea, orthopnoea, and evidence of severe diaphragm weakness. Expiratory muscle function was well preserved and abnormalities of gas exchange during sleep were only minor. PMID:3420560

  14. The "Special" Way: Mary Paxton and Her Journalism Degree.

    ERIC Educational Resources Information Center

    Flocke, Elizabeth Lynne

    The only woman in the first graduating class of the world's first school of journalism at the University of Missouri, Mary Paxton Keeley was offered a position as a special reporter for the "Kansas City Post" in 1910. As was typical for female journalists at the time, most of Paxton's assignments during her 15 months with the…

  15. Response to Mary J. Reichling, "Intersections: Form, Feeling, and Isomorphism"

    ERIC Educational Resources Information Center

    Stevenson, David

    2004-01-01

    David Stevenson's thoughts regarding Reichling's essay are offered in this article, and he begins his response by saying that Mary J. Reichling's essay regarding the three concepts, form, feeling, and isomorphism, is lucid, well structured, and aptly supported by research of other music education philosophers. He points out that Reichling states…

  16. Case Study of a College that Closed: Saint Mary's College

    ERIC Educational Resources Information Center

    Brown, Alice W.

    2011-01-01

    Few colleges choose to close. One that did was Saint Mary's College in Raleigh, North Carolina. Although trustees resisted for a decade, they ultimately made the decision before an anticipated denial of accreditation, allowing the college to control its final days in ways not possible for those who wait until an outside agency forces closure. This…

  17. Mari Belajar Sopan Santun Bahasa Indonesia. [Multimedia Kit

    ERIC Educational Resources Information Center

    DuFon, Margaret A.

    2004-01-01

    Filmed on location in East Java, Indonesia, the Mari Belajar Sopan Santun Bahasa Indonesia set consists of two videotapes, a manual, and extended notes on the individual video scenarios. The videos present interactions among Indonesian native speakers and foreign language learners as they engage in tasks and activities of everyday life. The…

  18. The "Special" Way: Mary Paxton and Her Journalism Degree.

    ERIC Educational Resources Information Center

    Flocke, Elizabeth Lynne

    The only woman in the first graduating class of the world's first school of journalism at the University of Missouri, Mary Paxton Keeley was offered a position as a special reporter for the "Kansas City Post" in 1910. As was typical for female journalists at the time, most of Paxton's assignments during her 15 months with the…

  19. Lift as You Climb: A Profile of President Mary Vosevich

    ERIC Educational Resources Information Center

    Blumenthal, Anita

    2012-01-01

    "My thumb got me into this!" declares the new APPA President Mary Vosevich when asked how she entered the field of educational facilities management. It was 1984, and Vosevich, a Midwest native, was working at Monsanto in St. Louis as a research biologist, having earned her B.S. in horticulture/agriculture from the University of…

  20. Astronaut Mary Ellen Weber during training session in WETF

    NASA Image and Video Library

    1994-05-01

    Attired in a training version of the Extravehicular Mobility Unit (EMU), Astronaut Mary Ellen Weber participates in a training session at JSC's Weightless Environment Training Facility (WETF). Training as a mission specialist for the STS-70 mission, Weber was about to rehearse a contingency space walk. One of several SCUBA-equipped divers waits to assist in the rehearsal in the water.

  1. William and Mary's President Exits on His Own Terms

    ERIC Educational Resources Information Center

    Fain, Paul

    2008-01-01

    The president and governing board at the College of William and Mary have parted ways in an unusually public split with a deeply partisan undercurrent. Gene R. Nichol says that the Board of Visitors forced him out for defending free speech and diversity on the campus, and that he turned down a generous severance package to go quietly. Board…

  2. Lift as You Climb: A Profile of President Mary Vosevich

    ERIC Educational Resources Information Center

    Blumenthal, Anita

    2012-01-01

    "My thumb got me into this!" declares the new APPA President Mary Vosevich when asked how she entered the field of educational facilities management. It was 1984, and Vosevich, a Midwest native, was working at Monsanto in St. Louis as a research biologist, having earned her B.S. in horticulture/agriculture from the University of…

  3. Romanticism or Reality? An Exploration of Frances Mary Hendry's "Chandra."

    ERIC Educational Resources Information Center

    Johnson, Jilaine

    This paper singles out a novel written for children about India, "Chandra" (1995) by Frances Mary Hendry, as a powerful and useful novel to present to today's 11 to 14 year old students. The paper contends that the novel allows students to explore and consider different value systems, challenges them to become aware of prejudice and the…

  4. The Mary Kay Way: The Feminization of a Corporate Discourse.

    ERIC Educational Resources Information Center

    Banks, Jane; Zimmerman, Patricia R.

    1987-01-01

    Investigates the strategies by which corporations adapt to social and cultural change. Argues that the contradiction between the ideology of the nuclear family and women's real needs for economic sustenance and autonomy are separated and deflected into a specific discursive strategy in the operation of Mary Kay Cosmetics. (JD)

  5. The Mary Kay Way: The Feminization of a Corporate Discourse.

    ERIC Educational Resources Information Center

    Banks, Jane; Zimmerman, Patricia R.

    1987-01-01

    Investigates the strategies by which corporations adapt to social and cultural change. Argues that the contradiction between the ideology of the nuclear family and women's real needs for economic sustenance and autonomy are separated and deflected into a specific discursive strategy in the operation of Mary Kay Cosmetics. (JD)

  6. Mary Somerville, mathematician and astronomer of underused talents

    NASA Astrophysics Data System (ADS)

    Bruck, M. T.

    1996-08-01

    Mary Somerville (1780-1872), self-taught mathematician, expert on theoretical astronomy and successful writer, has been described as `the most remarkable woman of her generation'. The publication of her mathematical treatise The Mechanism of the Heavens in 1831, followed by the more popular Connexion of the Physical Sciences in 1834, made her an international celebrity. Her life and work is described.

  7. William and Mary's President Exits on His Own Terms

    ERIC Educational Resources Information Center

    Fain, Paul

    2008-01-01

    The president and governing board at the College of William and Mary have parted ways in an unusually public split with a deeply partisan undercurrent. Gene R. Nichol says that the Board of Visitors forced him out for defending free speech and diversity on the campus, and that he turned down a generous severance package to go quietly. Board…

  8. Astronaut Mary Ellen Weber deploys life raft during bailout training

    NASA Image and Video Library

    1995-02-16

    S95-03501 (16 FEB 1995) --- Astronaut Mary Ellen Weber prepares to deploy a life raft during a training session at the Johnson Space Center's (JSC) Weightless Environment Training Facility (WET-F). Training as a mission specialist for the STS-70 mission, Weber was joined by four crew mates in the emergency bailout rehearsal.

  9. Astronaut Mary Ellen Weber during training session in WETF

    NASA Image and Video Library

    1994-05-01

    Attired in a training version of the Extravehicular Mobility Unit (EMU), astronaut Mary Ellen Weber gets help with the final touches of suit donning during a training session at JSC's Weightless Environment Training Facility (WETF). Training as a mission specialist for the STS-70 mission, Weber was about to rehearse a contingency space walk.

  10. The Rhetoric of Mary Daly: The Rhetoric of Naming.

    ERIC Educational Resources Information Center

    Larson, Suzanne

    As an initial step toward discovering whether a separate genre of women's rhetoric exists, this paper analyzes rhetorical forms used by Mary Daly in the book "Gyn/Ecology." The paper first outlines criteria for determining whether a form has rhetorical significance and traces the historical background of the contemporary feminist…

  11. Missionary Education in Colonial Africa: The Critique of Mary Kingsley.

    ERIC Educational Resources Information Center

    Pearce, Robert

    1988-01-01

    Discussing missionary education in colonial Africa, Pearce examines the ideas of Mary Kingsley, one of the major influences on British thinking towards Africa from the late 1890's. Focusing attention on her educational views, Pearce states that she had influence on all areas of British policy in Africa, and especially West Africa. (GEA)

  12. Measuring Ankle Instability in Pediatric Charcot-Marie-Tooth Disease.

    PubMed

    Mandarakas, Melissa; Hiller, Claire E; Rose, Kristy J; Burns, Joshua

    2013-11-01

    Children with Charcot-Marie-Tooth disease frequently suffer ankle sprain and experience chronic ankle instability; however, no pediatric self-reported measures of chronic ankle instability exist. The aim was to modify and validate the most reliable measure of chronic ankle instability in adults: the Cumberland Ankle Instability Tool. The Cumberland Ankle Instability Tool-Youth was tested for reliability, construct validity, and sensitivity to discriminate between 104 children aged 8 to 16 years: 31 children with Charcot-Marie-Tooth disease, 31 unaffected children with a history of ankle sprains, and 42 controls. Children with Charcot-Marie-Tooth disease had lower scores compared to unaffected children with a history of sprains (χ(2) = 15.10; P < .001) and controls (χ(2) = 33.69; P < .001). Scores moderately correlated to visual analog scale scores of ankle steadiness (r s = 0.684; P < .001), and "good" test-retest reliability was identified (ICC2,1 = 0.73). The Cumberland Ankle Instability Tool-Youth demonstrated excellent sensitivity and construct validity, identifying chronic ankle instability as a common problem for children with Charcot-Marie-Tooth disease.

  13. Mary Petroline Lovato: Courage and Compassion Conquer Cancer.

    ERIC Educational Resources Information Center

    Yuhas, Stephanie

    1998-01-01

    A survivor of leukemia, Mary Lovato has used support groups, fundraising, and workshops to educate Pueblo and other Native people about treatment and management of cancer and has made significant progress in breaking the silence that surrounds the disease among her people. (SAS)

  14. Missionary Education in Colonial Africa: The Critique of Mary Kingsley.

    ERIC Educational Resources Information Center

    Pearce, Robert

    1988-01-01

    Discussing missionary education in colonial Africa, Pearce examines the ideas of Mary Kingsley, one of the major influences on British thinking towards Africa from the late 1890's. Focusing attention on her educational views, Pearce states that she had influence on all areas of British policy in Africa, and especially West Africa. (GEA)

  15. M-ARY POISSON DETECTION AND OPTICAL COMMUNICATIONS.

    DTIC Science & Technology

    noise. When the observables correspond to counts of emitted photoelectrons, the problem models a discrete version of a coherent M-ary optical ... communication system using photon counters in the presence of background radiation. Consideration is given to an average distance and a detection probability

  16. Mary E. Hall: Dawn of the Professional School Librarian

    ERIC Educational Resources Information Center

    Alto, Teresa

    2012-01-01

    A century ago, a woman named Mary E. Hall convinced school leaders of the need for the professional school librarian--a librarian who cultivated a love of reading, academic achievement, and independent learning skills. After graduating from New York City's Pratt Institute Library School in 1895, Hall developed her vision for the high school…

  17. Mari Belajar Sopan Santun Bahasa Indonesia. [Multimedia Kit

    ERIC Educational Resources Information Center

    DuFon, Margaret A.

    2004-01-01

    Filmed on location in East Java, Indonesia, the Mari Belajar Sopan Santun Bahasa Indonesia set consists of two videotapes, a manual, and extended notes on the individual video scenarios. The videos present interactions among Indonesian native speakers and foreign language learners as they engage in tasks and activities of everyday life. The…

  18. Stirring the Waters: The Influence of Marie Clay.

    ERIC Educational Resources Information Center

    Gaffney, Janet S., Ed.; Askew, Billie J., Ed.

    Celebrating Marie Clay as a major theorist of child literacy acquisition, this book presents 15 essays by distinguished scholars that reflect on her contributions to the field of early literacy; early childhood, bilingual, and special education; developmental, cognitive, and school psychology; assessment; teacher education; professional…

  19. Sister Mary Joseph's nodule that originated from lung adenocarcinoma.

    PubMed

    Haruki, Tomohiro; Nakamura, Hiroshige; Kubouchi, Yasuaki; Taniguchi, Yuji; Miwa, Ken; Adachi, Yoshin; Fujioka, Shinji; Ito, Hisao

    2011-03-01

    Umbilical metastasis of cancer, known as Sister Mary Joseph's nodule (SMJN), is a rare phenomenon. It is usually due to intraabdominal malignancies and is quite rare from lung cancer. Here we describe a case of SMJN that originated from advanced lung adenocarcinoma. SMJN should be noted as an important sign of some hidden malignancy including lung cancer.

  20. The Rhetoric of Mary Daly: The Rhetoric of Naming.

    ERIC Educational Resources Information Center

    Larson, Suzanne

    As an initial step toward discovering whether a separate genre of women's rhetoric exists, this paper analyzes rhetorical forms used by Mary Daly in the book "Gyn/Ecology." The paper first outlines criteria for determining whether a form has rhetorical significance and traces the historical background of the contemporary feminist…

  1. Investigating the Inhibitory Effect of Wortmannin in the Hotspot Mutation at Codon 1047 of PIK3CA Kinase Domain: A Molecular Docking and Molecular Dynamics Approach.

    PubMed

    Kumar, D Thirumal; Doss, C George Priya

    2016-01-01

    Oncogenic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) are the most frequently reported in association with various forms of cancer. Several studies have reported the significance of hotspot mutations in a catalytic subunit of PIK3CA in association with breast cancer. Mutations are frequently observed in the highly conserved region of the kinase domain (797-1068 amino acids) of PIK3CA are activating or gain-of-function mutations. Mutation in codon 1047 occurs in the C-terminal region of the kinase domain with histidine (H) replaced by arginine (R), lysine (L), and tyrosine (Y). Pathogenicity and protein stability predictors PhD-SNP, Align GVGD, HANSA, iStable, and MUpro classified H1047R as highly deleterious when compared to H1047L and H1047Y. To explore the inhibitory activity of Wortmannin toward PIK3CA, the three-dimensional structure of the mutant protein was determined using homology modeling followed by molecular docking and molecular dynamics analysis. Docking studies were performed for the three mutants and native with Wortmannin to measure the differences in their binding pattern. Comparative docking study revealed that H1047R-Wortmannin complex has a higher number of hydrogen bonds as well as the best binding affinity next to the native protein. Furthermore, 100 ns molecular dynamics simulation was initiated with the docked complexes to understand the various changes induced by the mutation. Though Wortmannin was found to nullify the effect of H1047R over the protein, further studies are required for designing a better compound. As SNPs are major genetic variations observed in disease condition, personalized medicine would provide enhanced drug therapy.

  2. Molecular spectrum of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC somatic gene mutations in Arab patients with colorectal cancer: determination of frequency and distribution pattern

    PubMed Central

    Al-Shamsi, Humaid O.; Jones, Jeremy; Fahmawi, Yazan; Dahbour, Ibrahim; Tabash, Aziz; Abdel-Wahab, Reham; Abousamra, Ahmed O. S.; Shaw, Kenna R.; Xiao, Lianchun; Hassan, Manal M.; Kipp, Benjamin R.; Kopetz, Scott; Soliman, Amr S.; McWilliams, Robert R.; Wolff, Robert A.

    2016-01-01

    Background The frequency rates of mutations such as KRAS, NRAS, BRAF, and PIK3CA in colorectal cancer (CRC) differ among populations. The aim of this study was to assess mutation frequencies in the Arab population and determine their correlations with certain clinicopathological features. Methods Arab patients from the Arab Gulf region and a population of age- and sex-matched Western patients with CRC whose tumors were evaluated with next-generation sequencing (NGS) were identified and retrospectively reviewed. The mutation rates of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC were recorded, along with clinicopathological features. Other somatic mutation and their rates were also identified. Fisher’s exact test was used to determine the association between mutation status and clinical features. Results A total of 198 cases were identified; 99 Arab patients and 99 Western patients. Fifty-two point seven percent of Arab patients had stage IV disease at initial presentation, 74.2% had left-sided tumors. Eighty-nine point two percent had tubular adenocarcinoma and 10.8% had mucinous adenocarcinoma. The prevalence rates of KRAS, NRAS, BRAF, PIK3CA, TP53, APC, SMAD, FBXW7 mutations in Arab population were 44.4%, 4%, 4%, 13.1%, 52.5%, 27.3%, 2% and 3% respectively. Compared to 48.4%, 4%, 4%, 12.1%, 47.5%, 24.2%, 11.1% and 0% respectively in matched Western population. Associations between these mutations and patient clinicopathological features were not statistically significant. Conclusions This is the first study to report comprehensive hotspot mutations using NGS in Arab patients with CRC. The frequency of KRAS, NRAS, BRAF, TP53, APC and PIK3CA mutations were similar to reported frequencies in Western population except SMAD4 that had a lower frequency and higher frequency of FBXW7 mutation. PMID:28078112

  3. Gain-of-function mutation in PIK3R1 in a patient with a narrow clinical phenotype of respiratory infections.

    PubMed

    Martínez-Saavedra, María Teresa; García-Gomez, Sonia; Domínguez Acosta, Ana; Mendoza Quintana, Juan Jesús; Páez, Jesús Poch; García-Reino, Eduardo J; Camps, Gracián; Martinez-Barricarte, Rubén; Itan, Yuval; Boisson, Bertrand; Sánchez-Ramón, Silvia; Regueiro, José Ramón; Casanova, Jean-Laurent; Rodríguez-Gallego, Carlos; Pérez de Diego, Rebeca

    2016-12-01

    Antibody deficiencies can be caused by a variety of defects that interfere with B-cell development, maturation, and/or function. Using whole-exome sequencing we found a PIK3R1 mutation in a patient with hypogammaglobulinemia and a narrow clinical phenotype of respiratory infections. Early diagnosis is crucial; careful analysis of B and T-cells followed by genetic analyses may help to distinguish activated PI3K-delta syndrome (APDS) from other, less severe, predominantly antibody deficiencies.

  4. Molecular spectrum of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC somatic gene mutations in Arab patients with colorectal cancer: determination of frequency and distribution pattern.

    PubMed

    Al-Shamsi, Humaid O; Jones, Jeremy; Fahmawi, Yazan; Dahbour, Ibrahim; Tabash, Aziz; Abdel-Wahab, Reham; Abousamra, Ahmed O S; Shaw, Kenna R; Xiao, Lianchun; Hassan, Manal M; Kipp, Benjamin R; Kopetz, Scott; Soliman, Amr S; McWilliams, Robert R; Wolff, Robert A

    2016-12-01

    The frequency rates of mutations such as KRAS, NRAS, BRAF, and PIK3CA in colorectal cancer (CRC) differ among populations. The aim of this study was to assess mutation frequencies in the Arab population and determine their correlations with certain clinicopathological features. Arab patients from the Arab Gulf region and a population of age- and sex-matched Western patients with CRC whose tumors were evaluated with next-generation sequencing (NGS) were identified and retrospectively reviewed. The mutation rates of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC were recorded, along with clinicopathological features. Other somatic mutation and their rates were also identified. Fisher's exact test was used to determine the association between mutation status and clinical features. A total of 198 cases were identified; 99 Arab patients and 99 Western patients. Fifty-two point seven percent of Arab patients had stage IV disease at initial presentation, 74.2% had left-sided tumors. Eighty-nine point two percent had tubular adenocarcinoma and 10.8% had mucinous adenocarcinoma. The prevalence rates of KRAS, NRAS, BRAF, PIK3CA, TP53, APC, SMAD, FBXW7 mutations in Arab population were 44.4%, 4%, 4%, 13.1%, 52.5%, 27.3%, 2% and 3% respectively. Compared to 48.4%, 4%, 4%, 12.1%, 47.5%, 24.2%, 11.1% and 0% respectively in matched Western population. Associations between these mutations and patient clinicopathological features were not statistically significant. This is the first study to report comprehensive hotspot mutations using NGS in Arab patients with CRC. The frequency of KRAS, NRAS, BRAF, TP53, APC and PIK3CA mutations were similar to reported frequencies in Western population except SMAD4 that had a lower frequency and higher frequency of FBXW7 mutation.

  5. Mutually exclusive mutations in NOTCH1 and PIK3CA associated with clinical prognosis and chemotherapy responses of esophageal squamous cell carcinoma in China

    PubMed Central

    Song, Bin; Cui, Heyang; Li, Yaoping; Cheng, Caixia; Yang, Bin; Wang, Fang; Kong, Pengzhou; Li, Hongyi; Zhang, Ling; Jia, Zhiwu; Bi, Yanghui; Wang, Jiaqian; Zhou, Yong; Liu, Jing; Wang, Juan; Zhao, Zhenxiang; Zhang, Yanyan; Hu, Xiaoling; Shi, Ruyi; Yang, Jie; Liu, Haiyan; Yan, Ting; Li, Yike; Xu, Enwei; Qian, Yu; Xi, Yanfeng; Guo, Shiping; Chen, Yunqing; Wang, Jinfen; Li, Guodong; Liang, Jianfang; Jia, Junmei; Chen, Xing; Guo, Jiansheng; Wang, Tong; Zhang, Yanbo; Li, Qingshan; Wang, Chuangui; Cheng, Xiaolong; Zhan, Qimin; Cui, Yongping

    2016-01-01

    Background Recurrent genetic abnormalities that correlate with clinical features could be used to determine patients' prognosis, select treatments and predict responses to therapy. Esophageal squamous cell carcinoma (ESCC) contains genomic alterations of undefined clinical significance. We aimed to identify mutually exclusive mutations that are frequently detected in ESCCs and characterized their associations with clinical variables. Methods We analyzed next-generation-sequencing data from 104 ESCCs from Taihang Mountain region of China; 96 pairs were selected for deep target-capture-based validation and analysis of clinical and pathology data. We used model proposed by Szczurek to identify exclusive mutations and to associate these with pathology findings. Univariate and multivariate analyses with Cox proportional hazards model were used to examine the association between mutations and overall survival and response to chemotherapy. Findings were validated in an analysis of samples from 89 patients with ESCC from Taihang Mountain. Results We identified statistically significant mutual exclusivity between mutations in NOTCH1 and PIK3CA in ESCC samples. Mutations in NOTCH1 were associated with well-differentiated, early-stage malignancy and less metastasis to regional lymph nodes. Nonetheless, patients with NOTCH1 mutations had shorter survival times than patients without NOTCH1 mutations, and failed to respond to chemotherapy. In contrast, patients with mutations in PIK3CA had better responses to chemotherapy and longer survival times than patients without PIK3CA mutations. Conclusions In a genetic analysis of ESCCs from patients in China, we identified mutually exclusive mutations in NOTCH1 and PIK3CA. These findings might increase our understanding of ESCC development and be used as prognostic factors. PMID:26528858

  6. The Structural Basis for Substrate Anchoring, Active Site Selectivity, and Product Formation by P450 PikC from Streptomyces venezuelae

    PubMed Central

    Sherman, David H.; Li, Shengying; Yermalitskaya, Liudmila V.; Kim, Youngchang; Smith, Jarrod A.; Waterman, Michael R.; Podust, Larissa M.

    2010-01-01

    The pikromycin (Pik)/methymycin biosynthetic pathway of Streptomyces venezuelae represents a valuable system for dissecting the fundamental mechanisms of modular polyketide biosynthesis, aminodeoxysugar assembly, glycosyltransfer, and hydroxylation leading to the production of a series of macrolide antibiotics, including the natural ketolides narbomycin and pikromycin. In this study, we describe four x-ray crystal structures and allied functional studies for PikC, the remarkable P450 monooxygenase responsible for production of a number of related macrolide products from the Pik pathway. The results provide important new insights into the structural basis for the C10/C12, and C12/C14 hydroxylation patterns for the 12- (YC-17) and 14-membered ring (narbomycin) macrolides, respectively. This includes two different ligand-free structures in an asymmetric unit (resolution 2.1 Å) and two co-crystal structures with bound endogenous substrates YC-17 (resolution 2.35 Å) or narbomycin (resolution 1.7 Å). A central feature of the enzyme-substrate interaction involves anchoring of the desosamine residue in two alternative binding pockets based on a series of distinct amino acid residues that form a salt bridge and a hydrogen bonding network with the deoxysugar C3′ dimethylamino group. Functional significance of the salt bridge was corroborated by site-directed mutagenesis that revealed a key role for E94 in YC-17 binding, and E85 for narbomycin binding. Taken together, the x-ray structure analysis, site-directed mutagenesis and corresponding product distribution studies reveal that PikC substrate tolerance, and product diversity result from a combination of alternative anchoring modes, rather than an induced fit mechanism. PMID:16825192

  7. Frequent detection of PIK3CA mutations in single circulating tumor cells of patients suffering from HER2-negative metastatic breast cancer.

    PubMed

    Gasch, Christin; Oldopp, Theresa; Mauermann, Oliver; Gorges, Tobias M; Andreas, Antje; Coith, Cornelia; Müller, Volkmar; Fehm, Tanja; Janni, Wolfgang; Pantel, Klaus; Riethdorf, Sabine

    2016-10-01

    Modern technologies enable detection and characterization of circulating tumor cells (CTC) in peripheral blood samples. Thus, CTC have attracted interest as markers for therapeutic response in breast cancer. First studies have incorporated CTC analyses to guide therapeutic interventions and stratification of breast cancer patients. Aim of this study was to analyze characteristic features of CTC as biomarker for predicting resistance to HER2-targeted therapies. Therefore, CTC from metastatic breast cancer patients with HER2-negative primary tumors screened for the prospective randomized phase III trial DETECT III were explored for their HER2 status and the presence of PIK3CA mutations. Detection and characterization of HER2 expression of CTC were conducted with the CellSearch(®) system. Fifteen of 179 CTC-positive patients (8.4%) contained ≥1 CTC with strong HER2 expression. Genomic DNA from individual CTC isolated by micromanipulation was propagated by whole genome amplification and analyzed for PIK3CA mutations in exons 9 and 20 by Sanger sequencing. One or more CTC/7.5 mL were detected in 179/290 patients (61.7%). In 109 patients (34.8%), ≥5 CTC/7.5 mL were found. We detected at least one CTC with the mutation p.E542K, p.E545K, p.H1047R, p.H1047L or p.M1043V in 12/33 patients (36.4%). Thirty six of 114 CTC (31.6%) harbored one of these mutations. CTC in individual patients exhibited heterogeneity concerning PIK3CA mutations and HER2 expression. In conclusion, clinically relevant genomic aberrations such as mutations in the hotspot regions of exon 9 and 20 of the PIK3CA gene can be detected in single CTC and might provide insights into mechanisms of resistance to HER2-targeted therapies.

  8. The structural basis for substrate anchoring, active site selectivity, and product formation by P450 PikC from Streptomyces venezuelae.

    PubMed

    Sherman, David H; Li, Shengying; Yermalitskaya, Liudmila V; Kim, Youngchang; Smith, Jarrod A; Waterman, Michael R; Podust, Larissa M

    2006-09-08

    The pikromycin (Pik)/methymycin biosynthetic pathway of Streptomyces venezuelae represents a valuable system for dissecting the fundamental mechanisms of modular polyketide biosynthesis, aminodeoxysugar assembly, glycosyltransfer, and hydroxylation leading to the production of a series of macrolide antibiotics, including the natural ketolides narbomycin and pikromycin. In this study, we describe four x-ray crystal structures and allied functional studies for PikC, the remarkable P450 monooxygenase responsible for production of a number of related macrolide products from the Pik pathway. The results provide important new insights into the structural basis for the C10/C12 and C12/C14 hydroxylation patterns for the 12-(YC-17) and 14-membered ring (narbomycin) macrolides, respectively. This includes two different ligand-free structures in an asymmetric unit (resolution 2.1 A) and two co-crystal structures with bound endogenous substrates YC-17 (resolution 2.35 A)or narbomycin (resolution 1.7 A). A central feature of the enzyme-substrate interaction involves anchoring of the desosamine residue in two alternative binding pockets based on a series of distinct amino acid residues that form a salt bridge and a hydrogen-bonding network with the deoxysugar C3' dimethylamino group. Functional significance of the salt bridge was corroborated by site-directed mutagenesis that revealed a key role for Glu-94 in YC-17 binding and Glu-85 for narbomycin binding. Taken together, the x-ray structure analysis, site-directed mutagenesis, and corresponding product distribution studies reveal that PikC substrate tolerance and product diversity result from a combination of alternative anchoring modes rather than an induced fit mechanism.

  9. MicroRNA-432 targeting E2F3 and P55PIK inhibits myogenesis through PI3K/AKT/mTOR signaling pathway.

    PubMed

    Ma, Meilin; Wang, Xiangming; Chen, Xiaochang; Cai, Rui; Chen, Fenfen; Dong, Wuzi; Yang, Gongshe; Pang, Weijun

    2017-03-04

    Skeletal muscle is the dominant executant in locomotion and regulator in energy metabolism. Embryonic myogenesis and postnatal muscle growth are controlled by a cascade of transcription factors and epigenetic regulatory mechanisms. MicroRNAs (miRNAs), a family of non-coding RNA of 22 nucleotides in length, post-transcriptionally regulates expression of mRNA by pairing the seed sequence to 3' UTR of target mRNA. Increasing evidence has demonstrated that miRNAs are important regulators in diverse myogenic processes. The profiling of miRNA expression revealed that miR-432 is more enriched in the longissimus dorsi of 35-day-old piglets than that of adult pigs. Our gain of function study showed that miR-432 can negatively regulate both myoblast proliferation and differentiation. Mechanically, we found that miR-432 is able to down-regulate E2F transcription factor 3 (E2F3) to inactivate the expression of cell cycle and myogenic genes. We also identified that phosphatidylinositol 3-kinase regulatory subunit (P55PIK) is another target gene of miR-432 in muscle cells. downregulation of P55PIK by miR-432 leads to inhibition of P55PIK-mediated PI3K/AKT/mTOR signaling pathway during differentiation. The blocking effect of miR-432 on this pathway can be rescued by insulin treatment. Taken together, our findings identified microRNA-432 as a potent inhibitor of myogenesis which functions by targeting E2F3 and P55PIK in muscle cells.

  10. Germline PTPN11 and somatic PIK3CA variant in a boy with megalencephaly-capillary malformation syndrome (MCAP)--pure coincidence?

    PubMed

    Döcker, Dennis; Schubach, Max; Menzel, Moritz; Spaich, Christiane; Gabriel, Heinz-Dieter; Zenker, Martin; Bartholdi, Deborah; Biskup, Saskia

    2015-03-01

    Megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth syndrome that is diagnosed by clinical criteria. Recently, somatic and germline variants in genes that are involved in the PI3K-AKT pathway (AKT3, PIK3R2 and PIK3CA) have been described to be associated with MCAP and/or other related megalencephaly syndromes. We performed trio-exome sequencing in a 6-year-old boy and his healthy parents. Clinical features were macrocephaly, cutis marmorata, angiomata, asymmetric overgrowth, developmental delay, discrete midline facial nevus flammeus, toe syndactyly and postaxial polydactyly--thus, clearly an MCAP phenotype. Exome sequencing revealed a pathogenic de novo germline variant in the PTPN11 gene (c.1529A>G; p.(Gln510Arg)), which has so far been associated with Noonan, as well as LEOPARD syndrome. Whole-exome sequencing (>100 × coverage) did not reveal any alteration in the known megalencephaly genes. However, ultra-deep sequencing results from saliva (>1000 × coverage) revealed a 22% mosaic variant in PIK3CA (c.2740G>A; p.(Gly914Arg)). To our knowledge, this report is the first description of a PTPN11 germline variant in an MCAP patient. Data from experimental studies show a complex interaction of SHP2 (gene product of PTPN11) and the PI3K-AKT pathway. We hypothesize that certain PTPN11 germline variants might drive toward additional second-hit alterations.

  11. Germline PTPN11 and somatic PIK3CA variant in a boy with megalencephaly-capillary malformation syndrome (MCAP) - pure coincidence?

    PubMed Central

    Döcker, Dennis; Schubach, Max; Menzel, Moritz; Spaich, Christiane; Gabriel, Heinz-Dieter; Zenker, Martin; Bartholdi, Deborah; Biskup, Saskia

    2015-01-01

    Megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth syndrome that is diagnosed by clinical criteria. Recently, somatic and germline variants in genes that are involved in the PI3K-AKT pathway (AKT3, PIK3R2 and PIK3CA) have been described to be associated with MCAP and/or other related megalencephaly syndromes. We performed trio-exome sequencing in a 6-year-old boy and his healthy parents. Clinical features were macrocephaly, cutis marmorata, angiomata, asymmetric overgrowth, developmental delay, discrete midline facial nevus flammeus, toe syndactyly and postaxial polydactyly—thus, clearly an MCAP phenotype. Exome sequencing revealed a pathogenic de novo germline variant in the PTPN11 gene (c.1529A>G; p.(Gln510Arg)), which has so far been associated with Noonan, as well as LEOPARD syndrome. Whole-exome sequencing (>100 × coverage) did not reveal any alteration in the known megalencephaly genes. However, ultra-deep sequencing results from saliva (>1000 × coverage) revealed a 22% mosaic variant in PIK3CA (c.2740G>A; p.(Gly914Arg)). To our knowledge, this report is the first description of a PTPN11 germline variant in an MCAP patient. Data from experimental studies show a complex interaction of SHP2 (gene product of PTPN11) and the PI3K-AKT pathway. We hypothesize that certain PTPN11 germline variants might drive toward additional second-hit alterations. PMID:24939587

  12. 75 FR 23589 - Safety Zones; Blasting Operations and Movement of Explosives, St. Marys River, Sault Sainte Marie...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-04

    ... SECURITY Coast Guard 33 CFR Part 165 RIN 1625-AA00 Safety Zones; Blasting Operations and Movement of... operations and the movement of explosives for those operations. The danger posed by the volume of marine... also require the movement of explosives via barge from Sault Sainte Marie, Michigan to the work site...

  13. Deregulation of ARID1A, CDH1, cMET and PIK3CA and target-related microRNA expression in gastric cancer

    PubMed Central

    Ibarrola-Villava, Maider; Llorca-Cardeñosa, Marta J.; Tarazona, Noelia; Mongort, Cristina; Fleitas, Tania; Perez-Fidalgo, José Alejandro; Roselló, Susana; Navarro, Samuel; Ribas, Gloria; Cervantes, Andrés

    2015-01-01

    Genetic and epigenetic alterations play an important role in gastric cancer (GC) pathogenesis. Aberrations of the phosphatidylinositol-3-kinase signaling pathway are well described. However, emerging genes have been described such as, the chromatin remodeling gene ARID1A. Our aim was to determine the expression levels of four GC-related genes, ARID1A, CDH1, cMET and PIK3CA, and 14 target-related microRNAs (miRNAs). We compared mRNA and miRNA expression levels among 66 gastric tumor and normal adjacent mucosa samples using quantitative real-time reverse transcription PCR. Moreover, ARID1A, cMET and PIK3CA protein levels were assessed by immunohistochemistry (IHC). Finally, gene and miRNAs associations with clinical characteristics and outcome were also evaluated. An increased cMET and PIK3CA mRNA expression was found in 78.0% (P = 2.20 × 10−5) and 73.8% (P = 1.00 × 10−3) of the tumors, respectively. Moreover, IHC revealed that cMET and PIK3CA expression was positive in 63.6% and 87.8% of the tumors, respectively. Six miRNAs had significantly different expression between paired-samples, finding five up-regulated [miR-223-3p (P = 1.65 × 10−6), miR-19a-3p (P = 1.23 × 10−4), miR-128-3p (P = 3.49 × 10−4), miR-130b-3p (P = 1.00 × 10−3) and miR-34a-5p (P = 4.00 × 10−3)] and one down-regulated [miR-124-3p (P = 0.03)]. Our data suggest that cMET, PIK3CA and target-related miRNAs play an important role in GC and may serve as potential targets for therapy. PMID:26334097

  14. Deregulation of ARID1A, CDH1, cMET and PIK3CA and target-related microRNA expression in gastric cancer.

    PubMed

    Ibarrola-Villava, Maider; Llorca-Cardeñosa, Marta J; Tarazona, Noelia; Mongort, Cristina; Fleitas, Tania; Perez-Fidalgo, José Alejandro; Roselló, Susana; Navarro, Samuel; Ribas, Gloria; Cervantes, Andrés

    2015-09-29

    Genetic and epigenetic alterations play an important role in gastric cancer (GC) pathogenesis. Aberrations of the phosphatidylinositol-3-kinase signaling pathway are well described. However, emerging genes have been described such as, the chromatin remodeling gene ARID1A. Our aim was to determine the expression levels of four GC-related genes, ARID1A, CDH1, cMET and PIK3CA, and 14 target-related microRNAs (miRNAs). We compared mRNA and miRNA expression levels among 66 gastric tumor and normal adjacent mucosa samples using quantitative real-time reverse transcription PCR. Moreover, ARID1A, cMET and PIK3CA protein levels were assessed by immunohistochemistry (IHC). Finally, gene and miRNAs associations with clinical characteristics and outcome were also evaluated. An increased cMET and PIK3CA mRNA expression was found in 78.0% (P = 2.20 × 10-5) and 73.8% (P = 1.00 × 10-3) of the tumors, respectively. Moreover, IHC revealed that cMET and PIK3CA expression was positive in 63.6% and 87.8% of the tumors, respectively. Six miRNAs had significantly different expression between paired-samples, finding five up-regulated [miR-223-3p (P = 1.65 × 10-6), miR-19a-3p (P = 1.23 × 10-4), miR-128-3p (P = 3.49 × 10-4), miR-130b-3p (P = 1.00 × 10-3) and miR-34a-5p (P = 4.00 × 10-3)] and one down-regulated [miR-124-3p (P = 0.03)]. Our data suggest that cMET, PIK3CA and target-related miRNAs play an important role in GC and may serve as potential targets for therapy.

  15. Loss of ARID1A protein expression occurs as an early event in ovarian clear-cell carcinoma development and frequently coexists with PIK3CA mutations.

    PubMed

    Yamamoto, Sohei; Tsuda, Hitoshi; Takano, Masashi; Tamai, Seiichi; Matsubara, Osamu

    2012-04-01

    ARID1A is a recently identified tumor suppressor gene that is mutated in ∼50% of ovarian clear-cell carcinomas. This mutation is associated with loss of ARID1A protein expression as assessed by immunohistochemistry. The present study aimed at determining the timing of the loss of ARID1A protein expression during the development of ovarian clear-cell carcinoma and assessing its relevance in correlation to PIK3CA gene mutations. A total of 42 clear-cell carcinoma cases with adjacent putative precursor lesions (endometriosis-associated carcinoma cases (n=28) and (clear-cell) adenofibroma-associated carcinoma cases (n=14)) were selected and subjected to immunohistochemical analysis for ARID1A protein expression and direct genomic DNA sequencing of exons 9 and 20 of the PIK3CA gene. ARID1A immunoreactivity was deficient in 17 (61%) of the 28 endometriosis-associated carcinomas and 6 (43%) of the 14 adenofibroma-associated carcinomas. Among the precursor lesions adjacent to the 23 ARID1A-deficient carcinomas, 86% of the non-atypical endometriosis (12 of 14) and 100% of the atypical endometriosis (14 of 14), benign (3 of 3), and borderline (6 of 6) clear-cell adenofibroma components were found to be ARID1A deficient. In contrast, in the 19 patients with ARID1A-intact carcinomas, all of the adjacent precursor lesions retained ARID1A expression regardless of their types and cytological atypia. Analysis of 22 solitary endometrioses and 10 endometrioses distant from ARID1A-deficient carcinomas showed that all of these lesions were diffusely immunoreactive for ARID1A. Among the 42 clear-cell carcinomas, somatic mutations of PIK3CA were detected in 17 (40%) tumors and majority (71%) of these were ARID1A-deficient carcinomas. These results suggest that loss of ARID1A protein expression occurs as a very early event in ovarian clear-cell carcinoma development, similar to the pattern of PIK3CA mutation recently reported by our group, and frequently coexists (not mutually

  16. High resolution melting analysis of KRAS, BRAF and PIK3CA in KRAS exon 2 wild-type metastatic colorectal cancer

    PubMed Central

    2013-01-01

    Background KRAS is an EGFR effector in the RAS/RAF/ERK cascade that is mutated in about 40% of metastatic colorectal cancer (mCRC). Activating mutations in codons 12 and 13 of the KRAS gene are the only established negative predictors of response to anti-EGFR therapy and patients whose tumors harbor such mutations are not candidates for therapy. However, 40 to 60% of wild-type cases do not respond to anti-EGFR therapy, suggesting the involvement of other genes that act downstream of EGFR in the RAS-RAF-MAPK and PI3K-AKT pathways or activating KRAS mutations at other locations of the gene. Methods DNA was obtained from a consecutive series of 201 mCRC cases (FFPE tissue), wild-type for KRAS exon 2 (codons 12 and 13). Mutational analysis of KRAS (exons 3 and 4), BRAF (exons 11 and 15), and PIK3CA (exons 9 and 20) was performed by high resolution melting (HRM) and positive cases were then sequenced. Results One mutation was present in 23.4% (47/201) of the cases and 3.0% additional cases (6/201) had two concomitant mutations. A total of 53 cases showed 59 mutations, with the following distribution: 44.1% (26/59) in KRAS (13 in exon 3 and 13 in exon 4), 18.6% (11/59) in BRAF (two in exon 11 and nine in exon 15) and 37.3% (22/59) in PIK3CA (16 in exon 9 and six in exon 20). In total, 26.4% (53/201) of the cases had at least one mutation and the remaining 73.6% (148/201) were wild-type for all regions studied. Five of the mutations we report, four in KRAS and one in BRAF, have not previously been described in CRC. BRAF and PIK3CA mutations were more frequent in the colon than in the sigmoid or rectum: 20.8% vs. 1.6% vs. 0.0% (P=0.000) for BRAF and 23.4% vs. 12.1% vs. 5.4% (P=0.011) for PIK3CA mutations. Conclusions About one fourth of mCRC cases wild-type for KRAS codons 12 and 13 present other mutations either in KRAS, BRAF, or PIK3CA, many of which may explain the lack of response to anti-EGFR therapy observed in a significant proportion of these patients. PMID

  17. [Scanning for KRAS, NRAS, BRAF, and PIK3CA mutations by DNA melting analysis with TaqMan probes].

    PubMed

    Botezatu, I V; Panchuk, I O; Stroganova, A M; Senderovich, A I; Kondratova, V N; Shelepov, V P; Lichtenstein, A V

    2017-01-01

    Scanning for mutations by DNA melting analysis (DMA) is based on asymmetric PCR followed by the melting of duplexes formed by single-stranded amplicons with TaqMan probes. The method is optimally suited for clinical genetic testing; it is easy to perform, high-throughput, and sensitive. The detection limit of mutant alleles by the DMA method is about 3%, which is much higher than the sensitivity of Sanger sequencing. In addition, the DMA method is realized in a closed-tube format, while 2-h assay is carried out in a single tube without any intermediate or additional procedures thereby minimizing the risk of cross contamination of the samples. The validation of the DMA method was performed by scanning for mutations of clinically significant genes KRAS, NRAS, BRAF, and   PIK3CA in 324 DNA samples from tumors of patients with melanoma, colorectal and lung cancer. DNA was isolated either directly from tumor tissues, or from formalin-fixed paraffin-embedded tumor tissues. The detected mutations were verified by Sanger sequencing. The spectra of mutations identified in each tumor type correspond to the literature data and, thus, validate the use of DMA.

  18. 33 CFR 165.T09-0290 - Safety Zones; Blasting Operations and Movement of Explosives, St. Marys River, Sault Sainte Marie...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Safety Zones; Blasting Operations and Movement of Explosives, St. Marys River, Sault Sainte Marie, MI. 165.T09-0290 Section 165.T09-0290 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) PORTS AND WATERWAYS SAFETY REGULATED NAVIGATION AREAS AN...

  19. AKT1 E17K in Colorectal Carcinoma Is Associated with BRAF V600E but Not MSI-H Status: A Clinicopathologic Comparison to PIK3CA Helical and Kinase Domain Mutants

    PubMed Central

    Hechtman, Jaclyn F.; Sadowska, Justyna; Huse, Jason T.; Borsu, Laetitia; Yaeger, Rona; Shia, Jinru; Vakiani, Efsevia; Ladanyi, Marc; Arcila, Maria E.

    2016-01-01

    The PI3K/AKT/mTOR pathway is activated through multiple mechanisms in colorectal carcinoma. Here, the clinicopathologic and molecular features of AKT1 E17K–mutated colorectal carcinoma in comparison with PIK3CA-mutated colorectal carcinoma are described in detail. Interestingly, in comparison with PIK3CA mutants, AKT1 E17K was significantly associated with mucinous morphology and concurrent BRAF V600E mutation. Among PIK3CA mutants, exon 21 mutations were significantly associated with BRAF V600E mutation, MSI-H status, and poor differentiation, while exon 10 mutations were associated with KRAS/NRAS mutations. Three of four AKT1 mutants with data from both primary and metastatic lesions had concordant AKT1 mutation status in both. Both AKT1-and PIK3CA-mutant colorectal carcinoma demonstrated frequent loss of PTEN expression (38% and 34%, respectively) and similar rates of p-PRAS 40 expression (63% and 50%, respectively). Both patients with AKT1 E17K alone had primary resistance to cetuximab, whereas 7 of 8 patients with PIK3CA mutation alone experienced tumor shrinkage or stability with anti-EGFR therapy. These results demonstrate that AKT1 E17K mutation in advanced colorectal carcinoma is associated with mucinous morphology, PIK3CA wild-type status, and concurrent RAS/RAF mutations with similar pattern to PIK3CA exon 21 mutants. Thus, AKT1 E17K mutations contribute to primary resistance to cetuximab and serve as an actionable alteration. PMID:25714871

  20. Overview of environmental and hydrogeologic conditions at Saint Marys, Alaska

    USGS Publications Warehouse

    Nakanishi, Allan S.; Dorava, Joseph M.

    1994-01-01

    The Federal Aviation Administration (FAA) owns or operates airway support facilities near Saint Marys along the Yukon River in west-central Alaska. The FAA is evaluating the severity of environmental contamination and options for remediation of environmental contamination at their facilities. Saint Marys is on a flood plain near the continence of the Yukon and Andreafsky Rivers and has long cold winters and short summers. Residents obtain their drinking water from an infiltration gallery fed by a creek near the village. Surface spills and disposal of hazardous materials combined with potential flooding may affect the quality of the surface and ground water. Alternative drinking-water sources are available, but would likely cost more than existing supplies to develop.

  1. Experimental Physical Sciences Vistas: MaRIE (draft)

    SciTech Connect

    Shlachter, Jack

    2010-09-08

    To achieve breakthrough scientific discoveries in the 21st century, a convergence and integration of world-leading experimental facilities and capabilities with theory, modeling, and simulation is necessary. In this issue of Experimental Physical Sciences Vistas, I am excited to present our plans for Los Alamos National Laboratory's future flagship experimental facility, MaRIE (Matter-Radiation Interactions in Extremes). MaRIE is a facility that will provide transformational understanding of matter in extreme conditions required to reduce or resolve key weapons performance uncertainties, develop the materials needed for advanced energy systems, and transform our ability to create materials by design. Our unique role in materials science starting with the Manhattan Project has positioned us well to develop a contemporary materials strategy pushing the frontiers of controlled functionality - the design and tailoring of a material for the unique demands of a specific application. Controlled functionality requires improvement in understanding of the structure and properties of materials in order to synthesize and process materials with unique characteristics. In the nuclear weapons program today, improving data and models to increase confidence in the stockpile can take years from concept to new knowledge. Our goal with MaRIE is to accelerate this process by enhancing predictive capability - the ability to compute a priori the observables of an experiment or test and pertinent confidence intervals using verified and validated simulation tools. It is a science-based approach that includes the use of advanced experimental tools, theoretical models, and multi-physics codes, simultaneously dealing with multiple aspects of physical operation of a system that are needed to develop an increasingly mature predictive capability. This same approach is needed to accelerate improvements to other systems such as nuclear reactors. MaRIE will be valuable to many national security

  2. Mary Shelley's Frankenstein: what made the Monster monstrous?

    PubMed

    Britton, Ronald

    2015-02-01

    This paper discusses the genesis of the famous story of Frankenstein which arose from a dream experienced by Mary Shelley whilst on a holiday shared with her husband Percy Shelley, Lord Byron, Dr Polidori and her step sister Claire Clairmont. The novel relates how the creature created by Victor Frankenstein horrifies him, is rejected by him and called a monster. The monster's ensuing despair and subsequent murderousness is eloquently described. The whole book is clearly connected to Mary Shelley's experience as an infant whose mother died after giving birth to her and her subsequent loss, as a mother, of her own new born infant. It is suggested that the novel imaginatively describes what it is to have been primarily rejected as an infant and to feel regarded as a monster. © 2015, The Society of Analytical Psychology.

  3. Charcot Marie Tooth disease (CMT): historical perspectives and evolution.

    PubMed

    Kazamel, Mohamed; Boes, Christopher J

    2015-01-01

    Prior to Charcot and Marie's and Tooth's reports, patients with peroneal muscular atrophy had been described by Virchow, Eulenburg, Friedreich, Osler, and others. In February 1886, Charcot and Marie published their original description of five patients who had what they called Progressive Muscular Atrophy. They surmised that the lesion could be in the spinal cord. Three months later, Tooth presented his M.D. degree thesis entitled "Peroneal Type of Progressive Muscular Atrophy", to the University of Cambridge, UK. Tooth localized the pathology to the peripheral nerves. Dyck and Lambert (Arch Neurol 18:619-625, 1968) classified several CMT kinships based on differences in modes of inheritance, natural history, biochemical features, nerve conduction velocity, and pathologic characteristics. This article will focus on historical landmarks and major discoveries pertinent to the disease since its original description through the second half of the twentieth century.

  4. Unilateral opercular infarction presenting with Foix-Chavany-Marie syndrome

    PubMed Central

    Sá, Francisca; Menezes Cordeiro, Inês; Mestre, Susana; Nzwalo, Hipólito

    2014-01-01

    Foix-Chavany-Marie syndrome (FCMS) also known as bilateral anterior opercular syndrome is a form of suprabulbar palsy defined by the presence of bilateral voluntary facial, pharyngeal, lingual and masticatory paralysis with automatic–voluntary movement dissociation. We report an extremely rare case of FCMS in a patient with a unilateral left opercular lesion associated with a chronic asymptomatic contralateral cerebellar lesion. Despite intensive rehabilitation, little improvement was noticed at hospital discharge. PMID:25427932

  5. Jean-Marie Mariotti (1955 - 28 July 1998).

    NASA Astrophysics Data System (ADS)

    Léna, P.

    1998-09-01

    Jean-Marie Mariotti, head of the VLTI programme at ESO since the fall of 1997, passed away at the age of 43 on July 28 in Munich, taken by a sudden and acute leukaemia. Together with his wife, Françoise, and their children, Appolline and Octave (6 and 3 years old), a brief ceremony was held on July 31 at the Ost-Friedhof in Munich, attended by his family and a number of his ESO friends and colleagues.

  6. View of 'Cape St. Mary' from 'Cape Verde' (Altered Contrast)

    NASA Technical Reports Server (NTRS)

    2006-01-01

    As part of its investigation of 'Victoria Crater,' NASA's Mars Exploration Rover Opportunity examined a promontory called 'Cape St. Mary' from the from the vantage point of 'Cape Verde,' the next promontory counterclockwise around the crater's deeply scalloped rim. This view of Cape St. Mary combines several exposures taken by the rover's panoramic camera into an approximately true-color mosaic with contrast adjusted to improve the visibility of details in shaded areas.

    The upper portion of the crater wall contains a jumble of material tossed outward by the impact that excavated the crater. This vertical cross-section through the blanket of ejected material surrounding the crater was exposed by erosion that expanded the crater outward from its original diameter, according to scientists' interpretation of the observations. Below the jumbled material in the upper part of the wall are layers that survive relatively intact from before the crater-causing impact. Near the base of the Cape St. Mary cliff are layers with a pattern called 'crossbedding,' intersecting with each other at angles, rather than parallel to each other. Large-scale crossbedding can result from material being deposited as wind-blown dunes.

    The images combined into this mosaic were taken during the 970th Martian day, or sol, of Opportunity's Mars-surface mission (Oct. 16, 2006). The panoramic camera took them through the camera's 750-nanometer, 530-nanometer and 430-nanometer filters.

  7. The Pasteurization of Marie Curie: A (meta)biographical experiment.

    PubMed

    Wirtén, Eva Hemmungs

    2015-08-01

    Biographies of scientists occupy a liminal space, highly popular with general readers but questioned in academia. Nonetheless, in recent years, historians of science have not only embraced the genre with more enthusiasm and less guilt, they have also turned to the metabiography in order to renew the study and story of scientists' roles. This essay focuses on Marie Curie, the world's most famous female scientist, in order to unpack some of the theoretical and methodological claims of the science biography, and especially to address the sexing mechanisms at play in the construction of the biographical subject. Pierre Curie (1923), Marie's biography of her husband Pierre, paid tribute to her dead husband and collaborator, but also allowed Curie a legitimate outlet to construct her own persona and legacy. Categories such as personhood, person, and persona are not only central to the biography genre but also are essential to the sense of self and self-fashioning of scientists. Looking at how Marie Curie negotiated these categories in Pierre Curie not only gives new insight into Curie's self-fashioning strategies but may also shed some light on the more general analytical lacunae of the science biography.

  8. [The umbilical metastasis. Sister Mary Joseph and her time].

    PubMed

    Trebing, D; Göring, H-D

    2004-02-01

    Although Baluff in 1854 and Nelaton in 1860 had already described umbilical metastases, the best known description of the metastasis of carcinomas to this site as "trouser button navel" was published in 1928 by William James Mayo (1861-1939), son of William Worrall Mayo (1815-1911), the founder of the Mayo Clinic in Rochester, Minnesota, This phenomenon is supposed to have been pointed out to Mayo by his long-serving head surgical nurse Sister Mary Joseph (1856-1939). The English surgeon Hamilton Bailey, in his famous textbook "Physical Signs in Clinical Surgery" in 1949, coined the term "Sister Joseph's nodule" for an umbilical metastasis. The expression has become widely accepted and used. Sister Mary Joseph, daughter of Irish immigrants, belonged to the 3rd order of the Holy Francis, was distinguished for her skills, intelligence and devotion to nursing which was also her calling. She worked for many decades at the world-famous Mayo Clinic and taught generations of young nurses. In recent years, the original surgical building at Saint Mary's Hospital has been named "Joseph Building" in her memory. Among the numerous eponyms occurring in the dermatology and the medicine, the association with the name of a nurse represents beyond doubt a special feature.

  9. A different voice: Mary Hays's the Memoirs of Emma Courtney.

    PubMed

    Sharma, A

    2001-01-01

    Mary Hays wrote in the decade of the 1790s, a period of intense creative flowering in England. Writing in a period enshrined to the works of the canonical Wordsworth and Coleridge, Hays explored through her Jacobinical novel, The Memoirs of Emma Courtney, the contentious relationship between self and society. Like other Jacobin women writers - Elizabeth Inchbald, Charlotte Smith and Mary Wollstonecraft - Mary Hays too used her novel to explode the insidious connection between education and gender construction. Emma Courtney is a landmark novel that wrestles with the paradigm of decorum and propriety which disallows women from voicing their aspirations. In the process, Hays merges the plots of the domestic novel of courtship and love with the novel of ideas to create a searing portrait of women's intellectual confinement and psychic dissonance in a society that only projects them in terms of their gender construction. Memoirs of Emma Courtney is a remarkable novel in its depiction of the emotional imbalance created by thwarted desire: intellectual and sexual.

  10. Ectopic expressed miR-203 contributes to chronic obstructive pulmonary disease via targeting TAK1 and PIK3CA.

    PubMed

    Shi, Liang; Xin, Qinghong; Chai, Ruonan; Liu, Lei; Ma, Zhuang

    2015-01-01

    MiRNA is a group of powerful short non-coding RNAs that suppress the expression of protein coding genes by targeting to the 3'UTRs of mRNAs. Some researchers have detected the miRNAs expression profile in tissue and blood samples of chronic obstructive pulmonary disease (COPD) patients recently. Several disturbed miRNAs were found to be related to COPD; however, the mechanisms were still well understood. In this study, we first detected the expression of 11 candidate miRNAs in the lung samples of COPD patients, non-COPD smokers and non-smock controls. We found that the expression of miR-181a, miR-203, miR-338, miR-1 and miR-199a was altered compared with control. Subsequently, we detected these five miRNAs expression in the blood samples of the participants. A significant higher expression of miR-203 was found in the blood samples of smokers and COPD patients. Predicted by bioinformatics tools and confirmed by luciferase assay and western blot, we demonstrated that TAK1 and PIK3CA are two direct targets of miR-203. Furthermore, we detected a lower p-IκBα and p-p65 level in the bronchial/tracheal epithelial cells from COPD patients compared with the cells from healthy controls, when stimulated by LPS. The concentration of TNF-α and IL-6 in the medium from bronchial/tracheal epithelial cells from COPD patients is also lower. Meanwhile, the miR-203 level was down-regulated significantly in the control cells, but non-significant change in the cells from COPD patients. miR-203 represses NF-κB signaling via targeting TAK1 and PI3KCA and miR-203 overexpression may contribute to the COPD initiation.

  11. An Analysis of the Symptomatic Domains Most Relevant to Charcot Marie Tooth Neuropathy (CMT) Patients

    ClinicalTrials.gov

    2015-04-28

    Charcot Marie Tooth Disease (CMT); Hereditary Sensory and Motor Neuropathy; Nerve Compression Syndromes; Tooth Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Heredodegenerative Disorders, Nervous System

  12. NBS-LRR Protein Pik-H4 Interacts with OsBIHD1 to Balance Rice Blast Resistance and Growth by Coordinating Ethylene-Brassinosteroid Pathway

    PubMed Central

    Liu, Hao; Dong, Shuangyu; Gu, Fengwei; Liu, Wei; Yang, Guili; Huang, Ming; Xiao, Wuming; Liu, Yongzhu; Guo, Tao; Wang, Hui; Chen, Zhiqiang; Wang, Jiafeng

    2017-01-01

    The regulation of innate immunity and plant growth, along with the trade-off between them, affects the defense and recovery mechanisms of the plant after it is attacked by pathogens. Although it is known that hormonal crosstalk plays a major role in regulating interaction of plant growth and PAMP-triggered immunity, the relationship between plant growth and effector-triggered immunity (ETI) remains unclear. In a large-scale yeast two-hybrid screening for Pik-H4-interacting proteins, a homeodomain transcription factor OsBIHD1 was identified, which is previously known to function in biotic and abiotic stress responses. The knockout of OsBIHD1 in rice lines carrying Pik-H4 largely compromised the resistance of the rice lines to Magnaporthe oryzae, the fungus that causes rice blast. While overexpression of OsBIHD1 resulted in enhanced expression of the pathogenesis-related (PR) and ethylene (ET) synthesis genes. Moreover, OsBIHD1 was also found to directly bind to the promoter region of ethylene-synthesis enzyme OsACO3. In addition, OsBIHD1 overexpression or deficiency provoked dwarfism and reduced brassinosteroid (BR) insensitivity through repressing the expression of several critical genes involved in BR biosynthesis and BR signaling. During M. oryzae infection, transcript levels of the crucial BR catabolic genes (CYP734A2, CYP734A4, and CYP734A6) were significantly up-regulated in OsBIHD1-OX plants. Furthermore, OsBIHD1 was found to be capable of binding to the sequence-specific cis-elements on the promoters of CYP734A2 to suppress the plant growth under fungal invasion. Our results collectively suggest a model that OsBIHD1 is required for Pik-H4-mediated blast resistance through modulating the trade-off between resistance and growth by coordinating brassinosteroid-ethylene pathway. PMID:28220140

  13. Alterations of the p53 and PIK3CA/AKT/mTOR pathways in angiosarcomas: a pattern distinct from other sarcomas with complex genomics.

    PubMed

    Italiano, Antoine; Chen, Chun-Liang; Thomas, Rachael; Breen, Matthew; Bonnet, Françoise; Sevenet, Nicolas; Longy, Michel; Maki, Robert G; Coindre, Jean-Michel; Antonescu, Cristina R

    2012-12-01

    The p53 and phosphoinositide-3-kinase, catalytic, alpha polypeptide/v-akt murine thymoma viral oncogene homolog/mechanistic target of rapamycin (PIK3CA/AKT/mTOR) pathways frequently are altered in sarcoma with complex genomics, such as leiomyosarcoma (LMS) or undifferentiated pleomorphic sarcoma (UPS). The scale of genetic abnormalities in these pathways remains unknown in angiosarcoma (AS). The authors investigated the status of critical genes involved in the p53 and PIK3CA/AKT/mTOR pathways in a series of 62 AS. The mutation and deletion rates of tumor protein 53 (TP53) were 4% and 0%, respectively. Overexpression of p53 was detected by immunohistochemistry in 49% of patients and was associated with inferior disease-free survival. Although p14 inactivation or overexpression of the human murine double minute homolog (HDM2) were frequent in LMS and UPS and could substitute for TP53 mutation or deletion, such alterations were rare in angiosarcomas. Phosphorylated ribosomal protein S6 kinase (p-S6K) and/or phosphorylated eukaryotic translation initiation factor 4E binding protein 1 (p-4eBP1) overexpression was observed in 42% of patients, suggesting frequent activation of the PIK3CA/AKT/mTOR pathway in angiosarcomas. Activation was not related to intragenic deletion of phosphatase and tensin homolog (PTEN), an aberration that is frequent in LMS and UPS but absent in angiosarcomas. The current results indicated that angiosarcomas constitute a distinct subgroup among sarcomas with complex genomics. Although TP53 mutation and PTEN deletion are frequent in LMS and UPS, these aberrations are rarely involved in the pathogenesis of angiosarcoma. Copyright © 2012 American Cancer Society.

  14. Prevention of tumor growth driven by PIK3CA and HPV oncogenes by targeting mTOR signaling with metformin in oral squamous carcinomas expressing OCT3.

    PubMed

    Madera, Dmitri; Vitale-Cross, Lynn; Martin, Daniel; Schneider, Abraham; Molinolo, Alfredo A; Gangane, Nitin; Carey, Thomas E; McHugh, Jonathan B; Komarck, Christine M; Walline, Heather M; William, William N; Seethala, Raja R; Ferris, Robert L; Gutkind, J Silvio

    2015-03-01

    Most squamous cell carcinomas of the head and neck (HNSCC) exhibit a persistent activation of the PI3K-mTOR signaling pathway. We have recently shown that metformin, an oral antidiabetic drug that is also used to treat lipodystrophy in HIV-infected (HIV(+)) individuals, diminishes mTOR activity and prevents the progression of chemically induced experimental HNSCC premalignant lesions. Here, we explored the preclinical activity of metformin in HNSCCs harboring PIK3CA mutations and HPV oncogenes, both representing frequent HNSCC alterations, aimed at developing effective targeted preventive strategies. The biochemical and biologic effects of metformin were evaluated in representative HNSCC cells expressing mutated PIK3CA or HPV oncogenes (HPV(+)). The oral delivery of metformin was optimized to achieve clinical relevant blood levels. Molecular determinants of metformin sensitivity were also investigated, and their expression levels were examined in a large collection of HNSCC cases. We found that metformin inhibits mTOR signaling and tumor growth in HNSCC cells expressing mutated PIK3CA and HPV oncogenes, and that these activities require the expression of organic cation transporter 3 (OCT3/SLC22A3), a metformin uptake transporter. Coexpression of OCT3 and the mTOR pathway activation marker pS6 were observed in most HNSCC cases, including those arising in HIV(+) patients. Activation of the PI3K-mTOR pathway is a widespread event in HNSCC, including HPV(-) and HPV(+) lesions arising in HIV(+) patients, all of which coexpress OCT3. These observations may provide a rationale for the clinical evaluation of metformin to halt HNSCC development from precancerous lesions, including in HIV(+) individuals at risk of developing HPV(-) associated cancers. ©2015 American Association for Cancer Research.

  15. Coexistence of EGFR with KRAS, or BRAF, or PIK3CA somatic mutations in lung cancer: a comprehensive mutation profiling from 5125 Chinese cohorts

    PubMed Central

    Li, S; Li, L; Zhu, Y; Huang, C; Qin, Y; Liu, H; Ren-Heidenreich, L; Shi, B; Ren, H; Chu, X; Kang, J; Wang, W; Xu, J; Tang, K; Yang, H; Zheng, Y; He, J; Yu, G; Liang, N

    2014-01-01

    Background: Determining the somatic mutations of epidermal growth factor receptor (EGFR)-pathway networks is the key to effective treatment for non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors (TKIs).The somatic mutation frequencies and their association with gender, smoking history and histology was analysed and reported in this study. Methods: Five thousand one hundred and twenty-five NSCLC patients' pathology samples were collected, and EGFR, KRAS, BRAF and PIK3CA mutations were detected by multiplex testing. The mutation status of EGFR, KRAS, BRAF and PIK3CA and their association with gender, age, smoking history and histological type were evaluated by appropriate statistical analysis. Results: EGFR, KRAS, BRAF and PIK3CA mutation rates revealed 36.2%, 8.4%, 0.5% and 3.3%, respectively, across the 5125 pathology samples. For the first time, evidence of KRAS mutations were detected in two female, non-smoking patients, age 5 and 14, with NSCLC. Furthermore, we identified 153 double and coexisting mutations and 7 triple mutations. Interestingly, the second drug-resistant mutations, T790M or E545K, were found in 44 samples from patients who had never received TKI treatments. Conclusions: EGFR exons 19, 20 and 21, and BRAF mutations tend to happen in females and non-smokers, whereas KRAS mutations were more inclined to males and smokers. Activating and resistant mutations to EGFR-TKI drugs can coexist and ‘second drug-resistant mutations', T790M or E545K, may be primary mutations in some patients. These results will help oncologists to decide candidates for mutation testing and EGFR-TKI treatment. PMID:24743704

  16. NBS-LRR Protein Pik-H4 Interacts with OsBIHD1 to Balance Rice Blast Resistance and Growth by Coordinating Ethylene-Brassinosteroid Pathway.

    PubMed

    Liu, Hao; Dong, Shuangyu; Gu, Fengwei; Liu, Wei; Yang, Guili; Huang, Ming; Xiao, Wuming; Liu, Yongzhu; Guo, Tao; Wang, Hui; Chen, Zhiqiang; Wang, Jiafeng

    2017-01-01

    The regulation of innate immunity and plant growth, along with the trade-off between them, affects the defense and recovery mechanisms of the plant after it is attacked by pathogens. Although it is known that hormonal crosstalk plays a major role in regulating interaction of plant growth and PAMP-triggered immunity, the relationship between plant growth and effector-triggered immunity (ETI) remains unclear. In a large-scale yeast two-hybrid screening for Pik-H4-interacting proteins, a homeodomain transcription factor OsBIHD1 was identified, which is previously known to function in biotic and abiotic stress responses. The knockout of OsBIHD1 in rice lines carrying Pik-H4 largely compromised the resistance of the rice lines to Magnaporthe oryzae, the fungus that causes rice blast. While overexpression of OsBIHD1 resulted in enhanced expression of the pathogenesis-related (PR) and ethylene (ET) synthesis genes. Moreover, OsBIHD1 was also found to directly bind to the promoter region of ethylene-synthesis enzyme OsACO3. In addition, OsBIHD1 overexpression or deficiency provoked dwarfism and reduced brassinosteroid (BR) insensitivity through repressing the expression of several critical genes involved in BR biosynthesis and BR signaling. During M. oryzae infection, transcript levels of the crucial BR catabolic genes (CYP734A2, CYP734A4, and CYP734A6) were significantly up-regulated in OsBIHD1-OX plants. Furthermore, OsBIHD1 was found to be capable of binding to the sequence-specific cis-elements on the promoters of CYP734A2 to suppress the plant growth under fungal invasion. Our results collectively suggest a model that OsBIHD1 is required for Pik-H4-mediated blast resistance through modulating the trade-off between resistance and growth by coordinating brassinosteroid-ethylene pathway.

  17. Prevention of tumor growth driven by PIK3CA and HPV oncogenes by targeting mTOR signaling with metformin in oral squamous carcinomas expressing OCT3

    PubMed Central

    Madera, Dmitri; Vitale-Cross, Lynn; Martin, Daniel; Schneider, Abraham; Molinolo, Alfredo A.; Gangane, Nitin; Carey, Thomas E.; McHugh, Jonathan B.; Komarck, Christine M.; Walline, Heather M.; William, William N.; Seethala, Raja R.; Ferris, Robert; Gutkind, J. Silvio

    2015-01-01

    Most head and neck squamous cell carcinomas (HNSCC) exhibit a persistent activation of the PI3K-mTOR signaling pathway. We have recently shown that metformin, an oral antidiabetic drug that is also used to treat lipodystrophy in HIV-infected (HIV+) individuals, diminishes mTOR activity and prevents the progression of chemically-induced experimental HNSCC premalignant lesions. Here, we explored the preclinical activity of metformin in HNSCCs harboring PIK3CA mutations and HPV oncogenes, both representing frequent HNSCC alterations, aimed at developing effective targeted preventive strategies. The biochemical and biological effects of metformin were evaluated in representative HNSCC cells expressing mutated PIK3CA or HPV oncogenes (HPV+). The oral delivery of metformin was optimized to achieve clinical relevant blood levels. Molecular determinants of metformin sensitivity were also investigated, and their expression levels examined in a large collection of HNSCC cases. We found that metformin inhibits mTOR signaling and tumor growth in HNSCC cells expressing mutated PIK3CA and HPV oncogenes, and that these activities require the expression of organic cation transporter 3 (OCT3/SLC22A3), a metformin uptake transporter. Co-expression of OCT3 and the mTOR pathway activation marker pS6 were observed in most HNSCC cases, including those arising in HIV+ patients. Activation of the PI3K-mTOR pathway is a widespread event in HNSCC, including HPV− and HPV+ lesions arising in HIV+ patients, all of which co-express OCT3. These observations may provide a rationale for the clinical evaluation of metformin to halt HNSCC development from precancerous lesions, including in HIV+ individuals at risk of developing HPV-associated cancers. PMID:25681087

  18. A cardiac myocyte-restricted Lin28/let-7 regulatory axis promotes hypoxia-mediated apoptosis by inducing the AKT signaling suppressor PIK3IP1.

    PubMed

    Joshi, Shaurya; Wei, Jianqin; Bishopric, Nanette H

    2016-02-01

    The let-7 family of microRNAs (miRs) regulates critical cell functions, including survival signaling, differentiation, metabolic control and glucose utilization. These functions may be important during myocardial ischemia. MiR-let-7 expression is under tight temporal and spatial control through multiple redundant mechanisms that may be stage-, isoform- and tissue-specific. To determine the mechanisms and functional consequences of miR-let-7 regulation by hypoxia in the heart. MiR-let-7a, -7c and -7g were downregulated in the adult mouse heart early after coronary occlusion, and in neonatal rat ventricular myocytes subjected to hypoxia. Let-7 repression did not require glucose depletion, and occurred at a post-transcriptional level. Hypoxia also induced the RNA binding protein Lin28, a negative regulator of let-7. Hypoxia ineither induced Lin28 nor repressed miR-let-7 in cardiac fibroblasts. Both changes were abrogated by treatment with the histone deacetylase inhibitor trichostatin A. Restoration of let-7g to hypoxic myocytes and to ischemia-reperfused mouse hearts in vivo via lentiviral transduction potentiated the hypoxia-induced phosphorylation and activation of Akt, and prevented hypoxia-dependent caspase activation and death. Mechanistically, phosphatidyl inositol 3-kinase interacting protein 1 (Pik3ip1), a negative regulator of PI3K, was identified as a novel target of miR-let-7 by a crosslinking technique showing that miR-let-7g specifically targets Pik3ip1 to the cardiac myocyte Argonaute complex RISC. Finally, in non-failing and failing human myocardium, we found specific inverse relationships between Lin28 and miR-let-7g, and between miR-let-7g and PIK3IP1. A conserved hypoxia-responsive Lin28-miR-let-7-Pik3ip1 regulatory axis is specific to cardiac myocytes and promotes apoptosis during myocardial ischemic injury. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Analysis of PIK3CA exon 9 and 20 mutations in breast cancers using PCR-HRM and PCR-ARMS: correlation with clinicopathological criteria.

    PubMed

    Harlé, Alexandre; Lion, Maëva; Lozano, Nicolas; Husson, Marie; Harter, Valentin; Genin, Pascal; Merlin, Jean-Louis

    2013-03-01

    Phosphatidylinositol-3-kinases (PI3K) are essential for cell signaling, proliferation, differentiation and survival. The catalytic subunit of PI3K, encoded by the PIK3CA oncogene, is mutated in 18-45% of breast carcinomas. These mutations, involved in tumorigenic processes, activate the PI3K/AKT/mTOR signaling pathway. Resistance to anti‑human epidermal growth factor receptor, hormonal or anti-PI3K therapies have been described in breast carcinomas bearing activation of the PI3K signaling pathway. The present study reports the evaluation of PIK3CA exon 9 and 20 mutations in 149 invasive breast cancer cases using a validated PCR-high resolution melting assay (PCR-HRM). An amplification refractory mutation system (PCR-ARMS) using allele-specific scorpion primers was used to detect hotspot mutations in exons 9 (c.1624G→A and c.1633G→A) and 20 (c.3140A→G and c.3140A→T) in 118 tumor specimens. No correlation was observed with age at diagnosis, histological type, hormone receptor and HER2 status. PIK3CA exon 9 and 20 mutations were found to be related to Scarff-Bloom-Richardson (SBR) grade with a lower rate of mutations and a higher frequency of exon 9 mutations in SBRI and exon 20 mutations in SBRII/III tumors. No difference was observed in the incidence rates of the two different mutations screened for each exon in any subcategory. A statistically significant correlation was found between PCR-HRM and PCR-ARMS (κ=0.845; P<0.001). PCR-ARMS was found to be more sensitive than PCR-HRM (sensitivity 0.5 and 5-10% of mutated DNA, respectively). We propose that PCR-HRM and PCR-ARMS can be combined for the cost-effective routine clinical identification of PIK3CA mutations for the purpose of personalizing therapy for invasive breast cancers.

  20. Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes

    PubMed Central

    2013-01-01

    Background More than half of patients with KRAS-wild type advanced colorectal cancer (CRC) fail anti-EGFR monoclonal antibodies. We studied EGFR-axis messenger RNA (mRNA) expression and RAS, RAF, PIK3CA mutations in order to identify additional biomarkers of cetuximab efficacy. Methods Previously genotyped (KRAS, NRAS, BRAF, PIK3CA mutations) formalin-fixed paraffin-embedded tumour biopsies of 226 cetuximab-treated CRC patients (1st to 3rd line therapy) were assessed for mRNA expression of epidermal growth factor receptor (EGFR) and its ligands EGF, Transofrming Growth Factor-a (TGFA), Amphiregulin (AREG) and Epiregulin (EREG) with real time quantitative PCR. Mutations were detected in 72 (31.9%) tumours for KRAS, in 6 (2.65%) for BRAF, in 7 (3.1%) for NRAS and in 37 (16.4%) for PIK3CA. Results Only PIK3CA mutations occasionally coexisted with other gene mutations. In univariate analysis, prognostic significance for survival ( from metastases until death) was seen for BRAF mutations (Hazard Ratio HR 8.1, 95% CI 3.4-19), codon 12-only KRAS mutations (HR 1.62, 95% CI 1.1-2.4), high AREG mRNA expression only in KRAS wild type CRC (HR 0.47, 95% CI 0.3-0.7) and high EREG mRNA expression irrespective of KRAS mutation status (HR 0.45, 95% CI 0.28-0.7). EREG tumoural mRNA expression was significantly associated with a 2.26-fold increased likelihood of objective response to cetuximab therapy (RECIST 1.1). In multivariate analysis, favourable predictive factors were high AREG mRNA in KRAS wild type tumours, high EREG mRNA, low Ephrin A2 receptor mRNA. Cetuximab-treated patients with AREG-low KRAS wild type CRC fared very poorly, their survival being similar to KRAS mutant CRC. Patients with KRAS codon 13 or other non-codon 12 mutations had a median survival (30 months, 95% CI 20–35) similar to that of patients with KRAS wild-type (median survival 29 months, 95% CI 25–35), in contrast to patients with KRAS codon 12 mutations who fared worse (median survival 19

  1. STS-70 Mission Specialist Mary Ellen Weber suits up

    NASA Technical Reports Server (NTRS)

    1995-01-01

    A relaxed and smiling STS-70 Mission Specialist Mary Ellen Weber dons her launch/entry suit in the Operations and Checkout Building with help from a suit technician. The 70th Shuttle mission will be Weber's first trip into space. She and four crew mates will depart shortly for Launch Pad 39B, where the Space Shuttle Discovery is undergoing final preparations for a liftoff scheduled during a two and a half hour launch window opening at 9:41 a.m. EDT.

  2. Astronaut Mary Ellen Weber during emergency bailout training at WETF

    NASA Image and Video Library

    1995-02-16

    S95-03469 (16 FEB 1995) --- Attired in a training version of the Shuttle launch and entry garment, astronaut Mary Ellen Weber gets help with the final touches of suit donning during a training session at the Johnson Space Center's (JSC) Weightless Environment Training Facility (WET-F). Helping out is Rockwell's William L. Todd (right), while Staffon Isaacs looks on. Training as a mission specialist for the STS-70 mission, Weber was about to rehearse emergency bailout. The crew members made use of a nearby 25-feet deep pool to practice parachute landings in water and subsequent deployment of life rafts.

  3. 7. Photocopy of photograph (original print in possession of Mary ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    7. Photocopy of photograph (original print in possession of Mary Lane Knott, 508 Central Avenue, Ridgely MD 21660). Photographer and date unknown, Circa 1900. VIEW EAST, SOUTHWEST FRONT, NORTHWEST SIDE Front and side elevations. Note the duplication of the recessed store front with display windows. Note the break in the original clapboard siding toward the rear on the Northwest side and the new clapboard siding near the buggy. Near the buggy wheel an original brick pier. Note the panelling below the display windows and the penny gumball machine on the wall marked 'Adams Tutti-Frutti'. - 510 Central Avenue (Commercial Building), Ridgely, Caroline County, MD

  4. [Ascorbic Acid and Charcot-Marie-Tooth Disease].

    PubMed

    Noto, Yu-ichi

    2015-10-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is a disease for which no drug treatments are available. Passage et al. reported that ascorbic acid reduced the mRNA level of PMP22, improved motor function and increased the numbers of myelinated peripheral nerve axons in a mouse model of CMT1A. Based on these results, five clinical trials were undertaken at different centers worldwide. However, none of them demonstrated significant effectiveness. Although these outcomes were disappointing, these studies have provided many useful insights for conducting the next randomised controlled trial for CMT1A.

  5. Mary Wakefield: Health Resources and Services Administrator. Interview.

    PubMed

    Wakefield, Mary

    2014-06-01

    Dr. Mary Wakefield is the administrator of the Health Resources and Services Administration. She came from the University of North Dakota, where she directed the Center for Rural Health. She has served as director of the Center for Health Policy, Research and Ethics at George Mason University and has worked with the World Health Organization's Global Programme on AIDS in Geneva, Switzerland. She is a fellow in the American Academy of Nursing and was elected to the Institute of Medicine of the National Academies. A native of North Dakota, Wakefield holds a doctoral degree in nursing from the University of Texas.

  6. Remembering Joan (Jan) Mary Anderson (1932-2015).

    PubMed

    Chow, Wah Soon; Horton, Peter; Barrett, Martin; Osmond, Charles Barry

    2016-08-01

    Joan Mary Anderson, known to most people as Jan, was born on May 12, 1932 in Dunedin, New Zealand. She died on August 28, 2015 in Canberra, Australia. To celebrate her life, we present here a brief biography, some comments on her discoveries in photosynthesis during a career spanning more than half a century, and reminiscences from family and friends. We remember this wonderful person who had an unflagging curiosity, creative ability to think laterally, enthusiasm, passion, generosity and love of color and culture.

  7. Aspects of emic and etic measurement: lessons from Mary Poppins.

    PubMed

    Lee, Christopher J

    2002-01-01

    This article describes emic and etic approaches to measurement in terms of a process of associating indicators and constructs. In this process, it is important to establish evidence of an adequate range of indicators and a relevant association of indicators and constructs and to recognize that such evidence places bounds on the interpretation of measurement outcomes. A passage from one of P. L. Travers's Mary Poppins stories provides a counterpoint for this article's discussion of these key aspects of emic and etic methods of measuring human individuality.

  8. The Mary Ingraham Bunting Institute of Radcliffe College.

    DTIC Science & Technology

    1992-08-31

    AD-A284 034 II~huI~ hI~iRADCLIFFE COLLEGE The Mary Ingraham Bunting Institute Radcliffe Research and Study Center 34 Concord Avenue, Cambridge...time sites for fellows’ work . The ninth fellow was writing her results into a book, and did not need a laboratory affiliation. Accesior For NrTS CRA...stipend, office, and research fund allow them to carry their work in the directions they choose, rather than making them deisndent on the projects

  9. Using the "Mary Tyler Moore Show" as a Feminist Teaching Tool

    ERIC Educational Resources Information Center

    Jule, Allyson

    2010-01-01

    This paper explores the use of "The Mary Tyler Moore Show" as a teaching tool used with a group of final-year undergraduate students who gathered together last academic year (2007-8) to explore Women in Leadership, as part of a Communications course. The research focus was: How can the use of "The Mary Tyler Moore Show" (a…

  10. "Does Broca's Area Exist?:" Christofredo Jakob's 1906 Response to Pierre Marie's Holistic Stance

    ERIC Educational Resources Information Center

    Tsapkini, Kyrana; Vivas, Ana B.; Triarhou, Lazaros C.

    2008-01-01

    In 1906, Pierre Marie triggered a heated controversy and an exchange of articles with Jules Dejerine over the localization of language functions in the human brain. The debate spread internationally. One of the timeliest responses, that appeared in print 1 month after Marie's paper, came from Christofredo Jakob, a Bavarian-born neuropathologist…

  11. Use of FlUKA in the Analysis of the Mars Odyssey MARIE Experiment

    NASA Technical Reports Server (NTRS)

    Pinsky, Lawrence S.; Wilson, Thomas L; Andersen, Victor

    2006-01-01

    UH researchers have significantly improved the calibration of the MARIE by simulating its response to energetic protons using FLUKA. Analysis of MARIE data shows that the intensity of solar energetic particles depends strongly on how well the observation point is connected magnetically to the site at which the particles are accelerated.

  12. Mary Catherine and Me: Building Cross-Cultural Relationships in "Post-Racial" America

    ERIC Educational Resources Information Center

    Bruno, Holly Elissa

    2009-01-01

    In 1963, President Obama's parents could not have married legally in a number of states. Mary Catherine and the author graduated from Corning Free Academy in Corning, New York, in June 1963. The lessons they learned were wrenching: "Someone is going to get hurt." Doors that opened for the author slammed in Mary Catherine's face. Holding Mary…

  13. "The Bravest of the Brave": A Conversation with Mary Bitterman and James Narduzzi

    ERIC Educational Resources Information Center

    Continuing Higher Education Review, 2008

    2008-01-01

    This article presents an interview with Mary Bitterman and James Narduzzi. Mary Bitterman, former President and CEO of The James Irvine Foundation, is President of The Bernard Osher Foundation and Immediate Past Chairman of the Public Broadcasting Service (PBS). James Narduzzi is Dean of the University of Richmond's School of Continuing Studies.…

  14. 33 CFR 161.45 - Vessel Traffic Service St. Marys River.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 33 Navigation and Navigable Waters 2 2013-07-01 2013-07-01 false Vessel Traffic Service St. Marys... SECURITY (CONTINUED) PORTS AND WATERWAYS SAFETY VESSEL TRAFFIC MANAGEMENT Vessel Traffic Service and Vessel Movement Reporting System Areas and Reporting Points § 161.45 Vessel Traffic Service St. Marys River. (a...

  15. 33 CFR 161.45 - Vessel Traffic Service St. Marys River.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 33 Navigation and Navigable Waters 2 2011-07-01 2011-07-01 false Vessel Traffic Service St. Marys... SECURITY (CONTINUED) PORTS AND WATERWAYS SAFETY VESSEL TRAFFIC MANAGEMENT Vessel Traffic Service and Vessel Movement Reporting System Areas and Reporting Points § 161.45 Vessel Traffic Service St. Marys River. (a...

  16. 33 CFR 161.45 - Vessel Traffic Service St. Marys River.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 33 Navigation and Navigable Waters 2 2014-07-01 2014-07-01 false Vessel Traffic Service St. Marys... SECURITY (CONTINUED) PORTS AND WATERWAYS SAFETY VESSEL TRAFFIC MANAGEMENT Vessel Traffic Service and Vessel Movement Reporting System Areas and Reporting Points § 161.45 Vessel Traffic Service St. Marys River. (a...

  17. 33 CFR 161.45 - Vessel Traffic Service St. Marys River.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 2 2012-07-01 2012-07-01 false Vessel Traffic Service St. Marys... SECURITY (CONTINUED) PORTS AND WATERWAYS SAFETY VESSEL TRAFFIC MANAGEMENT Vessel Traffic Service and Vessel Movement Reporting System Areas and Reporting Points § 161.45 Vessel Traffic Service St. Marys River. (a...

  18. Quality-of-Life in Charcot Marie Tooth Disease: The Patient's Perspective

    PubMed Central

    Johnson, Nicholas E; Heatwole, Chad R; Dilek, Nuran; Sowden, Janet; Kirk, Callyn A; Shereff, Denise; Shy, Michael E; Herrmann, David N

    2014-01-01

    This study determines the impact of symptoms associated with Charcot-Marie-Tooth disease on quality-of-life. Charcot-Marie-Tooth patients in the Inherited Neuropathies Consortium Rare Diseases Clinical Research Network Contact Registry were surveyed. The survey inquired about 214 symptoms and 20 themes previously identified as important to Charcot-Marie-Tooth patients through patient interviews. Symptom population impact was calculated as the prevalence multiplied by the relative importance of each symptom identified. Prevalence and symptom impact were analyzed by age, symptom duration, gender, Charcot-Marie-Tooth type, and employment status. 407 respondents identified foot and ankle weakness (99.7%) and impaired balance (98.6%) as the most prevalent themes. Foot and ankle weakness and limitations with mobility were the themes with the highest impact. Both symptom prevalence and impact gradually increased with age and symptom duration. Several themes were more prevalent in women with Charcot-Marie-Tooth, including activity limitations, pain, fatigue, hip-thigh weakness, and gastrointestinal issues. All of the themes, except emotional or body image issues, were more prevalent among unemployed individuals. There were minimal differences in symptom prevalence between Charcot-Marie-Tooth types. There are multiple symptoms that impact Charcot-Marie-Tooth quality-of-life in adults. These symptoms have different levels of importance, are readily recognized by patients, and represent critical areas of Charcot-Marie-Tooth health. PMID:25092060

  19. Quality-of-life in Charcot-Marie-Tooth disease: the patient's perspective.

    PubMed

    Johnson, Nicholas E; Heatwole, Chad R; Dilek, Nuran; Sowden, Janet; Kirk, Callyn A; Shereff, Denise; Shy, Michael E; Herrmann, David N

    2014-11-01

    This study determines the impact of symptoms associated with Charcot-Marie-Tooth disease on quality-of-life. Charcot-Marie-Tooth patients in the Inherited Neuropathies Consortium Rare Diseases Clinical Research Network Contact Registry were surveyed. The survey inquired about 214 symptoms and 20 themes previously identified as important to Charcot-Marie-Tooth patients through patient interviews. Symptom population impact was calculated as the prevalence multiplied by the relative importance of each symptom identified. Prevalence and symptom impact were analyzed by age, symptom duration, gender, Charcot-Marie-Tooth type, and employment status. 407 participants returned the survey, identifying foot and ankle weakness (99.7%) and impaired balance (98.6%) as the most prevalent themes. Foot and ankle weakness and limitations with mobility were the themes with the highest impact. Both symptom prevalence and impact gradually increased with age and symptom duration. Several themes were more prevalent in women with Charcot-Marie-Tooth, including activity limitations, pain, fatigue, hip-thigh weakness, and gastrointestinal issues. All of the themes, except emotional or body image issues, were more prevalent among unemployed individuals. There were minimal differences in symptom prevalence between Charcot-Marie-Tooth types. There are multiple symptoms that impact Charcot-Marie-Tooth quality-of-life in adults. These symptoms have different levels of importance, are readily recognized by patients, and represent critical areas of Charcot-Marie-Tooth health.

  20. 33 CFR 117.353 - Atlantic Intracoastal Waterway, Savannah River to St. Marys River.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., Savannah River to St. Marys River. 117.353 Section 117.353 Navigation and Navigable Waters COAST GUARD....353 Atlantic Intracoastal Waterway, Savannah River to St. Marys River. (a) General. Public vessels of... Bridge, SR 204, mile 592.9 near Savannah. The draw will open as necessary on the hour from 7 a.m. to 9...

  1. 33 CFR 117.353 - Atlantic Intracoastal Waterway, Savannah River to St. Marys River.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., Savannah River to St. Marys River. 117.353 Section 117.353 Navigation and Navigable Waters COAST GUARD....353 Atlantic Intracoastal Waterway, Savannah River to St. Marys River. (a) General. Public vessels of... Bridge, SR 204, mile 592.9 near Savannah. The draw will open as necessary on the hour from 7 a.m. to 9...

  2. 33 CFR 117.353 - Atlantic Intracoastal Waterway, Savannah River to St. Marys River.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., Savannah River to St. Marys River. 117.353 Section 117.353 Navigation and Navigable Waters COAST GUARD....353 Atlantic Intracoastal Waterway, Savannah River to St. Marys River. (a) General. Public vessels of... Bridge, SR 204, mile 592.9 near Savannah. The draw will open as necessary on the hour from 7 a.m. to 9...

  3. 33 CFR 117.353 - Atlantic Intracoastal Waterway, Savannah River to St. Marys River.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., Savannah River to St. Marys River. 117.353 Section 117.353 Navigation and Navigable Waters COAST GUARD....353 Atlantic Intracoastal Waterway, Savannah River to St. Marys River. (a) General. Public vessels of... Bridge, SR 204, mile 592.9 near Savannah. The draw will open as necessary on the hour from 7 a.m. to 9...

  4. 33 CFR 117.353 - Atlantic Intracoastal Waterway, Savannah River to St. Marys River.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ..., Savannah River to St. Marys River. 117.353 Section 117.353 Navigation and Navigable Waters COAST GUARD....353 Atlantic Intracoastal Waterway, Savannah River to St. Marys River. (a) General. Public vessels of... Bridge, SR 204, mile 592.9 near Savannah. The draw will open as necessary on the hour from 7 a.m. to 9...

  5. "Does Broca's Area Exist?:" Christofredo Jakob's 1906 Response to Pierre Marie's Holistic Stance

    ERIC Educational Resources Information Center

    Tsapkini, Kyrana; Vivas, Ana B.; Triarhou, Lazaros C.

    2008-01-01

    In 1906, Pierre Marie triggered a heated controversy and an exchange of articles with Jules Dejerine over the localization of language functions in the human brain. The debate spread internationally. One of the timeliest responses, that appeared in print 1 month after Marie's paper, came from Christofredo Jakob, a Bavarian-born neuropathologist…

  6. Potential Hosts for Lambertella corni-maris and Phacidium lacerum within the Family Rosaceae

    USDA-ARS?s Scientific Manuscript database

    Two fungi were described in 2015 and 2016 as pathogens of pome fruit in the Pacific Northwest USA: Lambertella corni-maris on apple (Malus domestica), and Phacidium lacerum (synonym, Ceuthospora pinastri) on apple and d’Anjou pear (Pyrus communis). We documented pathogenicity of L. corni-maris to d...

  7. The Children in the Story: Metafiction in "Mary Poppins in the Park."

    ERIC Educational Resources Information Center

    Didicher, Nicole E.

    1997-01-01

    Reflects on story and storytelling. Uses the "Mary Poppins" series to chart the increasing "literariness" of P.L. Travers' novels, contending that "Mary Poppins in the Park" is the most clearly and consistently metafictional (i.e., self-consciously reflexive). Calls for examining more children's books for how they…

  8. 33 CFR 207.441 - St. Marys Falls Canal and Locks, Mich.; security.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 3 2012-07-01 2012-07-01 false St. Marys Falls Canal and Locks... OF THE ARMY, DEPARTMENT OF DEFENSE NAVIGATION REGULATIONS § 207.441 St. Marys Falls Canal and Locks... locks in the direction of the approaching tank vessel, unless the tank vessel is certified gas free or...

  9. 33 CFR 207.441 - St. Marys Falls Canal and Locks, Mich.; security.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 33 Navigation and Navigable Waters 3 2014-07-01 2014-07-01 false St. Marys Falls Canal and Locks... OF THE ARMY, DEPARTMENT OF DEFENSE NAVIGATION REGULATIONS § 207.441 St. Marys Falls Canal and Locks... locks in the direction of the approaching tank vessel, unless the tank vessel is certified gas free or...

  10. Using the "Mary Tyler Moore Show" as a Feminist Teaching Tool

    ERIC Educational Resources Information Center

    Jule, Allyson

    2010-01-01

    This paper explores the use of "The Mary Tyler Moore Show" as a teaching tool used with a group of final-year undergraduate students who gathered together last academic year (2007-8) to explore Women in Leadership, as part of a Communications course. The research focus was: How can the use of "The Mary Tyler Moore Show" (a…

  11. 75 FR 39956 - Certificate of Alternative Compliance for the Offshore Supply Vessel MARIE ELISE

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-13

    ... SECURITY Coast Guard Certificate of Alternative Compliance for the Offshore Supply Vessel MARIE ELISE... Alternative Compliance was issued for the offshore supply vessel MARIE ELISE as required by 33 U.S.C. 1605(c... Title 33, Code of Federal Regulation, Parts 81 and 89, has been issued for the offshore supply...

  12. The Madonna's Reproduction(s): Mieville, Godard, and the Figure of Mary.

    ERIC Educational Resources Information Center

    Erb, Cynthia

    1993-01-01

    Discusses how an assessment of "Le Livre de Marie" and "Je Vous Salue, Marie" risks reproducing the feminine/masculine dynamic by posing the films as male and female versions of the Marian myth. Acknowledges that evidence for this dichotomy exists, but both directors succeed in activating the Marian myth in ways that do not…

  13. In situ single-cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2-positive breast cancer.

    PubMed

    Janiszewska, Michalina; Liu, Lin; Almendro, Vanessa; Kuang, Yanan; Paweletz, Cloud; Sakr, Rita A; Weigelt, Britta; Hanker, Ariella B; Chandarlapaty, Sarat; King, Tari A; Reis-Filho, Jorge S; Arteaga, Carlos L; Park, So Yeon; Michor, Franziska; Polyak, Kornelia

    2015-10-01

    Detection of minor, genetically distinct subpopulations within tumors is a key challenge in cancer genomics. Here we report STAR-FISH (specific-to-allele PCR-FISH), a novel method for the combined detection of single-nucleotide and copy number alterations in single cells in intact archived tissues. Using this method, we assessed the clinical impact of changes in the frequency and topology of PIK3CA mutation and HER2 (ERBB2) amplification within HER2-positive breast cancer during neoadjuvant therapy. We found that these two genetic events are not always present in the same cells. Chemotherapy selects for PIK3CA-mutant cells, a minor subpopulation in nearly all treatment-naive samples, and modulates genetic diversity within tumors. Treatment-associated changes in the spatial distribution of cellular genetic diversity correlated with poor long-term outcome following adjuvant therapy with trastuzumab. Our findings support the use of in situ single cell-based methods in cancer genomics and imply that chemotherapy before HER2-targeted therapy may promote treatment resistance.

  14. In situ single cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2+ breast cancer

    PubMed Central

    Janiszewska, Michalina; Liu, Lin; Almendro, Vanessa; Kuang, Yanan; Paweletz, Cloud; Sakr, Rita A.; Weigelt, Britta; Hanker, Ariella B.; Chandarlapaty, Sarat; King, Tari A.; Reis-Filho, Jorge S.; Arteaga, Carlos L.; Park, So Yeon; Michor, Franziska; Polyak, Kornelia

    2015-01-01

    Detection of minor genetically distinct subpopulations within tumors is a key challenge in cancer genomics. Here we report STAR-FISH (Specific-To-Allele PCR – FISH), a novel method for the combined detection of single nucleotide and copy number alterations in single cells in intact archived tissues. Using this method, we assessed the clinical impact of changes in the frequency and topology of PIK3CA mutation and HER2/ERBB2 amplification within HER2+ breast cancer during neoadjuvant therapy. We found that the two genetic events are not always present within the same cell. Chemotherapy selects for PIK3CA mutant cells, a minor subpopulation in nearly all treatment-naïve samples, and modulates genetic diversity within tumors. Treatment-associated changes in spatial distribution of cellular genetic diversity correlated with poor long-term outcome following adjuvant trastuzumab therapy. Our findings support the use of in situ single-cell based methods in cancer genomics and imply that chemotherapy before HER2-targeted therapy may promote treatment resistance. PMID:26301495

  15. High-Throughput Mutation Profiling of Primary and Metastatic Endometrial Cancers Identifies KRAS, FGFR2 and PIK3CA to Be Frequently Mutated

    PubMed Central

    Seidel, Danila; Kusonmano, Kanthida; Petersen, Kjell; Mjøs, Siv; Hoivik, Erling A.; Wik, Elisabeth; Halle, Mari Kyllesø; Øyan, Anne M.; Kalland, Karl-Henning; Werner, Henrica Maria Johanna; Trovik, Jone; Salvesen, Helga

    2012-01-01

    Background Despite being the most common pelvic gynecologic malignancy in industrialized countries, no targeted therapies are available for patients with metastatic endometrial carcinoma. In order to improve treatment, underlying molecular characteristics of primary and metastatic disease must be explored. Methodology/Principal Findings We utilized the mass spectrometric-based mutation detection technology OncoMap to define the types and frequency of point somatic mutations in endometrial cancer. 67 primary tumors, 15 metastases corresponding to 7 of the included primary tumors and 11 endometrial cancer cell lines were screened for point mutations in 28 known oncogenes. We found that 27 (40.3%) of 67 primary tumors harbored one or more mutations with no increase in metastatic lesions. FGFR2, KRAS and PIK3CA were consistently the most frequently mutated genes in primary tumors, metastatic lesions and cell lines. Conclusions/Significance Our results emphasize the potential for targeting FGFR2, KRAS and PIK3CA mutations in endometrial cancer for development of novel therapeutic strategies. PMID:23300780

  16. Promoter variant of PIK3C3 is associated with autoimmunity against Ro and Sm epitopes in African-American lupus patients.

    PubMed

    Kariuki, Silvia N; Franek, Beverly S; Mikolaitis, Rachel A; Utset, Tammy O; Jolly, Meenakshi; Skol, Andrew D; Niewold, Timothy B

    2010-01-01

    The PIK3C3 locus was implicated in case-case genome-wide association study of systemic lupus erythematosus (SLE) which we had performed to detect genes associated with autoantibodies and serum interferon-alpha (IFN-alpha). Herein, we examine a PIK3C3 promoter variant (rs3813065/-442 C/T) in an independent multiancestral cohort of 478 SLE cases and 522 controls. rs3813065 C was strongly associated with the simultaneous presence of both anti-Ro and anti-Sm antibodies in African-American patients [OR = 2.24 (1.34-3.73), P = 2.0 x 10(-3)]. This autoantibody profile was associated with higher serum IFN-alpha (P = 7.6 x 10(-6)). In the HapMap Yoruba population, rs3813065 was associated with differential expression of ERAP2 (P = 2.0 x 10(-5)), which encodes an enzyme involved in MHC class I peptide processing. Thus, rs3813065 C is associated with a particular autoantibody profile and altered expression of an MHC peptide processing enzyme, suggesting that this variant modulates serologic autoimmunity in African-American SLE patients.

  17. Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer.

    PubMed

    Wang, Dong; Wang, Min; Jiang, Nan; Zhang, Yuan; Bian, Xing; Wang, Xiaoqing; Roberts, Thomas M; Zhao, Jean J; Liu, Pixu; Cheng, Hailing

    2016-03-15

    Recent preclinical studies revealed the efficacy of combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib in breast and prostate cancers. The current study investigated the effect of such drug combination on ovarian cancer. Here we showed that combined inhibition of PI3K and PARP effectively synergized to inhibit proliferation, survival and invasion in the majority of ovarian cancer cell lines harboring PIK3CA mutations, including SKOV3, HEYA8, and IGROV1. Mechanistically, combined treatment of PARP and PI3K inhibitors resulted in an exacerbated DNA damage response and more substantially reduced AKT/mTOR signaling when compared to single-agent. Notably, ovarian cancer cells responsive to the PI3K/PARP combination displayed decreased BRCA1/2 expression upon drug treatment. Furthermore, the effect of the drug combination was corroborated in an intraperitoneal dissemination xenograft mouse model in which SKOV3 ovarian cancer cells responded with significantly decreased BRCA1 expression, suppressed PI3K/AKT signaling and reduced tumor burden. Collectively, our data suggested that combined inhibition of PI3K and PARP may be an effective therapeutic strategy for ovarian cancers with PIK3CA mutations and that the accompanied BRCA downregulation following PI3K inhibition could serve as a biomarker for the effective response to PARP inhibition.

  18. Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer

    PubMed Central

    Wang, Dong; Wang, Min; Jiang, Nan; Zhang, Yuan; Bian, Xing; Wang, Xiaoqing; Roberts, Thomas M.; Zhao, Jean J.; Liu, Pixu; Cheng, Hailing

    2016-01-01

    Recent preclinical studies revealed the efficacy of combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib in breast and prostate cancers. The current study investigated the effect of such drug combination on ovarian cancer. Here we showed that combined inhibition of PI3K and PARP effectively synergized to inhibit proliferation, survival and invasion in the majority of ovarian cancer cell lines harboring PIK3CA mutations, including SKOV3, HEYA8, and IGROV1. Mechanistically, combined treatment of PARP and PI3K inhibitors resulted in an exacerbated DNA damage response and more substantially reduced AKT/mTOR signaling when compared to single-agent. Notably, ovarian cancer cells responsive to the PI3K/PARP combination displayed decreased BRCA1/2 expression upon drug treatment. Furthermore, the effect of the drug combination was corroborated in an intraperitoneal dissemination xenograft mouse model in which SKOV3 ovarian cancer cells responded with significantly decreased BRCA1 expression, suppressed PI3K/AKT signaling and reduced tumor burden. Collectively, our data suggested that combined inhibition of PI3K and PARP may be an effective therapeutic strategy for ovarian cancers with PIK3CA mutations and that the accompanied BRCA downregulation following PI3K inhibition could serve as a biomarker for the effective response to PARP inhibition. PMID:26909613

  19. Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signaling

    PubMed Central

    Chandler, Ronald L.; Damrauer, Jeffrey S.; Raab, Jesse R.; Schisler, Jonathan C.; Wilkerson, Matthew D.; Didion, John P.; Starmer, Joshua; Serber, Daniel; Yee, Della; Xiong, Jessie; Darr, David B.; Pardo-Manuel de Villena, Fernando; Kim, William Y.; Magnuson, Terry

    2014-01-01

    Ovarian clear-cell carcinoma (OCCC) is an aggressive form of ovarian cancer with high ARID1A mutation rates. Here we present a mutant mouse model of OCCC. We find that ARID1A inactivation is not sufficient for tumor formation, but requires concurrent activation of the phosphoinositide 3-kinase catalytic subunit, PIK3CA. Remarkably, the mice develop highly penetrant tumors with OCCC-like histopathology, culminating in hemorrhagic ascites and a median survival period of 7.5 weeks. Therapeutic treatment with the pan-PI3K inhibitor, BKM120, prolongs mouse survival by inhibiting tumor cell growth. Cross-species gene expression comparisons support a role for IL-6 inflammatory cytokine signaling in OCCC pathogenesis. We further show that ARID1A and PIK3CA mutations cooperate to promote tumor growth through sustained IL-6 overproduction. Our findings establish an epistatic relationship between SWI/SNF chromatin remodeling and PI3K pathway mutations in OCCC and demonstrate that these pathways converge on pro-tumorigenic cytokine signaling. We propose that ARID1A protects against inflammation-driven tumorigenesis. PMID:25625625

  20. 33 CFR 165.731 - Safety/Security Zone: Cumberland Sound, Georgia and St. Marys River Entrance Channel.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Sound, Georgia and St. Marys River Entrance Channel. 165.731 Section 165.731 Navigation and Navigable... Seventh Coast Guard District § 165.731 Safety/Security Zone: Cumberland Sound, Georgia and St. Marys River... waters and land from bank to bank within Cumberland Sound and the St. Marys Entrance Channel:...

  1. 33 CFR 165.731 - Safety/Security Zone: Cumberland Sound, Georgia and St. Marys River Entrance Channel.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Sound, Georgia and St. Marys River Entrance Channel. 165.731 Section 165.731 Navigation and Navigable... Seventh Coast Guard District § 165.731 Safety/Security Zone: Cumberland Sound, Georgia and St. Marys River... waters and land from bank to bank within Cumberland Sound and the St. Marys Entrance Channel:...

  2. 33 CFR 165.731 - Safety/Security Zone: Cumberland Sound, Georgia and St. Marys River Entrance Channel.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Sound, Georgia and St. Marys River Entrance Channel. 165.731 Section 165.731 Navigation and Navigable... Seventh Coast Guard District § 165.731 Safety/Security Zone: Cumberland Sound, Georgia and St. Marys River... waters and land from bank to bank within Cumberland Sound and the St. Marys Entrance Channel:...

  3. 33 CFR 165.731 - Safety/Security Zone: Cumberland Sound, Georgia and St. Marys River Entrance Channel.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Sound, Georgia and St. Marys River Entrance Channel. 165.731 Section 165.731 Navigation and Navigable... Seventh Coast Guard District § 165.731 Safety/Security Zone: Cumberland Sound, Georgia and St. Marys River... waters and land from bank to bank within Cumberland Sound and the St. Marys Entrance Channel:...

  4. Antoni Quintana-Mari (1907-1998): A Pioneer of the Use of History of Science in Science Education

    ERIC Educational Resources Information Center

    Roca-Rosell, Antoni; Grapi-Vilumara, Pere

    2010-01-01

    In the early 1930s, the young Antoni Quintana-Mari undertook some research on Antoni de Marti i Franques, one of the most prominent Catalan scientists of the Enlightenment. This scientist worked in Tarragona, where Quintana-Mari lived. Quintana-Mari learnt about Marti i Franques from Josep Estalella, his teacher of physics and chemistry at the…

  5. A space radiation shielding model of the Martian radiation environment experiment (MARIE)

    NASA Technical Reports Server (NTRS)

    Atwell, W.; Saganti, P.; Cucinotta, F. A.; Zeitlin, C. J.

    2004-01-01

    The 2001 Mars Odyssey spacecraft was launched towards Mars on April 7, 2001. Onboard the spacecraft is the Martian radiation environment experiment (MARIE), which is designed to measure the background radiation environment due to galactic cosmic rays (GCR) and solar protons in the 20-500 MeV/n energy range. We present an approach for developing a space radiation-shielding model of the spacecraft that includes the MARIE instrument in the current mapping phase orientation. A discussion is presented describing the development and methodology used to construct the shielding model. For a given GCR model environment, using the current MARIE shielding model and the high-energy particle transport codes, dose rate values are compared with MARIE measurements during the early mapping phase in Mars orbit. The results show good agreement between the model calculations and the MARIE measurements as presented for the March 2002 dataset. c2003 COSPAR. Published by Elsevier Ltd. All rights reserved.

  6. A space radiation shielding model of the Martian radiation environment experiment (MARIE)

    NASA Technical Reports Server (NTRS)

    Atwell, W.; Saganti, P.; Cucinotta, F. A.; Zeitlin, C. J.

    2004-01-01

    The 2001 Mars Odyssey spacecraft was launched towards Mars on April 7, 2001. Onboard the spacecraft is the Martian radiation environment experiment (MARIE), which is designed to measure the background radiation environment due to galactic cosmic rays (GCR) and solar protons in the 20-500 MeV/n energy range. We present an approach for developing a space radiation-shielding model of the spacecraft that includes the MARIE instrument in the current mapping phase orientation. A discussion is presented describing the development and methodology used to construct the shielding model. For a given GCR model environment, using the current MARIE shielding model and the high-energy particle transport codes, dose rate values are compared with MARIE measurements during the early mapping phase in Mars orbit. The results show good agreement between the model calculations and the MARIE measurements as presented for the March 2002 dataset. c2003 COSPAR. Published by Elsevier Ltd. All rights reserved.

  7. A space radiation shielding model of the Martian radiation environment experiment (MARIE).

    PubMed

    Atwell, W; Saganti, P; Cucinotta, F A; Zeitlin, C J

    2004-01-01

    The 2001 Mars Odyssey spacecraft was launched towards Mars on April 7, 2001. Onboard the spacecraft is the Martian radiation environment experiment (MARIE), which is designed to measure the background radiation environment due to galactic cosmic rays (GCR) and solar protons in the 20-500 MeV/n energy range. We present an approach for developing a space radiation-shielding model of the spacecraft that includes the MARIE instrument in the current mapping phase orientation. A discussion is presented describing the development and methodology used to construct the shielding model. For a given GCR model environment, using the current MARIE shielding model and the high-energy particle transport codes, dose rate values are compared with MARIE measurements during the early mapping phase in Mars orbit. The results show good agreement between the model calculations and the MARIE measurements as presented for the March 2002 dataset.

  8. Marie Bonaparte, her first two patients and the literary world.

    PubMed

    Amouroux, Rémy

    2010-08-01

    Marie Bonaparte (1882-1962) played a critical role in the development of psychoanalysis in France. Her clinical activity is not well known yet she was one of the first female French psychoanalysts. The journalist-writers Alice and Valerio Jahier were Bonaparte's first two patients. She conducted this dual analysis with Rudolph Loewenstein (1898-1976). Alice and Valerio exchanged analysts on several occasions. During his analysis, Valerio began corresponding with Italo Svevo (1861-1928), the author of La Coscienza di Zeno, who imparted his doubts on the therapeutic merits of psychoanalysis. Valerio described his difficult analysis in his letters to Svevo. Bonaparte consulted Freud on the subject, but was not able to prevent Valerio's suicide in 1939. The Princess of Greece encouraged Alice in her vocation as a writer and enabled her to benefit from her connections in literary circles. On the margins of this unpublished story of the two analyses, which is based on archived documents recently made available, we discover the importance of the links which were formed - around Marie Bonaparte - between psychoanalysis and literature. In addition to Italo Svevo, we come across the acerbic writer, Maurice Sachs, as well as the famous novelist, Stefan Zweig. Copyright © 2010 Institute of Psychoanalysis.

  9. Mary, a Pipeline to Aid Discovery of Optical Transients

    NASA Astrophysics Data System (ADS)

    Andreoni, I.; Jacobs, C.; Hegarty, S.; Pritchard, T.; Cooke, J.; Ryder, S.

    2017-09-01

    The ability to quickly detect transient sources in optical images and trigger multi-wavelength follow up is key for the discovery of fast transients. These include events rare and difficult to detect such as kilonovae, supernova shock breakout, and `orphan' Gamma-ray Burst afterglows. We present the Mary pipeline, a (mostly) automated tool to discover transients during high-cadenced observations with the Dark Energy Camera at Cerro Tololo Inter-American Observatory (CTIO). The observations are part of the `Deeper Wider Faster' programme, a multi-facility, multi-wavelength programme designed to discover fast transients, including counterparts to Fast Radio Bursts and gravitational waves. Our tests of the Mary pipeline on Dark Energy Camera images return a false positive rate of 2.2% and a missed fraction of 3.4% obtained in less than 2 min, which proves the pipeline to be suitable for rapid and high-quality transient searches. The pipeline can be adapted to search for transients in data obtained with imagers other than Dark Energy Camera.

  10. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis.

    PubMed

    De Roock, Wendy; Claes, Bart; Bernasconi, David; De Schutter, Jef; Biesmans, Bart; Fountzilas, George; Kalogeras, Konstantine T; Kotoula, Vassiliki; Papamichael, Demetris; Laurent-Puig, Pierre; Penault-Llorca, Frédérique; Rougier, Philippe; Vincenzi, Bruno; Santini, Daniele; Tonini, Giuseppe; Cappuzzo, Federico; Frattini, Milo; Molinari, Francesca; Saletti, Piercarlo; De Dosso, Sara; Martini, Miriam; Bardelli, Alberto; Siena, Salvatore; Sartore-Bianchi, Andrea; Tabernero, Josep; Macarulla, Teresa; Di Fiore, Frédéric; Gangloff, Alice Oden; Ciardiello, Fortunato; Pfeiffer, Per; Qvortrup, Camilla; Hansen, Tine Plato; Van Cutsem, Eric; Piessevaux, Hubert; Lambrechts, Diether; Delorenzi, Mauro; Tejpar, Sabine

    2010-08-01

    Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients with KRAS wild-type tumours still do not respond. We studied the effect of other downstream mutations on the efficacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre-KRAS selection era. 1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries. 773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses; mass spectrometry genotyping of tumour samples for KRAS, BRAF, NRAS, and PIK3CA was done centrally. We analysed objective response, progression-free survival (PFS), and overall survival in molecularly defined subgroups of the 649 chemotherapy-refractory patients treated with cetuximab plus chemotherapy. 40.0% (299/747) of the tumours harboured a KRAS mutation, 14.5% (108/743) harboured a PIK3CA mutation (of which 68.5% [74/108] were located in exon 9 and 20.4% [22/108] in exon 20), 4.7% (36/761) harboured a BRAF mutation, and 2.6% (17/644) harboured an NRAS mutation. KRAS mutants did not derive benefit compared with wild types, with a response rate of 6.7% (17/253) versus 35.8% (126/352; odds ratio [OR] 0.13, 95% CI 0.07-0.22; p<0.0001), a median PFS of 12 weeks versus 24 weeks (hazard ratio [HR] 1.98, 1.66-2.36; p<0.0001), and a median overall survival of 32 weeks versus 50 weeks (1.75, 1.47-2.09; p<0.0001). In KRAS wild types, carriers of BRAF and NRAS mutations had a significantly lower response rate than did BRAF and NRAS wild types

  11. PIK3R1 targeting by miR-21 suppresses tumor cell migration and invasion by reducing PI3K/AKT signaling and reversing EMT, and predicts clinical outcome of breast cancer.

    PubMed

    Yan, Li-Xu; Liu, Yan-Hui; Xiang, Jian-Wen; Wu, Qi-Nian; Xu, Lei-Bo; Luo, Xin-Lan; Zhu, Xiao-Lan; Liu, Chao; Xu, Fang-Ping; Luo, Dong-Lan; Mei, Ping; Xu, Jie; Zhang, Ke-Ping; Chen, Jie

    2016-02-01

    We have previously shown that dysregulation of miR-21 functioned as an oncomiR in breast cancer. The aim of the present study was to elucidate the mechanisms by which miR-21 regulate breast tumor migration and invasion. We applied pathway analysis on genome microarray data and target-predicting algorithms for miR-21 target screening, and used luciferase reporting assay to confirm the direct target. Thereafter, we investigated the function of the target gene phosphoinositide-3-kinase, regulatory subunit 1 (α) (PIK3R1), and detected PIK3R1 coding protein (p85α) by immunohistochemistry and miR-21 by RT-qPCR on 320 archival paraffin-embedded tissues of breast cancer to evaluate the correlation of their expression with prognosis. First, we found that PIK3R1 suppressed growth, invasiveness, and metastatic properties of breast cancer cells. Next, we identified the PIK3R1 as a direct target of miR-21 and showed that it was negatively regulated by miR-21. Furthermore, we demonstrated that p85α overexpression phenocopied the suppression effects of antimiR-21 on breast cancer cell growth, migration and invasion, indicating its tumor suppressor role in breast cancer. On the contrary, PIK3R1 knockdown abrogated antimiR‑21-induced effect on breast cancer cells. Notably, antimiR-21 induction increased p85α, accompanied by decreased p-AKT level. Besides, antimiR-21/PIK3R1-induced suppression of invasiveness in breast cancer cells was mediated by reversing epithelial-mesenchymal transition (EMT). p85α downregulation was found in 25 (7.8%) of the 320 breast cancer patients, and was associated with inferior 5-year disease-free survival (DFS) and overall survival (OS). Taken together, we provide novel evidence that miR-21 knockdown suppresses cell growth, migration and invasion partly by inhibiting PI3K/AKT activation via direct targeting PIK3R1 and reversing EMT in breast cancer. p85α downregulation defined a specific subgroup of breast cancer with shorter 5-year DFS and OS

  12. "Inhumanly brought back to life and misery": Mary Wollstonecraft, Frankenstein, and the Royal Humane Society.

    PubMed

    Williams, C

    2001-01-01

    While thorough investigation of many aspects of contemporary scientific developments and Mary Shelley's personal history have provided illuminating contexts for the study of Frankenstein, the activities of the Royal Humane Society, and other bodies and individuals who pioneered and publicized resuscitation techniques, have been comparatively neglected. Here we find a richly documented, highly conspicuous area of scientific endeavour, which generated much excitement in life and literature from the last quarter of the eighteenth century onwards. There are three major points of contact with Frankenstein: Victor Frankenstein's revival of dead tissue to make his creature; the frequent occurrences of unconsciousness and asphyxia, both in the novel and in Mary Shelley's family during the period leading up to its composition, and the widely differing degrees of competence and success with which they are treated; and the possibility that resuscitative techniques were used to revive Mary Shelley's mother, Mary Wollstonecraft, after a suicide attempt. The impact on Frankenstein of Mary Shelley's lifelong distress at the role she played in bringing about her mother's death in childbirth has been thoroughly canvassed by other critics, notably Anne Mellor, but the thought that Mary Shelley, who was herself conceived after her mother's second suicide attempt, might be, in a sense, a child of the dead adds a further turn to the Gothic screw. This study traces a hitherto unexplored intersection between Mary Shelley's first novel and her family history, as well as showing how it launches a formidable attack on the shady ethics and inconsiderate arrogance of some early resuscitators.

  13. A cardiac myocyte-restricted Lin28/let7 regulatory axis promotes hypoxia-mediated apoptosis by inducing the AKT signaling suppressor PIK3IP1

    PubMed Central

    Joshi, Shaurya; Wei, Jianqin; Bishopric, Nanette H.

    2015-01-01

    Rationale The let-7 family of microRNAs (miRs) regulates critical cell functions, including survival signaling, differentiation, metabolic control and glucose utilization. These functions may be important during myocardial ischemia. MiR-let-7 expression is under tight temporal and spatial control through multiple redundant mechanisms that may be stage-, isoform- and tissue-specific. Objective To determine the mechanisms and functional consequences of miR-let-7 regulation by hypoxia in the heart. Methods and Results MiR-let-7a, -7c and -7g were downregulated in the adult mouse heart early after coronary occlusion, and in neonatal rat ventricular myocytes subjected to hypoxia. Let-7 repression did not require glucose depletion, and occurred at a post-transcriptional level. Hypoxia also induced the RNA binding protein Lin28, a negative regulator of let-7. Hypoxia induced neither Lin28 induction nor miR-let-7 repression in cardiac fibroblasts. Both changes were abrogated by treatment with the histone deacetylase inhibitor trichostatin A. Restoration of let-7g to hypoxic myocytes and to ischemia-reperfused mouse hearts in vivo via lentiviral transduction potentiated the hypoxia-induced phosphorylation and activation of Akt, and prevented hypoxia-dependent caspase activation and death. Mechanistically, phosphotidyl inositol 3’kinase interacting protein 1 (PIK3IP1), a negative regulator of PI3K, was identified as a novel target of miR-let-7 by a crosslinking technique showing that miR-let-7g specifically targets PI3KIP1 to the cardiac myocyte Argonaute complex RISC. Finally, in non-failing and failing human myocardium, we found specific inverse relationships between Lin28 and miR-let-7g, and between miR-let-7g and PIK3IP1. Conclusion A conserved hypoxia-responsive Lin28-miR-let-7-PIK3IP1 regulatory axis is specific to cardiac myocytes and promotes apoptosis during myocardial ischemic injury. PMID:26655604

  14. Evaluation of PTEN loss and PIK3CA mutations and their correlation with efficacy of trastuzumab treatment in HER2-positive metastatic breast cancer: A retrospective study (KBC-SG 1001).

    PubMed

    Nishimura, Reiki; Arima, Nobuyuki; Toyoshima, Satoshi; Ohi, Yasuyo; Anan, Keisei; Sagara, Yasuaki; Mitsuyama, Shoshu; Tamura, Kazuo

    2013-01-01

    Trastuzumab (T) has contributed to improving the prognosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Although some patients have been unresponsive or resistant to T. Loss of phosphatase and tensin homolog (PTEN) deleted on chromosome 10, PIK3CA mutation and p95HER2 expression have been reported to potentially be responsible for the poor response to T. This is a small-scale pilot study to be followed by a large-scale investigation examining the association between the biomarkers and clinical response. Based on the response to T, patients were divided into 3 groups in terms of progression-free survival (PFS): PFS >8 months (group A, n=15), 3-8 months (group B, n=7) and PFS <3 months (group C, n=11). PTEN protein expression was detected by immunohistochemistry and PIK3CA mutation by direct sequencing. The median age was 61, 60 and 47 years in groups A, B and C, respectively, with statistically significant differences among the groups. No additional patient background factors differed between the groups. A decreased PTEN expression (H score, <100) was observed in 33.3 and 72.7% of patients in groups A and C, respectively. PTEN loss was slightly correlated with poor response to T. PIK3CA mutation frequency in exons 9/20 was 33.3% in group A and 27.3% in group C, with no significant correlation between PIK3CA mutation and clinical response. In this small-scale pilot study, a weak correlation was demonstrated between PTEN loss and poor response to T. This potential correlation is likely to be confirmed in the planned large-scale study, while the association of PIK3CA mutation and p95HER2 expression with poor response to T also requires examination.

  15. Alterations in p53, BRCA1, ATM, PIK3CA, and HER2 genes and their effect in modifying clinicopathological characteristics and overall survival of Bulgarian patients with breast cancer.

    PubMed

    Bozhanov, Stefan S; Angelova, Svetla G; Krasteva, Maria E; Markov, Tsanko L; Christova, Svetlana L; Gavrilov, Ivan G; Georgieva, Elena I

    2010-11-01

    Though p53, BRCA1, ATM, PIK3CA, and HER2 genes are shown to be involved in various aspects of breast carcinogenesis, their functional relationship and clinical value are still disputable. We investigated the genetic status or expression profile of these genes to further elucidate their clinical significance. PCR-SSCP-Sequencing of p53, BRCA1, ATM, and PIK3CA was performed in 145 Bulgarian patients with sporadic breast cancer. Expression profiles of HER2 were determined by ICH and CISH. Relationship between mutations and clinicopathological characteristics was evaluated by Chi-squared and Fisher's exact tests. Multivariate Cox proportional hazard test and Kaplan-Meier analysis were used to evaluate differences in overall survival between groups. The frequency of p53 (22.07%), BRCA1 (0.69%), ATM (7.59%), and PIK3CA (31.25%) alterations and HER2 (21.21%) overexpression was estimated. Mutated p53 was associated with tumor size (P = 0.033) and grade of malignancy (P = 0.001), ATM--with grade of malignancy (P = 0.032), and PIK3CA--with PR-positive tumors (P = 0.047). HER2 overexpression correlated with age of diagnosis (P = 0.009), tumor size (P = 0.0004), and ER expression (P = 0.011). Univariate survival analysis showed that mutated p53 is an indicator for worse outcome (P = 0.041). Combination of two genetic abnormalities did not correlate with more aggressive carcinogenesis and worse overall survival. Our data indicated that p53, BRCA1, ATM, PIK3CA, and HER2 alterations specifically correlate with clinicopathological characteristics of Bulgarian patients with breast cancer. Of these genes, only mutated p53 showed significant, though not independent, negative effect on overall survival.

  16. MaRIE: an experimental facility concept revolutionizing materials in extremes

    SciTech Connect

    Barnes, Cris W

    2011-01-07

    The Matter-Radiation Interactions in Extremes (MaRIE) project intends to create an experimental facility that will revolutionize the control of materials in extremes. That control extends to extreme regimes where solid material has failed and begins to flow - the regimes of fluid dynamics and turbulent mixing. This presentation introduces the MaRIE facility concept, demonstrates examples of the science case that determine its functional requirements, and kicks-off the discussion of the decadal scientific challenges of mixing in extremes, including those MaRIE might address.

  17. St. Mary cooks up awareness with heart-healthy booklet, television.

    PubMed

    Botvin, Judith D

    2003-01-01

    St. Mary Medical Center, Langhorne, Pa., distributed a half-million copies of its copyrighted booklet, "Heart Healthy Living" as the first of a larger, long-term marketing initiative to raise awareness of the suburban medical center. In addition to the medical center and physicians' offices, St. Mary had the booklet distributed by regional food markets and Fleet Bank. These partnerships and those with food products manufacturers helped reduce expenses. St. Mary physicians appeared on a cable television cooking show as well as in selected grocery markets.

  18. MaRIE: Probing Dynamic Processes in Soft Materials Using Advanced Light Sources

    SciTech Connect

    Sykora, Milan; Kober, Edward Martin

    2016-02-16

    Los Alamos National Laboratory has developed a concept for a new research facility, MaRIE: Matter-Radiation Interactions in Extremes. The key motivation for MaRIE is to develop new experimental capabilities needed to fill the existing gaps in our fundamental understanding of materials important for key National Nuclear Security Agency (NNSA) goals. MaRIE will bring two major new capabilities: (a) the ability to characterize the meso- and microstructure of materials in bulk as well as local dynamic response characteristics, and (b) the ability to characterize how this microstructure evolves under NNSA-relevant conditions and impacts the material’s performance in this regime.

  19. Noncompaction Cardiomyopathy with Charcot-Marie-Tooth Disease.

    PubMed

    Eltawansy, Sherif Ali; Bakos, Andrea; Checton, John

    2015-01-01

    We report a case of a 53-year-old female presenting with a new-onset heart failure that was contributed secondary to noncompaction cardiomyopathy. The diagnosis was made by echocardiogram and confirmed by cardiac MRI. Noncompaction cardiomyopathy (also known as ventricular hypertrabeculation) is a newly discovered disease. It is considered to be congenital (genetic) cardiomyopathy. It is usually associated with genetic disorders and that could explain the genetic pathogenesis of the non-compaction cardiomyopathy. Our case had a history of Charcot-Marie-Tooth disease. There is a high incidence of arrhythmia and embolic complications. The treatment usually consists of the medical management, defibrillator placement, and lifelong anticoagulation. Heart transplantation will be the last resort.

  20. Therapeutic options in Charcot-Marie-Tooth diseases.

    PubMed

    Mathis, Stéphane; Magy, Laurent; Vallat, Jean-Michel

    2015-04-01

    Charcot-Marie-Tooth (CMT) diseases represent a heterogeneous genetic disorder (more than 80 genes are implicated in these inherited neuropathies), but sharing a similar phenotype. In recent years, advances in molecular genetics and molecular biology, and also the development of various animal models of CMT, have led to a better understanding. Taken together, this knowledge represents a prerequisite for the development of future therapies in CMT, and in peripheral nervous system disorders in general. The efficacy of various substances has been shown in vitro and also in vivo (in animal models); but, no significant positive effect has yet been confirmed in humans. However, some of these trials are still in development, and we may expect positive results in the future. Although CMT is still an incurable disease, symptomatic treatments (physiotherapy, surgery, analgesic, etc.) are crucial to improve the quality of life of CMT patients.

  1. Unilateral opercular infarction presenting with Foix-Chavany-Marie Syndrome.

    PubMed

    Ohtomo, Ryo; Iwata, Atsushi; Tsuji, Shoji

    2014-01-01

    A 76-year-old man with a history of pontine, cerebellar infaction suddenly became speechless during the procedure of percutaneous coronary intervention. On examination, he was unable to close his mouth voluntarily, but spontaneous closing was preserved when smiling. He had anarthria and hypophonia, although his comprehension was preserved. He also had a severe dysphagia. Radiological studies revealed an acute stroke in the left anterior operculum, indicating Foix-Chavany-Marie Syndrome (FCMS) caused by a unilateral opercular lesion. Pathophysiology of the previous cases reported as unilateral FCMS remains controversial, but in our case, it could be delineated by the combination of the new lesion in the unilateral operculum and the old one in the contralateral pons. Since FCMS is not only related to biopercular lesions, we should consider thorough radiologic examination to clarify its anatomic basis.

  2. Bandwidth efficient block codes for M-ary PSK modulation

    NASA Technical Reports Server (NTRS)

    Lin, Shu

    1987-01-01

    A class of bandwidth efficient block codes for M-ary PSK modulation is presented. A soft-decision decoding for this class of codes is devised. Some specific short codes for Quad Phase Shift Key (QPSK), 8-PSK and 16-PSK modulations are constructed. These codes have good minimum squared Euclidean distances and provide 2 to 5.8 dB coding gains over uncoded QPSK modulation without (or with little) bandwidth expansion. The complete weight distributions of these specific codes are determined. Based on these weight distributions, their error probabilities are evaluated. Some of these codes have simple trellis structures and hence can be decoded by Viterbi decoding algorithm with relatively simple implementation. Moreover, the codes are very suitable for use as inner codes for various cascaded coding schemes with Reed-Solomon codes as outer codes.

  3. The lives of Mary Foote: painter and Jungian.

    PubMed

    Trousdell, Richard

    2016-11-01

    Mary Foote (1872-1968) was a successful early twentieth century American artist who suddenly closed her New York studio in 1926 to go to Zurich to study with Jung. There she joined his 'Interpretation of Visions' seminars (1930-1934), which she recorded and edited. This work won Jung's praise and his friendship, but all too often Foote was seen merely as a secretary or background figure. Deirdre Bair's biography of Jung suggested that Foote's life and work deserved fuller study, if only to rebalance our view of Jung's early women followers. This paper takes up that work to ask how Foote's early life and career led to her important work in preserving and describing Jung's earliest attempts to apply his theories to clinical practice. © 2016, The Society of Analytical Psychology.

  4. Florence Nightingale and Mary Seacole on nursing and health care.

    PubMed

    McDonald, Lynn

    2014-06-01

    The purpose of this article is to correct inaccurate information about both Mary Seacole and Florence Nightingale, material that promotes Seacole as a pioneer nurse and heroine, while either ignoring Nightingale or trivializing her contribution. Nursing journals have been prominent in promoting inaccurate accounts of the contribution of Seacole to nursing. Some have intermittently published positive material about Nightingale, but none has published redress. Discussion paper. Primary sources from 1855-2012 were found, which contradict some key claims made about Seacole. Further sources - not included here - are identified, with a website reference. It is argued that Nightingale remains relevant as a model for nurses, with the many crises in patient care and continuing challenges of hospital safety. Greater accuracy and honesty are required in reporting about nursing heroes. Without these, great ideas and examples can be lost to nursing and health care. © 2013 John Wiley & Sons Ltd.

  5. Sister Mary Joseph's nodule as initial pancreatic cancer manifestation.

    PubMed

    Vallejo Bernad, Cristina; Casamayor Franco, María Carmen; Hakim Alonso, Sofía

    2017-02-01

    We report the case of an 85-year-old female patient who presented with umbilical pain associated with an indurated growth, the whole being apparently consistent with incarcerated umbilical hernia, which prompted an urgent surgical procedure for its removal. The pathology study revealed dermal infiltration by a malignancy. Gland tumor cells expressed an immunohistochemical profile initially consistent with a pancreatic origin. In view of these findings a CT scan was performed, which revealed a pancreatic tail tumor as well as multiple hepatic metastasis. Skin metastasis is a rare sign usually reflecting a carcinoma of unknown origin. Umbilical skin metastasis, called Sister Mary Joseph´s nodule, reflect an intra-abdominal tumor, being pancreatic cancer strange.

  6. Overexpression of microRNA-634 suppresses survival and matrix synthesis of human osteoarthritis chondrocytes by targeting PIK3R1

    PubMed Central

    Cui, Xu; Wang, Shaojie; Cai, Heguo; Lin, Yuan; Zheng, Xinpeng; Zhang, Bing; Xia, Chun

    2016-01-01

    Osteoarthritis (OA) is a degenerative disease characterized by deterioration of articular cartilage. Recent studies have demonstrated the importance of some microRNAs in cartilage damage. The aim of this study was to identify and characterize the expression of microRNA-634 (miR-634) in normal and OA chondrocytes, and to determine its role in OA pathogenesis. Human normal and OA chondrocytes obtained from patients were cultured in vitro. Transfection with miR-634 mimic or inhibitor was employed to investigate the effect of miR-634 on chondrocyte survival and matrix synthesis, and to identify miR-634 target. The results indicated that miR-634 was expressed at lower level in high grade OA chondrocyte compared with normal chondrocytes. Overexpression of miR-634 could inhibit cell survival and matrix synthesis in high grade OA chondrocytes. Furthermore, miR-634 targeted PIK3R1 gene that encodes the regulatory subunit 1 of class I PI3K (p85α) and exerted its inhibitory effect on the phosphorylation of Akt, mTOR, and S6 signal molecules in high grade OA chondrocytes. Therefore, the data suggested that miR-634 could suppress survival and matrix synthesis of high grade OA chondrocytes through targeting PIK3R1 gene to modulate the PI3K/Akt/S6 and PI3K/Akt/mTOR/S6 axes, with important implication for validating miR-634 as a potential target for OA therapy. PMID:26972586

  7. Oncogenic mutations mimic and enhance dynamic events in the natural activation of phosphoinositide 3-kinase p110α (PIK3CA)

    PubMed Central

    Burke, John E.; Perisic, Olga; Masson, Glenn R.; Vadas, Oscar; Williams, Roger L.

    2012-01-01

    The p110α catalytic subunit (PIK3CA) is one of the most frequently mutated genes in cancer. We have examined the activation of the wild-type p110α/p85α and a spectrum of oncogenic mutants using hydrogen/deuterium exchange mass spectrometry (HDX-MS). We find that for the wild-type enzyme, the natural transition from an inactive cytosolic conformation to an activated form on membranes entails four distinct events. Analysis of oncogenic mutations shows that all up-regulate the enzyme by enhancing one or more of these dynamic events. We provide the first insight into the activation mechanism by mutations in the linker between the adapter-binding domain (ABD) and the Ras-binding domain (RBD) (G106V and G118D). These mutations, which are common in endometrial cancers, enhance two of the natural activation events: movement of the ABD and ABD–RBD linker relative to the rest of the catalytic subunit and breaking the C2–iSH2 interface on binding membranes. C2 domain mutants (N345K and C420R) also mimic these events, even in the absence of membranes. A third event is breaking the nSH2–helical domain contact caused by phosphotyrosine-containing peptides binding to the enzyme, which is mimicked by a helical domain mutation (E545K). Interaction of the C lobe of the kinase domain with membranes is the fourth activation event, and is potentiated by kinase domain mutations (e.g., H1047R). All mutations increased lipid binding and basal activity, even mutants distant from the membrane surface. Our results elucidate a unifying mechanism in which diverse PIK3CA mutations stimulate lipid kinase activity by facilitating allosteric motions required for catalysis on membranes. PMID:22949682

  8. Impact of KRAS, BRAF, PIK3CA, TP53 status and intraindividual mutation heterogeneity on outcome after liver resection for colorectal cancer metastases.

    PubMed

    Løes, Inger Marie; Immervoll, Heike; Sorbye, Halfdan; Angelsen, Jon-Helge; Horn, Arild; Knappskog, Stian; Lønning, Per Eystein

    2016-08-01

    We determined prognostic impact of KRAS, BRAF, PIK3CA and TP53 mutation status and mutation heterogeneity among 164 colorectal cancer (CRC) patients undergoing liver resections for metastatic disease. Mutation status was determined by Sanger sequencing of a total of 422 metastatic deposits. In univariate analysis, KRAS (33.5%), BRAF (6.1%) and PIK3CA (13.4%) mutations each predicted reduced median time to relapse (TTR) (7 vs. 22, 3 vs. 16 and 4 vs. 17 months; p < 0.001, 0.002 and 0.023, respectively). KRAS and BRAF mutations also predicted a reduced median disease-specific survival (DSS) (29 vs. 51 and 16 vs. 49 months; p <0.001 and 0.008, respectively). No effect of TP53 (60.4%) mutation status was observed. Postoperative, but not preoperative chemotherapy improved both TTR and DSS (p < 0.001 for both) with no interaction with gene mutation status. Among 94 patients harboring two or more metastatic deposits, 13 revealed mutation heterogeneity across metastatic deposits for at least one gene. Mutation heterogeneity predicted reduced median DSS compared to homogeneous mutations (18 vs. 37 months; p = 0.011 for all genes; 16 vs. 26 months; p < 0.001 analyzing BRAF or KRAS mutations separately). In multivariate analyses, KRAS or BRAF mutations consistently predicted poor TRR and DSS. Mutation heterogeneity robustly predicted DSS but not TTR, while postoperative chemotherapy improved both TTR and DSS. Our findings indicate that BRAF and KRAS mutations as well as mutation heterogeneity predict poor outcome in CRC patients subsequent to liver resections and might help guide treatment decisions. © 2016 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.

  9. DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations

    PubMed Central

    Abba, Martín C.; Zhong, Yi; Lee, Jaeho; Kil, Hyunsuk; Lu, Yue; Takata, Yoko; Simper, Melissa S.; Gaddis, Sally; Shen, Jianjun; Aldaz, C. Marcelo

    2016-01-01

    Controversy always existed on the utility of chemically induced mouse mammary carcinogenesis models as valid equivalents for the study of human breast cancer. Here, we performed whole exome and RNA sequencing on long latency mammary tumors (218 ± 27 days) induced by the carcinogen 7,12-Dimethylbenzathracene (DMBA) and short latency tumors (65 ± 11 days) induced by the progestin Medroxyprogesterone Acetate (MPA) plus DMBA in CD2F1 mice. Long latency tumors displayed a high frequency of Pi3kca and/or Pten mutations detected in 11 of 13 (85%) long latency cases (14/22, 64% overall). Eighty-two percent (9/11) of tumors carried the Pik3ca H1047L/R hot-spot mutation, as frequently found in human breast cancer. These tumors were luminal-like and mostly ER/PR+, as in humans. Transcriptome profiling indicated a significant activation of the PI3K-Akt pathway (p=3.82e-6). On the other hand MPA+DMBA induced short latency tumors displayed mutations in cancer drivers not commonly found mutated in human breast cancer (e.g. Hras and Apc). These tumors were mostly basal-like and MPA exposure led to Rankl overexpression (60 fold induction) and immunosuppressive gene expression signatures. In summary, long latency DMBA induced mouse mammary tumors reproduce the molecular profile of human luminal breast carcinomas representing an excellent preclinical model for the testing of PIK3CA/Akt/mTOR pathway inhibitory therapies and a good platform for the developing of additional preclinical tools such as syngeneic transplants in immunocompetent hosts. PMID:27588403

  10. Phosphatidylinositol 3-kinase p85 alpha regulatory subunit gene PIK3R1 haplotype is associated with body fat and serum leptin in a female twin population

    PubMed Central

    Jamshidi, Y.; Snieder, H.; Wang, X.; Pavitt, M. J.; Spector, T. D.; Carter, N. D.; O’Dell, S. D.

    2006-01-01

    Aims/hypothesis Phosphatidylinositol 3-kinase (PI3K) couples the leptin and insulin signalling pathways via IRS-1 and IRS-2. Hence, defective activation of PI3K could be a novel mechanism of peripheral leptin or insulin resistance. We investigated association of tagging SNPs (tSNPs) in the PI3K p85α regulatory subunit gene PIK3R1 with anthropometry, leptin, body fat and insulin sensitivity in a female twin population of European extraction. Methods Eight tSNPs were genotyped in 2778 women (mean age 47.4±12.5 years) from the St Thomas’ UK Adult Twin Registry (Twins UK). Results SNP rs1550805 was associated with serum leptin (P=0.028), BMI (P=0.025), weight (P=0.019), total fat (P=0.004), % total fat (P=0.002), waist (P=0.025), central fat (P=0.005) and % central fat (P=0.005). SNPs rs7713645 and rs7709243 were associated with BMI (P=0.020; P=0.029), rs7709243 with weight, total and central fat, (P=0.026; P=0.031; P=0.023) and both SNPs with fasting glucose (P=0.003; P=0.001) and glucose 2h post OGTT (P=0.023; P=0.007). Haplotype 222 (freq. 7.2%) showed higher serum leptin (P=0.007) and body fat measures (Ps≤0.001) and haplotype 221 (freq. 38.7%) showed higher fasting and 2h-glucose (P=0.035; P=0.021), compared with the most common haplotype 111 (freq. 45.5%). Conclusions/interpretation Association of the PIK3R1 SNP rs1550805 with serum leptin and body fat may reflect diminished ability of PI3K to signal via IRS-1 or IRS-2 in response to leptin. PMID:17016694

  11. Mediated Career Education at the Marie H. Katzenbach School for the Deaf

    ERIC Educational Resources Information Center

    Lenox, James; Hamilton, Ronald

    1973-01-01

    A comprehensive career education program which uses varieties of audiovisual aids for aurally handicapped students, 4 through 21 years of age, at the Marie H. Katzenbach School for the Deaf is described. (MC)

  12. 77 FR 49719 - Amendment of Class D Airspace; Sault Ste Marie, ON

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-17

    ... control zone over Sault Ste Marie Airport. The FAA is taking this action to enhance the safety and..., creating additional controlled airspace to coincide with that portion of the control zone in...

  13. A m-ary linear feedback shift register with binary logic

    NASA Technical Reports Server (NTRS)

    Perlman, M. (Inventor)

    1973-01-01

    A family of m-ary linear feedback shift registers with binary logic is disclosed. Each m-ary linear feedback shift register with binary logic generates a binary representation of a nonbinary recurring sequence, producible with a m-ary linear feedback shift register without binary logic in which m is greater than 2. The state table of a m-ary linear feedback shift register without binary logic, utilizing sum modulo m feedback, is first tubulated for a given initial state. The entries in the state table are coded in binary and the binary entries are used to set the initial states of the stages of a plurality of binary shift registers. A single feedback logic unit is employed which provides a separate feedback binary digit to each binary register as a function of the states of corresponding stages of the binary registers.

  14. Old Houses and Old Women: An Approach to Teaching Sara Orne Jewett and Mary Wilkins Freeman.

    ERIC Educational Resources Information Center

    Williamson, Judith Barton

    1992-01-01

    Describes how the literary works of Sara Orne Jewett and Mary Wilkins Freeman provide a unique opportunity to look at the lives of older women. Discusses a "life stages" approach to teaching literature. (PRA)

  15. De novo PMP2 mutations in families with type 1 Charcot-Marie-Tooth disease.

    PubMed

    Motley, William W; Palaima, Paulius; Yum, Sabrina W; Gonzalez, Michael A; Tao, Feifei; Wanschitz, Julia V; Strickland, Alleene V; Löscher, Wolfgang N; De Vriendt, Els; Koppi, Stefan; Medne, Livija; Janecke, Andreas R; Jordanova, Albena; Zuchner, Stephan; Scherer, Steven S

    2016-06-01

    We performed whole exome sequencing on a patient with Charcot-Marie-Tooth disease type 1 and identified a de novo mutation in PMP2, the gene that encodes the myelin P2 protein. This mutation (p.Ile52Thr) was passed from the proband to his one affected son, and segregates with clinical and electrophysiological evidence of demyelinating neuropathy. We then screened a cohort of 136 European probands with uncharacterized genetic cause of Charcot-Marie-Tooth disease and identified another family with Charcot-Marie-Tooth disease type 1 that has a mutation affecting an adjacent amino acid (p.Thr51Pro), which segregates with disease. Our genetic and clinical findings in these kindred demonstrate that dominant PMP2 mutations cause Charcot-Marie-Tooth disease type 1. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  16. X-linked Charcot-Marie-Tooth disease predominates in a cohort of multiethnic Malaysian patients.

    PubMed

    Shahrizaila, Nortina; Samulong, Sarimah; Tey, Shelisa; Suan, Liaw Chiew; Meng, Lao Kah; Goh, Khean Jin; Ahmad-Annuar, Azlina

    2014-02-01

    Data regarding Charcot-Marie-Tooth disease is lacking in Southeast Asian populations. We investigated the frequency of the common genetic mutations in a multiethnic Malaysian cohort. Patients with features of Charcot-Marie-Tooth disease or hereditary liability to pressure palsies were investigated for PMP22 duplication, deletion, and point mutations and GJB1, MPZ, and MFN2 point mutations. Over a period of 3 years, we identified 25 index patients. A genetic diagnosis was reached in 60%. The most common were point mutations in GJB1, accounting for X-linked Charcot-Marie-Tooth disease (24% of the total patient population), followed by PMP22 duplication causing Charcot-Marie-Tooth disease type 1A (20%). We also discovered 2 novel GJB1 mutations, c.521C>T (Proline174Leucine) and c.220G>A (Valine74Methionine). X-linked Charcot-Marie-Tooth disease was found to predominate in our patient cohort. We also found a better phenotype/genotype correlation when applying a more recently recommended genetic approach to Charcot-Marie-Tooth disease. Copyright © 2013 Wiley Periodicals, Inc.

  17. Genetic epidemiology of Charcot-Marie-Tooth disease.

    PubMed

    Braathen, G J

    2012-01-01

    Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. The frequency of different CMT genotypes has been estimated in clinic populations, but prevalence data from the general population is lacking. Point mutations in the mitofusin 2 (MFN2) gene has been identified exclusively in Charcot-Marie-Tooth disease type 2 (CMT2), and in a single family with intermediate CMT. MFN2 point mutations are probably the most common cause of CMT2. The CMT phenotype caused by mutation in the myelin protein zero (MPZ) gene varies considerably, from early onset and severe forms to late onset and milder forms. The mechanism is not well understood. The myelin protein zero (P(0) ) mediates adhesion in the spiral wraps of the Schwann cell's myelin sheath. X-linked Charcot-Marie Tooth disease (CMTX) is caused by mutations in the connexin32 (cx32) gene that encodes a polypeptide which is arranged in hexameric array and form gap junctions. Estimate prevalence of CMT. Estimate frequency of Peripheral Myelin Protein 22 (PMP22) duplication and point mutations, insertions and deletions in Cx32, Early growth response 2 (EGR2), MFN2, MPZ, PMP22 and Small integral membrane protein of lysosome/late endosome (SIMPLE) genes. Description of novel mutations in Cx32, MFN2 and MPZ. Description of de novo mutations in MFN2. Our population based genetic epidemiological survey included persons with CMT residing in eastern Akershus County, Norway. The participants were interviewed and examined by one geneticist/neurologist, and classified clinically, neurophysiologically and genetically. Two-hundred and thirty-two consecutive unselected and unrelated CMT families with available DNA from all regions in Norway were included in the MFN2 study. We screened for point mutations in the MFN2 gene. We describe four novel mutations, two in the connexin32 gene and two in the MPZ gene. A total of 245 affected from 116 CMT families from the general population of eastern

  18. Princess Marie Bonaparte, Edgar Allan Poe, and psychobiography.

    PubMed

    Warner, S L

    1991-01-01

    Princess Marie Bonaparte was a colorful yet mysterious member of Freud's inner circle of psychoanalysis. In analysis with Freud beginning in 1925 (she was then 45 years old), she became a lay analyst and writer of many papers and books. Her most ambitious task was a 700-page psychobiography of Edgar Allan Poe that was first published in French in 1933. She was fascinated by Poe's gothic stories--with the return to life of dead persons and the eerie, unexpected turns of events. Her fascination with Poe can be traced to the similarity of their early traumatic life experiences. Bonaparte had lost her mother a month after her birth. Poe's father deserted the family when Edgar was two years old, and his mother died of tuberculosis when he was three. Poe's stories helped him to accommodate to these early traumatic losses. Bonaparte vicariously shared in Poe's loss and the fantasies of the return of the deceased parent in his stories. She was sensitive and empathetic to Poe's inner world because her inner world was similar. The result of this psychological fit between Poe and Bonaparte was her psychobiography, The Life and Works of Edgar Allan Poe. It was a milestone in psychobiography but limited in its psychological scope by its strong emphasis on early childhood trauma. Nevertheless it proved Bonaparte a bona fide creative psychoanalyst and not a dilettante propped up by her friendship with Freud.

  19. ACQUIRED PES CAVUS IN CHARCOT-MARIE-TOOTH DISEASE

    PubMed Central

    Carvalho Maranho, Daniel Augusto; Volpon, José Batista

    2015-01-01

    Hereditary motor and sensory neuropathies, especially Charcot-Marie-Tooth disease, are frequently expressed with an acquired cavusvarus foot which is characterized by a fixed increase of the plantar arch and hindfoot inversion. Diagnosis of the underlying condition achieved through careful patient assessment and local evaluations is the keystone for decision-making about the adequate treatment. The cavus may present as an isolated deformity of the forefoot, hindfoot or it may be a combination of both locations. Related deformities, mainly the varus and toe clawing require appropriate evaluation; clinical characteristics such as severity of the deformity, impairment of the muscular power, flexibility and patient's age are important characteristics in the treatment decision. Conservative treatment of the cavusvarus foot with physiotherapy, insoles and shoe modifications are reserved to young patients and mild deformities. However, there is a tendency of the deformity to become more severe over time because of the progressive feature of the underlying neurological condition. So, the surgical treatment by using classical techniques is performed in early stages. Most importantly is the identification of the primary and main components of each deformity to properly correct them, if possible. Muscular transfers are used to treat the dynamic unbalance, retracted structures should be either divided or lengthened and localized osteotomies should be preferred over arthrodeses, which are reserved for stiff and severely deformed feet in adults. PMID:27077056

  20. ACQUIRED PES CAVUS IN CHARCOT-MARIE-TOOTH DISEASE.

    PubMed

    Carvalho Maranho, Daniel Augusto; Volpon, José Batista

    2009-01-01

    Hereditary motor and sensory neuropathies, especially Charcot-Marie-Tooth disease, are frequently expressed with an acquired cavusvarus foot which is characterized by a fixed increase of the plantar arch and hindfoot inversion. Diagnosis of the underlying condition achieved through careful patient assessment and local evaluations is the keystone for decision-making about the adequate treatment. The cavus may present as an isolated deformity of the forefoot, hindfoot or it may be a combination of both locations. Related deformities, mainly the varus and toe clawing require appropriate evaluation; clinical characteristics such as severity of the deformity, impairment of the muscular power, flexibility and patient's age are important characteristics in the treatment decision. Conservative treatment of the cavusvarus foot with physiotherapy, insoles and shoe modifications are reserved to young patients and mild deformities. However, there is a tendency of the deformity to become more severe over time because of the progressive feature of the underlying neurological condition. So, the surgical treatment by using classical techniques is performed in early stages. Most importantly is the identification of the primary and main components of each deformity to properly correct them, if possible. Muscular transfers are used to treat the dynamic unbalance, retracted structures should be either divided or lengthened and localized osteotomies should be preferred over arthrodeses, which are reserved for stiff and severely deformed feet in adults.

  1. The contribution of women to radiobiology: Marie Curie and beyond.

    PubMed

    Gasinska, Anna

    2016-01-01

    Marie Sklodowska-Curie, an extraordinary woman, a Polish scientist who lived and worked in France, led to the development of nuclear energy and the treatment of cancer. She was the laureate of two Nobel Prizes, the first woman in Europe who obtained the degree of Doctor of Science and opened the way for women to enter fields which had been previously reserved for men only. As a result of her determination and her love of freedom, she has become an icon for many female scientists active in radiation sciences. They are successors of Maria Curie and without the results of their work, improvement in radiation oncology will not be possible. Many of them shared some elements of Maria Curie's biography, like high ethical and moral standards, passionate dedication to work, strong family values, and scientific collaboration with their husbands. The significance of Tikvah Alper, Alma Howard, Shirley Hornsey, Juliana Denekamp, Helen Evans, Eleanor Blakely, Elizabeth L. Travis, Fiona Stewart, Andree Dutreix, Catharine West, Peggy Olive, Ingela Turesson, Penny Jeggo, Irena Szumiel, Eleonor Blakely, Sara Rockwell and Carmel Mothersill contribution to radiation oncology is presented. All the above mentioned ladies made significant contribution to the development of radiotherapy (RT) and more efficient cancer treatment. Due to their studies, new schedules of RT and new types of ionizing radiation have been applied, lowering the incidence of normal tissue toxicity. Their achievements herald a future of personalized medicine.

  2. Charcot Marie Tooth (CMT) Subtypes and Genetic Testing Strategies

    PubMed Central

    Saporta, Anita S.D.; Sottile, Stephanie L.; Miller, Lindsey J.; Feely, Shawna M.E.; Siskind, Carly E; Shy, Michael E.

    2010-01-01

    Background Charcot Marie Tooth disease (CMT) affects one in 2500 people and is caused by mutations in more than 30 genes. Identifying the genetic cause of CMT is often necessary for family planning, natural history studies and for entry into clinical trials. However genetic testing can be both expensive and confusing to patients and physicians. Methods We analyzed data from 1024 of our patients to determine the percentage and features of each CMT subtype within this clinic population. We identified distinguishing clinical and physiological features of the subtypes that could be used to direct genetic testing for patients with CMT. Findings Of 1024 patients evaluated, 787 received CMT diagnoses. Five hundred twenty-seven patients with CMT (67%) received a genetic subtype, while 260 did not have a mutation identified. The most common CMT subtypes were CMT1A, CMT1X, HNPP, CMT1B, and CMT2A. All other subtypes accounted for less than 1% each. Eleven patients had more than one genetically identified subtype of CMT. Patients with genetically identified CMT were separable into specific groups based on age of onset and the degree of slowing of motor nerve conduction velocities. Interpretation Combining features of the phenotypic and physiology groups allowed us to identify patients who were highly likely to have specific subtypes of CMT. Based on these results, we propose a strategy of focused genetic testing for CMT illustrated in a series of flow diagrams created as testing guides. PMID:21280073

  3. The shifting paradigm of Charcot-Marie-Tooth disease.

    PubMed

    Echaniz-Laguna, A

    2015-01-01

    Molecular studies have created a paradigm shift in our perception of Charcot-Marie-Tooth disease (CMT). Indeed, CMT has evolved from the concept of a rather homogeneous hereditary disease exclusively involving peripheral nerves to the concept of a highly heterogeneous clinical and genetic syndrome mainly - but sometimes not exclusively - involving the peripheral nervous system. The phenotypic spectrum of CMT overlaps with other inherited neuropathies such as distal hereditary motor neuropathy (dHMN), hereditary sensory and autonomic neuropathy (HSAN), spinal muscular atrophy (SMA) subtypes, and the neuropathies of mitochondrial disorders. At a molecular level, mutations in one given gene may alternatively provoke CMT, HSAN, dHMN or SMA variants. Over the last years, there have been dramatic advances in deciphering the molecular basis for many CMT subtypes and more than 900 different mutations in more than 60 causative genes are now described. However, as 75% of CMT causative genes apparently remain unknown and as disease-specific therapies are not available, major advances are yet to come in the field of CMT.

  4. Systematic review of exercise for Charcot-Marie-Tooth disease.

    PubMed

    Sman, Amy D; Hackett, Daniel; Fiatarone Singh, Maria; Fornusek, Ché; Menezes, Manoj P; Burns, Joshua

    2015-12-01

    Charcot-Marie-Tooth disease (CMT) is a slowly progressive hereditary degenerative disease and one of the most common neuromuscular disorders. Exercise may be beneficial to maintain strength and function for people with CMT, however, no comprehensive evaluation of the benefits and risks of exercise have been conducted. A systematic review was completed searching numerous electronic databases from earliest records to February 2015. Studies of any design including participants of any age with confirmed diagnosis of CMT that investigated the effects of exercise were eligible for inclusion. Of 13,301 articles identified following removal of duplicates, 11 articles including 9 unique studies met the criteria. Methodological quality of studies was moderate, sample sizes were small, and interventions and outcome measures used varied widely. Although the majority of the studies identified changes in one or more outcome measurements across exercise modalities, the majority were non-significant, possibly due to Type II errors. Significant effects described included improvements in strength, functional activities, and physiological adaptations following exercise. Despite many studies showing changes in strength and function following exercise, findings of this review should be met with caution due to the few studies available and moderate quality of evidence. Well-powered studies, harmonisation of outcome measures, and clearly described interventions across studies would improve the quality and comparability of the evidence base. The optimal exercise modality and intensity for people with CMT as well as the long-term safety of exercise remain unclear.

  5. Modeling protein misfolding in charcot-marie-tooth disease.

    PubMed

    Theocharopoulou, Georgia; Vlamos, Panayiotis

    2015-01-01

    Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder. Recent advancements in molecular biology have elucidated the molecular bases of this genetically heterogeneous neuropathy. Still, the major challenge lies in determining the individual contributions by malfunctions of proteins to the disease's pathology. This paper reviews the identified molecular mechanisms underlying major forms of CMT disease. A growing body of evidence has highlighted the role of protein misfolding in demyelinating peripheral neuropathies and neurodegenerative diseases. Several hypotheses have been proposed to explain how misfolded aggregates induce neuronal damage. Current research focuses on developing novel therapeutic targets which aim to prevent, or even reverse the formation of protein aggregation. Interestingly, the role of the cellular defence mechanisms against accumulation of misfolded proteins may play a key role leading to novel strategies for treatment accelerating the clearance of their toxic early aggregates. Based on these findings we propose a model for describing in terms of a formal computer language, the biomolecular processes involving proteins associated with CMT disease.

  6. [Charcot-Marie-Tooth (CMT) disease: an update].

    PubMed

    Vallat, Jean-Michel; Funalot, Benoît

    2010-10-01

    Charcot-Marie-Tooth (CMT) is the generic name given to a group of genetic disorders characterized by a relatively isolated dysfunction of peripheral nerves, with combined motor and sensory impairment. These CMT syndromes are the most frequent genetically-determined peripheral neuropathies, with a global prevalence between 4.7 and 36/100,000. Their clinical phenotype is predominantly motor, with a grossly symmetrical distal amyotrophy involving both lower and upper limbs. Mode of inheritance is variable: autosomal dominant, autosomal recessive or X-linked. Apparently sporadic forms can be a difficult diagnosis and they must be considered in all patients with a chronic polyneuropathy which is not clearly of acquired origin. During the last two decades, the identification of more than 25 genes mutated in CMT syndromes has complicated the classification of these disorders. Knowledge of the function of some of these genes has improved our understanding of the pathogenesis of myelinic or axonal dysfunction in CMT, but for some others their function remains elusive or unknown.

  7. Murine therapeutic models for Charcot-Marie-Tooth (CMT) disease.

    PubMed

    Fledrich, Robert; Stassart, Ruth M; Sereda, Michael W

    2012-06-01

    Charcot-Marie-Tooth (CMT) disease represents a broad group of inherited motor and sensory neuropathies which can originate from various genetic aberrations, e.g. mutations, deletions and duplications. We performed a literature review on murine animal models of CMT disease with regard to experimental therapeutic approaches. Hereby, we focussed on the demyelinating subforms of CMT (CMT1). PubMed items were CMT, animal model, demyelination and therapy. Patients affected by CMT suffer from slowly progressive, distally pronounced muscle atrophy caused by an axonal loss. The disease severity is highly variable and impairments may result in wheelchair boundness. No therapy is available yet. Numerous rodent models for the various CMT subtypes are available today. The selection of the correct animal model for the specific CMT subtype provides an important prerequisite for the successful translation of experimental findings in patients. Despite more than 20 years of remarkable progress in CMT research, the disease is still left untreatable. There is a growing number of experimental therapeutic strategies that may be translated into future clinical trials in patients with CMT. The slow disease progression and insensitive outcome measures hamper clinical therapy trials in CMT. Biomarkers may provide powerful tools to monitor therapeutic efficacy. Recently, we have shown that transcriptional profiling can be utilized to assess and predict the disease severity in a transgenic rat model and in affected humans.

  8. Charcot-Marie-Tooth disease and other inherited neuropathies.

    PubMed

    Saporta, Mario A

    2014-10-01

    Inherited peripheral neuropathies are among the most common genetic neuromuscular disorders worldwide. However, their diagnosis can be challenging due to genotypic and phenotypic variability. Charcot-Marie-Tooth disease (CMT), the most common form, is associated with mutations or copy-number variations in over 70 genes, representing proteins with fundamental roles in the development and function of Schwann cells and peripheral axons. Other genetic peripheral neuropathies are associated with multisystem manifestations, including familial amyloid neuropathy and neuropathies associated with metabolic or other genetic syndromes. This article reviews the most recent discoveries in the field and how they are changing the way neurologists diagnose this specific group of peripheral neuropathies. In the past few years, several large cohort studies on the molecular diagnosis of CMT have been published, providing guidelines for genetic testing in clinical practice. In the same period, next-generation sequencing technology has accelerated the discovery of new CMT genes, expanding our knowledge on genotype-phenotype correlations. Recent advances in sequencing technology and genotype-phenotype correlation studies are changing the way neurologists diagnose inherited neuropathies. New therapeutic strategies for familial amyloid neuropathy are paving the way for innovative treatments for genetic neuropathies.

  9. Mary Lyon and the hypothesis of random X chromosome inactivation.

    PubMed

    Harper, Peter S

    2011-08-01

    The 50th anniversary of Mary Lyon's 1961 Nature paper, proposing random inactivation in early embryonic life of one of the two X chromosomes in the cells of mammalian females, provides an opportunity to remember and celebrate the work of those involved. While the hypothesis was initially put forward by Lyon based on findings in the mouse, it was founded on earlier studies, notably the work of Susumu Ohno; it was also suggested independently by Beutler and colleagues using experimental evidence from a human X-linked disorder, glucose-6-phosphate dehydrogenase deficiency, and has proved to be of as great importance for human and medical genetics as it has for general mammalian genetics. Alongside the hypothesis itself, previous cytological studies of mouse and human chromosomes, and the observations on X-linked mutants in both species deserve recognition for their essential role in underpinning the hypothesis of random X-inactivation, while subsequent research on the X-inactivation centre and the molecular mechanisms underlying the inactivation process represent some of the most outstanding contributions to human and wider mammalian genetics over the past 50 years.

  10. Current Therapy for Charcot-Marie-Tooth Disease.

    PubMed

    Grandis, Marina; Shy, Michael E

    2005-01-01

    Charcot-Marie-Tooth (CMT), or heritable peripheral neuropathies, is among the most frequent genetic neuromuscular disorders, with a prevalence of approximately 1:2500. Since 1991, remarkable advances have occurred in determining the precise genetic cause of many forms of CMT and in generating animal models of many of these disorders. However, these advances have not yet resulted in cures for CMT. Recently, potential treatments for the most common form of CMT, CMT-1A, have been shown in rodent models of the disorder. Treatment with onapristone, a progesterone antagonist, has improved the neuropathy of the CMT-1A rat. Treatment with large doses of ascorbic acid (vitamin C) has improved the neuropathy of the CMT-1A mouse. Multicentric trials with ascorbic acid are likely to start in the near future to assess if vitamin C supplementation is effective and what is the dosage required in humans to improve neurologic disability. Because of potential side effects with antiprogesterone therapy, particularly in women of child- bearing age, research is actively proceeding with progesterone antagonists to develop safe medications that also can be used in clinical trials of CMT-1A. Although no cures are available for CMT, there are many important treatments available for patients with CMT that can improve their quality of life and help them maintain their independence. Some of these therapies involve physiatry and orthopedic surgery. Others involve pain management. Lastly, there are potential concerns about medications or lifestyle issues that may exacerbate CMT. All of these issues will be discussed.

  11. Ecology and Mary: An Ecological Theology of Mary as the New Eve in Response to the Church's Challenge for a Faith-Based Education in Ecological Responsibility

    ERIC Educational Resources Information Center

    Thurmond, Gloria J.

    2007-01-01

    The Church's interpretation of the current ecological crisis as a moral crisis is the catalyst for this essay, which proposes a newly constructed faith-based model for ecological dialogue and education. The exploration and reinterpretation of the traditional Church doctrine of the Virgin Mary as the new Eve provides a theme from which an…

  12. Subcellular localization of FOXO3a as a potential biomarker of response to combined treatment with inhibitors of PI3K and autophagy in PIK3CA-mutant cancer cells

    PubMed Central

    Young, Chan Kim; Hwan, Yun Kim; Ju, Woong; Cheol, Seung Kim

    2017-01-01

    Autophagy is the process of lysosome-mediated degradation and recycling that functions as an adaptive survival mechanism during anti-cancer therapy. Aberrant activation of the phosphoinositide-3-kinase (PI3K) pathway frequently occurs in solid tumors, including cervical cancer. However, single-agent PI3K inhibitors show modest anti-tumor efficacy in clinics. To see whether autophagy inhibition improves the efficacy of PI3K inhibitor in PIK3CA-mutant cancer cells, cells were treated with BKM120, a pan-PI3K inhibitor, and the autophagy inhibitor hydroxychloroquine (HCQ). Autophagy inhibition augmented the efficacy of BKM120 depending on PIK3CA-mutant cancer cell type. BKM120 treatment led to the nuclear accumulation of forkhead box O3 (FOXO3a) in Caski and T47D cells, which showed a synergistic effect of BKM120 and HCQ and the strong induction of autophagy. However, most FOXO3a remained in cytoplasm in C33A and ME180 cells, which did not exhibit synergy. These data suggest that BKM120-induced nuclear translocation of FOXO3a might elicit autophagy and be a critical factor determining the synergistic activity of BKM120 and HCQ in PIK3CA-mutant cancer cells. The release of FOXO3a from 14-3-3 by BV02 or 14-3-3 knockdown induced autophagy by BKM120 in C33A cells and sensitized the cells to the combined BKM120 and HCQ treatment, suggesting that cytoplasmic retention of FOXO3a by 14-3-3 even in the presence of BKM120 inhibit autophagy induction and synergistic effect of BKM120 and HCQ combination. Taken together, our study shows that subcellular localization of FOXO3a might be a potential biomarker for predicting response to the combination treatment with PI3K and autophagy inhibitors in PIK3CA-mutant cervical cancer patients. PMID:28036259

  13. A Novel Workflow to Enrich and Isolate Patient-Matched EpCAM(high) and EpCAM(low/negative) CTCs Enables the Comparative Characterization of the PIK3CA Status in Metastatic Breast Cancer.

    PubMed

    Lampignano, Rita; Yang, Liwen; Neumann, Martin H D; Franken, André; Fehm, Tanja; Niederacher, Dieter; Neubauer, Hans

    2017-08-31

    Circulating tumor cells (CTCs), potential precursors of most epithelial solid tumors, are mainly enriched by epithelial cell adhesion molecule (EpCAM)-dependent technologies. Hence, these approaches may overlook mesenchymal CTCs, considered highly malignant. Our aim was to establish a workflow to enrich and isolate patient-matched EpCAM(high) and EpCAM(low/negative) CTCs within the same blood samples, and to investigate the phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutational status within single CTCs. We sequentially processed metastatic breast cancer (MBC) blood samples via CellSearch(®) (EpCAM-based) and via Parsortix™ (size-based) systems. After enrichment, cells captured in Parsortix™ cassettes were stained in situ for nuclei, cytokeratins, EpCAM and CD45. Afterwards, sorted cells were isolated via CellCelector™ micromanipulator and their genomes were amplified. Lastly, PIK3CA mutational status was analyzed by combining an amplicon-based approach with Sanger sequencing. In 54% of patients' blood samples both EpCAM(high) and EpCAM(low/negative) cells were identified and successfully isolated. High genomic integrity was observed in 8% of amplified genomes of EpCAM(low/negative) cells vs. 28% of EpCAM(high) cells suggesting an increased apoptosis in the first CTC-subpopulation. Furthermore, PIK3CA hotspot mutations were detected in both EpCAM(high) and EpCAM(low/negative) CTCs. Our workflow is suitable for single CTC analysis, permitting-for the first time-assessment of the heterogeneity of PIK3CA mutational status within patient-matched EpCAM(high) and EpCAM(low/negative) CTCs.

  14. Chromatin remodeling gene AT-rich interactive domain-containing protein 1A suppresses gastric cancer cell proliferation by targeting PIK3CA and PDK1

    PubMed Central

    Wang, Jie; Cui, Shu-Jian; Wang, Xiao-Qing; Jiang, Ying-Hua; Feng, Li; Yang, Peng-Yuan; Liu, Feng

    2016-01-01

    The tumor suppressor gene AT-rich interactive domain-containing protein 1A (ARID1A) was frequently mutated in cancers. The modulation mechanism of ARID1A for PI3K/AKT signaling in gastric cancer (GC) remains elusive. Here, we found that depletion of endogenous ARID1A enhanced the in vitro proliferation, colony formation, cellular growth, nutrient uptake and in vivo xenograft tumor growth of GC cells. PI3K/AKT activation by ARID1A-silencing was profiled using a phospho-protein antibody array. The phosphorylation of PDK1, AKT, GSK3β and 70S6K, and the protein and mRNA expressions of PI3K and PDK1, were upregulated by ARID1A-silencing. Chromatin immunoprecipitation and luciferase reporter assay revealed that ARID1A-involved SWI/SNF complex inhibited PIK3CA and PDK1 transcription by direct binding to their promoters. Serial deletion mutation analyses revealed that the ARID1A central region containing the HIC1-binding domain, but not the ARID DNA-binding domain and the C-terminal domain, was essential for the inhibition of GC cell growth, PI3K/AKT pathway phosphorylation and its transcriptional modulation activity of PIK3CA and PDK1. The proliferation, cellular growth and glucose consumption of ARID1A-deficient GC cells were efficiently prohibited by allosteric inhibitors mk2206 and LY294002, which targeting AKT and PI3K, respectively. Both inhibitors also downregulated the phosphorylation of PI3K/AKT pathway in ARID1A-deficient GC cells. Such cells were sensitized to the treatment of LY294002, and AT7867, another inhibitor of AKT and p70S6K. The administration of LY294002 alone inhibited the in vivo growth of ARID1A- deficient GC cells in mouse xenograft model. Our study provides a novel insight into the modulatory function and mechanism of ARID1A in PI3K/AKT signaling in GC. PMID:27323812

  15. Strategically Timing Inhibition of Phosphatidylinositol 3-Kinase to Maximize Therapeutic Index in Estrogen Receptor Alpha-Positive, PIK3CA-Mutant Breast Cancer.

    PubMed

    Yang, Wei; Hosford, Sarah R; Dillon, Lloye M; Shee, Kevin; Liu, Stephanie C; Bean, Jennifer R; Salphati, Laurent; Pang, Jodie; Zhang, Xiaolin; Nannini, Michelle A; Demidenko, Eugene; Bates, Darcy; Lewis, Lionel D; Marotti, Jonathan D; Eastman, Alan R; Miller, Todd W

    2016-05-01

    Phosphatidylinositol 3-kinase (PI3K) inhibitors are being developed for the treatment of estrogen receptor α (ER)-positive breast cancer in combination with antiestrogens. Understanding the temporal response and pharmacodynamic effects of PI3K inhibition in ER(+) breast cancer will provide a rationale for treatment scheduling to maximize therapeutic index. Antiestrogen-sensitive and antiestrogen-resistant ER(+) human breast cancer cell lines and mice bearing PIK3CA-mutant xenografts were treated with the antiestrogen fulvestrant, the PI3K inhibitor GDC-0941 (pictilisib; varied doses/schedules that provided similar amounts of drug each week), or combinations. Cell viability, signaling pathway inhibition, proliferation, apoptosis, tumor volume, and GDC-0941 concentrations in plasma and tumors were temporally measured. Treatment with the combination of fulvestrant and GDC-0941, regardless of dose/schedule, was significantly more effective than that with single-agent treatments in fulvestrant-resistant tumors. Short-term, complete PI3K inhibition blocked cell growth in vitro more effectively than chronic, incomplete inhibition. Longer-term PI3K inhibition hypersensitized cells to growth factor signaling upon drug withdrawal. Different schedules of GDC-0941 elicited similar tumor responses. While weekly high-dose GDC-0941 with fulvestrant continuously suppressed PI3K signaling for 72 hours, inducing a bolus of apoptosis and inhibiting proliferation, PI3K reactivation upon GDC-0941 washout induced a proliferative burst. Fulvestrant with daily low-dose GDC-0941 metronomically suppressed PI3K for 6 to 9 hours/day, repeatedly inducing small amounts of apoptosis and temporarily inhibiting proliferation, followed by proliferative rebound compared with fulvestrant alone. Continuous and metronomic PI3K inhibition elicits robust anticancer effects in ER(+), PIK3CA-mutant breast cancer. Clinical exploration of alternate treatment schedules of PI3K inhibitors with antiestrogens

  16. A High-Throughput Screen with Isogenic PTEN+/+ and PTEN−/− Cells Identifies CID1340132 as a Novel Compound That Induces Apoptosis in PTEN and PIK3CA Mutant Human Cancer Cells

    PubMed Central

    Li, Hui-Fang; Keeton, Adam; Vitolo, Michele; Maddox, Clinton; Rasmussen, Lynn; Hobrath, Judith; White, E. Lucille; Park, Ben Ho; Piazza, Gary A.; Kim, Jung-Sik; Waldman, Todd

    2013-01-01

    The PTEN tumor suppressor gene is one of the most commonly mutated genes in human cancer. Because inactivation of PTEN is a somatic event, PTEN mutations represent an important genetic difference between cancer cells and normal cells and therefore a potential anticancer drug target. However, it remains a substantial challenge to identify compounds that target loss-of-function events such as mutations of tumor suppressors. In an effort to identify small molecules that preferentially kill cells with mutations of PTEN, the authors developed and implemented a high-throughput, paired cell-based screen composed of parental HCT116 cells and their PTEN gene-targeted derivatives. From 138 758 compounds tested, two hits were identified, and one, N′-[(1-benzyl-1H-indol-3-yl)methylene]benzenesulfonohydrazide (CID1340132), was further studied using a variety of cell-based models, including HCT116, MCF10A, and HEC1A cells with targeted deletion of either their PTEN or PIK3CA genes. Preferential killing of PTEN and PIK3CA mutant cells was accompanied by DNA damage, inhibition of DNA synthesis, and apoptosis. taken together, these data validate a cell-based screening approach for identifying lead compounds that target cells with specific tumor suppressor gene mutations and describe a novel compound with preferential killing activity toward PTEN and PIK3CA mutant cells. PMID:21335596

  17. A high-throughput screen with isogenic PTEN+/+ and PTEN-/- cells identifies CID1340132 as a novel compound that induces apoptosis in PTEN and PIK3CA mutant human cancer cells.

    PubMed

    Li, Hui-Fang; Keeton, Adam; Vitolo, Michele; Maddox, Clinton; Rasmussen, Lynn; Hobrath, Judith; White, E Lucille; Park, Ben Ho; Piazza, Gary A; Kim, Jung-Sik; Waldman, Todd

    2011-04-01

    The PTEN tumor suppressor gene is one of the most commonly mutated genes in human cancer. Because inactivation of PTEN is a somatic event, PTEN mutations represent an important genetic difference between cancer cells and normal cells and therefore a potential anticancer drug target. However, it remains a substantial challenge to identify compounds that target loss-of-function events such as mutations of tumor suppressors. In an effort to identify small molecules that preferentially kill cells with mutations of PTEN, the authors developed and implemented a high-throughput, paired cell-based screen composed of parental HCT116 cells and their PTEN gene-targeted derivatives. From 138 758 compounds tested, two hits were identified, and one, N'-[(1-benzyl-1H-indol-3-yl)methylene]benzenesulfonohydrazide (CID1340132), was further studied using a variety of cell-based models, including HCT116, MCF10A, and HEC1A cells with targeted deletion of either their PTEN or PIK3CA genes. Preferential killing of PTEN and PIK3CA mutant cells was accompanied by DNA damage, inhibition of DNA synthesis, and apoptosis. Taken together, these data validate a cell-based screening approach for identifying lead compounds that target cells with specific tumor suppressor gene mutations and describe a novel compound with preferential killing activity toward PTEN and PIK3CA mutant cells.

  18. A novel liquidchip platform for simultaneous detection of 70 alleles of DNA somatic mutations on EGFR, KRAS, BRAF and PIK3CA from formalin-fixed and paraffin-embedded slides containing tumor tissue.

    PubMed

    Li, Guoqiang; Luo, Xiaodi; He, Jiaying; Zhu, Zeyao; Yu, Gang; Qin, Huijuan; Zeng, Tao; Liu, Zhiming; Wu, Shiyang; Xu, Jiasen; Ren-Heidenreich, Lifen

    2011-02-01

    DNA somatic mutations of EGFR, KRAS, BRAF and PIK3CA in the epidermal growth factor receptor (EGFR) signaling pathway play critical roles in the response or resistance of tumors to targeted therapy with tyrosine kinase inhibitors (EGFR-TKIs). To provide a high-throughput (HTP) clinical testing service for detecting these mutations, we developed a novel platform, SurPlex®-xTAG70plex-EGFR liquidchip. This platform was developed based on a universal 100-tag system. The procedures for multiplex PCR, allele specific primer extension (ASPE) and hybridization were optimized and standardized. A total of 70 alleles of somatic mutations of EGFR, KRAS, BRAF and PIK3CA can be detected simultaneously in one reaction from one formalin-fixed and paraffin-embedded (FFPE) slide within one day. Cross-reaction was < 8% between individual amplimers and 70 different ASPE primers. The sensitivity for detecting mutants in the wild-type DNA was 1%-5%. Seventy-three FFPE samples with somatic mutations were used to validate the 70plex. Seventy-one showed a complete match, while two were not detected. A simple, accurate, sensitive HTP technology was developed and standardized for detecting simultaneously 70 different alleles of EGFR, KRAS, BRAF and PIK3CA gene mutations from FFPE tumor slides.

  19. Marie Curie nurses: enabling patients with cancer to die at home.

    PubMed

    Higginson, Irene J; Wilkinson, Susie

    2002-05-01

    Marie Curie Cancer Care established its nursing service in 1958; however, the service has had little formal evaluation. This study aimed to describe and evaluate the care provided by Marie Curie nurse, and in particular to determine whether patients in their care remained and died at home. Two existing data sets were used: data on all patients referred to the Marie Curie Nursing Services in 147 areas of England, Wales, Scotland and Northern Ireland for 26 months, and data on cancer death registrations in England. A request for a Marie Curie nurse was made for 26,632 patients, 97% of whom had cancer and 11% of whom lived alone. The amount of care provided varied enormously (<1 hour-2862 hours), although the vast majority of patients less than 300 hours of nursing care. Place of death was recorded for only half these patients; 94% died at home, 2.5% in a hospice, 2.3% in a hospital, 0.2% in a nursing home and 0.6% other. Home death was most often associated with patients receiving medication via a syringe driver, patients living with other people, patients with cancer, other than prostate cancer, shorter time between referral and death and younger age. The results lend support to the theory that the care given to patients in their homes by Marie Curie nurses facilitated home death for many patients. Services need to ensure that mechanisms are in place to achieve data collection. Rigorous prospective evaluation is needed in the future.

  20. M-Ary Alpha-Stable Noise Modulation in Spread-Spectrum Communication

    NASA Astrophysics Data System (ADS)

    Cek, Mehmet Emre

    2015-04-01

    In this paper, a spread-spectrum communication system based on a random carrier is proposed which transmits M-ary information. The random signal is considered as a single realization of a random process taken from prescribed symmetric α-stable (SαS) distribution that carries digital M-ary information to be transmitted. Considering the noise model in the channel as additive white Gaussian noise (AWGN), the transmitter sends the information carrying random signal from non-Gaussian density. Alpha-stable distribution is used to encode the M-ary message. Inspired by the chaos shift keying techniques, the proposed method is called M-ary symmetric alpha-stable differential shift keying (M-ary SαS-DSK). The main purpose of preferring non-Gaussian noise instead of conventional pseudo-noise (PN) sequence is to overcome the drawback of self-repeating noise-like sequences which are detectable due to the periodic behavior of the autocorrelation function of PN sequences. Having infinite second order moment in α-stable random carrier offers secrecy of the information due to the non-constant autocorrelation behavior. The bit error rate (BER) performance of the proposed method is illustrated by Monte Carlo simulations with respect to various characteristic exponent values and different data length.

  1. Phenotypic Variability of Childhood Charcot-Marie-Tooth Disease.

    PubMed

    Cornett, Kayla M D; Menezes, Manoj P; Bray, Paula; Halaki, Mark; Shy, Rosemary R; Yum, Sabrina W; Estilow, Timothy; Moroni, Isabella; Foscan, Maria; Pagliano, Emanuela; Pareyson, Davide; Laurá, Matilde; Bhandari, Trupti; Muntoni, Francesco; Reilly, Mary M; Finkel, Richard S; Sowden, Janet; Eichinger, Katy J; Herrmann, David N; Shy, Michael E; Burns, Joshua

    2016-06-01

    Disease severity of childhood Charcot-Marie-Tooth disease (CMT) has not been extensively characterized, either within or between types of CMT to date. To assess the variability of disease severity in a large cohort of children and adolescents with CMT. A cross-sectional study was conducted among 520 children and adolescents aged 3 to 20 years at 8 universities and hospitals involved in the Inherited Neuropathies Consortium between August 6, 2009, and July 31, 2014, in Australia, Italy, the United Kingdom, and the United States. Data analysis was conducted from August 1, 2014, to December 1, 2015. Scores on the Charcot-Marie-Tooth Disease Pediatric Scale (CMTPedS), a well-validated unidimensional clinical outcome measure to assess disease severity. This instrument includes 11 items assessing fine and gross motor function, sensation, and balance to produce a total score ranging from 0 (unaffected) to 44 (severely affected). Among the 520 participants (274 males) aged 3 to 20 years, CMT type 1A (CMT1A) was the most prevalent type (252 [48.5%]), followed by CMT2A (31 [6.0%]), CMT1B (15 [2.9%]), CMT4C (13 [2.5%]), and CMTX1 (10 [1.9%]). Disease severity ranged from 1 to 44 points on the CMTPedS (mean [SD], 21.5 [8.9]), with ankle dorsiflexion strength and functional hand dexterity test being most affected. Participants with CMT1B (mean [SD] CMTPedS score, 24.0 [7.4]), CMT2A (29.7 [7.1]), and CMT4C (29.8 [8.6]) were more severely affected than those with CMT1A (18.9 [7.7]) and CMTX1 (males: 15.3 [7.7]; females: 13.0 [3.6]) (P < .05). Scores on the CMTPedS tended to worsen principally during childhood (ages, 3-10 years) for participants with CMT4C and CMTX1 and predominantly during adolescence for those with CMT1B and CMT2A (ages, 11-20 years), while CMT1A worsened consistently throughout childhood and adolescence. For individual items, participants with CMT4C recorded more affected functional dexterity test scores than did those with all other types of CMT (P

  2. Sleep disorders in Charcot-Marie-Tooth disease type 1.

    PubMed

    Boentert, Matthias; Knop, Katharina; Schuhmacher, Christine; Gess, Burkhard; Okegwo, Angelika; Young, Peter

    2014-03-01

    Obstructive sleep apnoea (OSA) and restless legs syndrome (RLS) have been reported in Charcot-Marie-Tooth disease (CMT) type 1A and axonal subtypes of CMT, respectively. The aim of this case-control study was to investigate both prevalence and severity of OSA, RLS and periodic limb movements in sleep (PLMS) in adult patients with genetically proven CMT1. 61 patients with CMT1 and 61 insomnic control subjects were matched for age, sex, and Body Mass Index. Neurological disability in patients with CMT was assessed using the Functional Disability Scale (FDS). RLS diagnosis was based on a screening questionnaire and structured clinical interviews. All participants underwent overnight polysomnography. OSA was present in 37.7% of patients with CMT1 and 4.9% of controls (p<0.0001). The mean Apnoea Hypoponea Index (AHI) was significantly higher in patients with CMT1 than in control individuals (9.1/h vs 1.2/h). RLS was present in 40.9% of patients with CMT1 and in 16.4% of controls (p<0.001). In the CMT1 group, OSA was significantly more common in men and RLS in women. The AHI correlated with both age and the FDS score, the latter being a significant independent predictor of OSA. PLMS were found in 41.0% of patients with CMT1, but were not correlated with measures of sleep quality. In addition to known risk factors, CMT may predispose to OSA. RLS is highly prevalent not only in axonal subtypes of CMT but also in primarily demyelinating subforms of CMT. PLMS are common in CMT1, but do not significantly impair sleep quality.

  3. Contaminant dispersion at the rehabilitated Mary Kathleen uranium mine, Australia

    NASA Astrophysics Data System (ADS)

    Lottermoser, B. G.; Ashley, P. M.; Costelloe, M. T.

    2005-09-01

    This study reports on the transfer of contaminants from waste rock dumps and mineralised ground into soils, sediments, waters and plants at the rehabilitated Mary Kathleen uranium mine in semi-arid northwest Queensland. Numerous waste rock dumps were partly covered with benign soil and the open pit mine was allowed to flood. The mineralised and waste calc-silicate rock in the open pit and dumps has major (>1 wt%) Ca, Fe and Mg, minor (>1,000 ppm) Ce, La, Mn, P and S, subminor (>100 ppm) Ba, Cu, Th and U, and trace (<100 ppm) As, Ni, Pb, Y and Zn values. Consequently, chemical and physical weathering processes have acted on waste rock and on rock faces within the open pit, mobilising many elements and leading to their dispersion into soils, stream sediments, pit water and several plant species. Chemical dispersion is initiated by sulfide mineral breakdown, generation of sulfuric acid and formation of several soluble, transient sulfate minerals as evaporative efflorescent precipitates. Radiation doses associated with the open pit average 5.65 mSv year-1; waste dumps commonly have lower values, especially where soil-covered. Surface pit water is slightly acid, with high sulfate values accompanied by levels of U, Cu and Ni close to or above Australian water guideline values for livestock. Dispersion of U and related elements into soils and stream sediments occurs by physical (erosional) processes and from chemical precipitation. Plants growing in the mine void, on waste dumps and contaminated soil display evidence of biological uptake of U, LREE, Cu and Th and to a lesser degree of As, Ni, Pb, Y and Zn, with values being up to 1-2 orders of magnitude above background sites for the same species. Although rehabilitation procedures have been partly successful in reducing dispersion of U and related elements into the surrounding environment, it is apparent that 20 years after rehabilitation, there is significant physical and chemical mobility, including transfer into

  4. [Guidelines for molecular diagnosis of Charcot-Marie-Tooth disease].

    PubMed

    Berciano, J; Sevilla, T; Casasnovas, C; Sivera, R; Vílchez, J J; Infante, J; Ramón, C; Pelayo-Negro, A L; Illa, I

    2012-04-01

    Charcot-Marie-Tooth disease (CMT) is the most frequent form of inherited neuropathy. In accordance with the inheritance pattern and degree of slowing of motor conduction velocity (MCV) of the median nerve, CMT encompasses five main forms: CMT1 (autosomal dominant [AD] or X-linked transmission and MCV < 38 m/s); CMT2 (AD or X-linked transmission and MCV > 38 m/s); CMT4 (autosomal recessive [AR] and severe slowing of MCV); AR-CMT2 (AR transmission and MCV > 38 m/s); and DI-CMT (intermediate form with AD transmission and MCV between 30 and 40 m/s). In spite of its stereotyped semiological repertoire (basically, symptoms and signs of sensory-motor polyneuropathy and pes cavus), CMT seems to be one of the most complex hereditary neurodegenerative syndromes, 31 causative genes having been cloned. This paper is aimed at performing a nosological review of the disease, emphasising the guidelines for its molecular diagnosis. Genetic epidemiological studies and genotypes reported in Spanish patients are revised. In the great majority of CMT cases, mutations involve a reduced number of genes, namely: for CMT1, PMP22, GJB1 and MPZ; for CMT2, MFN2 and GJB1; for CMT4, GDAP1, and NDRG1, HK1 and SH3TC2 (gypsies); for AR-CMT2, GDAP1; and for DI-CMT, GJB1 and MPZ. Given their low prevalence, mutations in other pathogenic genes should be investigated after discarding the previous ones. There is no place for the indiscriminate use of diagnostic CMT genetic panels. Copyright © 2011 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

  5. Cardiac robotics: a review and St. Mary's experience.

    PubMed

    Deeba, S; Aggarwal, R; Sains, P; Martin, S; Athanasiou, T; Casula, R; Darzi, A

    2006-03-01

    The introduction of the laparoscope led to the progress of surgery to a new era, where surgeries that were deemed major are now being performed through keyhole incisions with comparable outcomes to open surgery. However, with this new technique rose several problems like inaccurate depth perception, diminished tactile feedback, need for experienced assistance, and reduction in degrees of motion of the surgeons hands all of which inspired surgeons and engineers to look for mechanical tools to help in reducing these problems. Henceforth; came the application of robotics in surgery. A PubMed and Medline search was performed on cardiac robotic surgery and its applications in mitral valve repair and coronary artery surgery. A total of twenty one articles were picked that allude to the subject. A history of robotic surgery was outlined followed by applications of robotic manipulation in cardiac surgery was narrated. A quick overview of this technology in telemedicine was then outlined followed by future prospects of this technology in surgery was contemplated. The experience of the group from St. Mary's Hospital, London in this field was outlined. During the period of 4 years a total of 102 cases of robotic cardiac surgery were performed. The mean length of hospital stay was 3.1 days with a standard deviation of 1.4 days and the morbidity of the series explained. There was no mortality. Early studies have shown that minimally invasive cardiac surgery is feasible and yields results similar to conventional cardiac surgery, yet it is more technically demanding on the surgeon. As advantageous as this new modality is, further multicenter studies are needed to prove its efficacy. Copyright 2006 John Wiley & Sons, Ltd.

  6. Evaluating Marie Byrd Land stability using an improved basal topography

    NASA Astrophysics Data System (ADS)

    Holschuh, N.; Pollard, D.; Alley, R. B.; Anandakrishnan, S.

    2014-12-01

    Prior understanding of the ice-sheet setting in Marie Byrd Land (MBL) was derived primarily from geologic and geochemical studies of the current nunataks, with very few geophysical surveys imaging the ice covered regions. The geologic context suggested that the ice rests on a broad regional high, in contrast to the deep basins and trenches that characterize the majority of West Antarctica. This assumed topography would favor long-term stability for the West Antarctic Ice Sheet (WAIS) in MBL. Airborne geophysical data collected in 2009 reveal a much deeper bed than previously estimated, including a significant trough underlying DeVicq Glacier and evidence for extensive glacial erosion. Using these data, we produce a new map of subglacial topography, with which we model the sensitivity of WAIS to a warming ocean using the ice-sheet model of Pollard and DeConto (2012b). We compare the results to estimates of ice loss during WAIS collapse using the previously defined subglacial topography, to determine the impact of the newly discovered subglacial features. Our results indicate that the topographic changes are not sufficient to destabilize the northern margin of MBL currently feeding the Getz Ice Shelf; the majority of ice loss occurs from flow toward the Siple Coast. However, despite only slight dynamic differences, using the new bed as a boundary condition results in an additional 8 cm of sea-level rise during major glacial retreat, an increase of just over 2%. Precise estimation of past and future ice retreat, as well as a complete understanding of the geologic history of the region, will require a higher resolution picture of the bed topography around the Executive Committee mountains.

  7. Cranial nerve involvement in Charcot-Marie-Tooth Disease.

    PubMed

    Das, Nirav; Kandalaft, Savannah; Wu, Xiao; Malhotra, Ajay

    2017-03-01

    Charcot-Marie-Tooth Disease (CMT) is a rare disorder with less than 200,000 cases reported in the US every year, making diagnosis challenging. MR and CT imaging has become more common in the evaluation of CMT to identify areas of disease involvement. A 27-year-old female from Guatemala with a past history of polio initially presented to the emergency room for necrotizing pneumonia. MRI images demonstrated smoothly enlarged, mildly enhancing trigeminal nerves. CT showed bony widening of the skull base foramina. The patient was noted to have atrophy and weakness of her extremities with decreased sensation, distal more than proximal, and pes cavus. An electromyogram demonstrated absent response in the right median, ulnar, peroneal, and tibial motor studies and bilateral radial and right sural sensory studies. MRI of the spine demonstrated smooth, symmetric enlargement and mild enhancement of the distal spinal nerve roots and cauda equine. CMT is a group of disorders with a wide range of clinical presentations and abnormalities. Cranial nerve involvement is infrequently described in CMT 1A. In our case and prior studies, there does not appear to be a correlation between cranial nerve involvement and symptoms. Trigeminal neuralgia has been described in patients in CMT, but is not common and was not seen in our patient despite abnormal trigeminal nerve findings on imaging. Our patient also demonstrated involvement of the facial nerve without facial muscle weakness. Clinical features are key in distinguishing CMT 1A from other forms of HMSN. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Geology of the Lake Mary quadrangle, Iron County, Michigan

    USGS Publications Warehouse

    Bayley, Richard W.

    1959-01-01

    The Lake Mary quadrangle is in eastern Iron County, in the west part of the Upper Peninsula of Michigan. The quadrangle is underlain by Lower and Middle Precambrian rocks, formerly designated Archean and Algonkian rocks, and is extensively covered by Pleistocene glacial deposits. A few Upper Precambrian (Keweenawan) diabase dikes and two remnants of sandstone and dolomite of early Paleozoic age are also found in the area. The major structural feature is the Holmes Lake anticline, the axis of which strikes northwest through the northeast part of the quadrangle. Most of the quadrangle, therefore, is underlain by rock of the west limb of the anticline. To the northwest along the fold axis, the Holmes Lake anticline is separated from the Amasa oval by a saddle of transverse folds in the vicinity of Michigamme Mountain in the Kiernan quadrangle. The Lower Precambrian rocks are represented by the Dickinson group and by porphyritic red granite whose relation to the Dickinson group is uncertain, but which may be older. The rocks of the Dickinson group are chiefly green to black metavolcanic schist and red felsite, some of the latter metarhyolite. The dark schist is commonly magnetic. The Dickinson group underlies the core area of the Holmes Lake anticline, which is flanked by steeply dipping Middle Precambrian formations of the Animikie series. A major unconformity separates the Lower Precambrian rocks from the overlying Middle Precambrian rocks. In ascending order the formations of the Middle Precambrian are the Randville dolomite, the Hemlock formation, which includes the Mansfield iron-bearing slate member, and the Michigamme slate. An unconformity occurs between the Hemlock formation and Michigamme slate. The post-Hemlock unconformity is thought to be represented in the Lake Mary quadrangle by the absence of iron-formation of the Amasa formation, which is known to lie between the Hemlock and the Michigamme to the northwest of the Lake Mary quadrangle in the Crystal

  9. The Dual PI3K/mTOR Inhibitor NVP-BEZ235 Induces Tumor Regression in a Genetically Engineered Mouse Model of PIK3CA Wild-Type Colorectal Cancer

    PubMed Central

    Wang, Wei Vivian; Richard, Larissa Georgeon; Chen, Wei; Coffee, Erin M.; Sinnamon, Mark J.; Lee, Lydia; Chen, Peng-Chieh; Bronson, Roderick T.; Martin, Eric S.; Hung, Kenneth E.

    2011-01-01

    Purpose To examine the in vitro and in vivo efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type colorectal cancer (CRC). Experimental Design PIK3CA mutant and wild-type human CRC cell lines were treated in vitro with NVP-BEZ235, and the resulting effects on proliferation, apoptosis, and signaling were assessed. Colonic tumors from a genetically engineered mouse (GEM) model for sporadic wild-type PIK3CA CRC were treated in vivo with NVP-BEZ235. The resulting effects on macroscopic tumor growth/regression, proliferation, apoptosis, angiogenesis, and signaling were examined. Results In vitro treatment of CRC cell lines with NVP-BEZ235 resulted in transient PI3K blockade, sustained decreases in mTORC1/mTORC2 signaling, and a corresponding decrease in cell viability (median IC50 = 9.0–14.3 nM). Similar effects were seen in paired isogenic CRC cell lines that differed only in the presence or absence of an activating PIK3CA mutant allele. In vivo treatment of colonic tumor-bearing mice with NVP-BEZ235 resulted in transient PI3K inhibition and sustained blockade of mTORC1/mTORC2 signaling. Longitudinal tumor surveillance by optical colonoscopy demonstrated a 97% increase in tumor size in control mice (p = 0.01) vs. a 43% decrease (p = 0.008) in treated mice. Ex vivo analysis of the NVP-BEZ235-treated tumors demonstrated a 56% decrease in proliferation (p = 0.003), no effects on apoptosis, and a 75% reduction in angiogenesis (p = 0.013). Conclusions These studies provide the preclinical rationale for studies examining the efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type CRC. PMID:21966435

  10. Molecular regulation of apoptotic machinery and lipid metabolism by mTORC1/mTORC2 dual inhibitors in preclinical models of HER2+/PIK3CAmut breast cancer

    PubMed Central

    Qian, Jianchang; Chen, Yaqing; Meng, Tao; Ma, Lanping; Meng, Lanfang; Wang, Xin; Yu, Ting; Zask, Arie; Shen, Jingkang; Yu, Ker

    2016-01-01

    The mechanistic target of rapamycin (mTOR) is a rational target for cancer treatment. While the mTORC1-selective rapalogs have shown significant benefits in the clinic, antitumor response may be further improved by inhibiting both mTORC1 and mTORC2. Herein, we established target profile of a novel mTOR kinase inhibitor (mTOR-KI) MTI-31 and employed it to study new therapeutic mechanism in breast cancer. MTI-31 demonstrated a potent mTOR binding affinity with >5000 fold selectivity over the related PI3K family isoforms. MTI-31 inhibited mTORC1- and mTORC2 function at ≤120 nM in cellular assays or 5 mg/kg orally in tumor-bearing mice. In a panel of breast cancer lines, the antitumor efficacy of MTI-31 was dependent on HER2+ and/or PIK3CAmut (HER2+/PIK3CAmut) status of the tumors and required mTORC2-specific modulation of Bim, MCL-1 and GSK3. Inactivation of Bim or GSK3 each attenuated apoptotic death resulting in mTOR-KI resistance. The antitumor response also required a suppression of lipid metabolism in therapy-sensitive tumors. Treatment with MTI-31 or AZD8055 substantially reduced lipogenesis and acetyl-CoA homeostasis, which was mechanistically linked to a blockade of mTORC2-dependent glucose-to-lipid conversion rate. We also found that the basal levels of carnitine palmitoyltransferase 1A and lipid catabolism were elevated in HER2+/PIK3CAmut breast cells and were inhibited upon mTOR-KI treatment. A CPT1A inhibitor etomoxir mimicked MTI-31 action in selective downregulation of cellular lipid catabolism. Co-treatments with MTI-31 and etomoxir enhanced the suppression of cyclin D1, c-Myc and cell growth in HER2+/PIK3CAmut tumors. These new mechanistic findings provide a rationale for targeting mTORC1 and mTORC2 in HER2+/PIK3CAmut breast cancer. PMID:27563814

  11. A mutation in VPS15 (PIK3R4) causes a ciliopathy and affects IFT20 release from the cis-Golgi

    PubMed Central

    Stoetzel, Corinne; Bär, Séverine; De Craene, Johan-Owen; Scheidecker, Sophie; Etard, Christelle; Chicher, Johana; Reck, Jennifer R.; Perrault, Isabelle; Geoffroy, Véronique; Chennen, Kirsley; Strähle, Uwe; Hammann, Philippe; Friant, Sylvie; Dollfus, Hélène

    2016-01-01

    Ciliopathies are a group of diseases that affect kidney and retina among other organs. Here, we identify a missense mutation in PIK3R4 (phosphoinositide 3-kinase regulatory subunit 4, named VPS15) in a family with a ciliopathy phenotype. Besides being required for trafficking and autophagy, we show that VPS15 regulates primary cilium length in human fibroblasts, as well as ciliary processes in zebrafish. Furthermore, we demonstrate its interaction with the golgin GM130 and its localization to the Golgi. The VPS15-R998Q patient mutation impairs Golgi trafficking functions in humanized yeast cells. Moreover, in VPS15-R998Q patient fibroblasts, the intraflagellar transport protein IFT20 is not localized to vesicles trafficking to the cilium but is restricted to the Golgi. Our findings suggest that at the Golgi, VPS15 and GM130 form a protein complex devoid of VPS34 to ensure the IFT20-dependent sorting and transport of membrane proteins from the cis-Golgi to the primary cilium. PMID:27882921

  12. Acyl-CoA subunit selectivity in the pikromycin polyketide synthase PikAIV: steady-state kinetics and active-site occupancy analysis by FTICR-MS.

    PubMed

    Bonnett, Shilah A; Rath, Christopher M; Shareef, Abdur-Rafay; Joels, Joanna R; Chemler, Joseph A; Håkansson, Kristina; Reynolds, Kevin; Sherman, David H

    2011-09-23

    Polyketide natural products generated by type I modular polyketide synthases (PKSs) are vital components in our drug repertoire. To reprogram these biosynthetic assembly lines, we must first understand the steps that occur within the modular "black boxes." Herein, key steps of acyl-CoA extender unit selection are explored by in vitro biochemical analysis of the PikAIV PKS model system. Two complementary approaches are employed: a fluorescent-probe assay for steady-state kinetic analysis, and Fourier Transform Ion Cyclotron Resonance-mass spectrometry (FTICR-MS) to monitor active-site occupancy. Findings from five enzyme variants and four model substrates have enabled a model to be proposed involving catalysis based upon acyl-CoA substrate loading followed by differential rates of hydrolysis. These efforts suggest a strategy for future pathway engineering efforts using unnatural extender units with slow rates of hydrolytic off-loading from the acyltransferase domain. Copyright © 2011 Elsevier Ltd. All rights reserved.

  13. MARIE: Current Status and Results from 20 Months of Observations at Mars

    NASA Technical Reports Server (NTRS)

    Zeitlin, C.; Andersen, V.; Atwell, W.; Cleghorn, T. F.; Cucinotta, F. A.; Lee, K. T.; Pinsky, L.; Saganti, P.

    2004-01-01

    The MARIE instrument aboard the 2001 Mars Odyssey spacecraft detects energetic charged particles in the Galactic Cosmic Radiation (GCR) and during solar particle events (SPE) [1]. As of this writing (January 2004), MARIE has been turned off, after losing communication with the spacecraft during the large SPE of October 28, 2003. However, during the prior 20 months, MARIE collected data almost continuously, observing several solar events and the nearly-constant GCR. There is still a possibility the instrument can be recovered, and troubleshooting efforts are scheduled to begin in May 2004, following the completion of the primary missions of MER-A (Spirit) and MER-B (Opportunity). At present, Odyssey is acting as a telecommunications relay for the rovers and only routine science operations are permitted in this mode.

  14. Using superconducting undulator for enhanced imaging capabilities of MaRIE

    SciTech Connect

    Yampolsky, Nikolai

    2016-09-22

    MaRIE x-ray free electron laser (FEL) is envisioned to deliver a burst of closely spaced in time pulses for enabling the capability of studying the dynamic processes in a sample. MaRIE capability can be largely enhanced using the superconducting undulator, which has the capability of doubling its period. This technology will allow reaching the photon energy as low as ~200-500 eV. As a result, the MaRIE facility will have a broader photon energy range enabling a larger variety of experiments. The soft x-ray capability is more likely to achieve the 3D imaging of dynamic processes in noncrystal materials than the hard x-ray capability alone.

  15. The Rev. John Bracken v. the Visitors of William and Mary College: A Post-Revolutionary Problem in Visitatorial Jurisdiction.

    ERIC Educational Resources Information Center

    Bridge, J. W.

    1979-01-01

    Reforms in 1779 at the College of William and Mary caused a professor to be dismissed, after which he took legal action against the institution. It is concluded that English corporate law was abused in defending against the professor's action. (Journal availability: College of William and Mary, Williamsburg, VA 23185, $3.00.) (MSE)

  16. 76 FR 31839 - Safety Zones; Annual Events Requiring Safety Zones in the Captain of the Port Sault Sainte Marie...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-02

    ... Fourth of July Celebration Fireworks; Marquette, MI: (i) Location. All U.S. navigable waters of Marquette... section will be enforced July 5 from 9 p.m. until 11 p.m. (2) Munising Fourth of July Celebration.... (4) Sault Sainte Marie Fourth of July Celebration Fireworks; Sault Sainte Marie, MI: (i) Location...

  17. Computation of the bit error rate of coherent M-ary PSK with Gray code bit mapping

    NASA Technical Reports Server (NTRS)

    Lee, P. J.

    1986-01-01

    Efficient computation of the bit error rate (BER) for the coherent M-ary PSK signals with Gray code bit mapping is considered. A closed-form expression for the exact BER of 8-ary PSK is presented. Tight upper and lower bounds on BER are also obtained for M-ary PSK with larger M.

  18. Sister Mary Joseph Nodules on 99mTc HYNIC-TOC scintigraphy in patients with neuroendocrine tumors.

    PubMed

    Jing, Hongli; Zhang, Yingqiang; Li, Fang

    2015-02-01

    A Sister Mary Joseph nodule represents an umbilical metastasis, which is more commonly caused by a primary malignancy in gastrointestinal tract or from reproductive system. We report Sister Mary Joseph nodules caused by neuroendocrine tumor and revealed on Tc HYNIC-TOC scintigraphy.

  19. Biomechanical effects of sensorimotor orthoses in adults with Charcot-Marie-Tooth disease.

    PubMed

    Wegener, Caleb; Wegener, Katrin; Smith, Richard; Schott, Karl-Heinz; Burns, Joshua

    2016-08-01

    Charcot-Marie-Tooth disease is an inherited neuropathy causing progressive weakness, foot deformity and difficulty walking. Clinical anecdotes suggest orthoses designed on the 'sensorimotor' paradigm are beneficial for improving gait in Charcot-Marie-Tooth disease. Investigate the effect of sensorimotor orthoses on in-shoe and lower limb biomechanics in adults with Charcot-Marie-Tooth disease. Randomised, repeated-measures, exploratory study. Eight males and two females with Charcot-Marie-Tooth disease aged 31-68 years fitted with pedorthic shoes and custom-made sensorimotor orthoses were randomly tested at baseline and after 4 weeks of adaptation. In-shoe three-dimensional multi-segment foot and lower limb kinematics and kinetics were collected as were plantar pressures, electromyography and self-reported comfort, stability, cushioning and preference. Compared to the shoe only condition, sensorimotor orthoses increased midfoot eversion and plantarflexion, increased ankle eversion and produced small but significant changes at the knee and hip indicating increased internal rotation. The orthoses increased medial ground reaction forces and increased pressure at the heel, midfoot and toes. There were minimal effects on electromyography. The sensorimotor orthoses were rated higher for comfort, cushioning, stability and preference. Sensorimotor orthoses produced changes in kinematic, kinetic and pressure variables in adults with Charcot-Marie-Tooth disease and were regarded as more comfortable, cushioned and stable during walking. In this study, the walking ability of patients with Charcot-Marie-Tooth disease improved with the use of foot orthoses designed according to the sensorimotor paradigm. However, the mechanism of action appears to be primarily mechanical in origin. Randomised controlled trials are necessary to evaluate the long-term patient-reported outcomes of sensorimotor orthoses. © The International Society for Prosthetics and Orthotics 2015.

  20. Mary's Case: An Illustration of Interprofessional Collaborative Practice for a Child With Severe Disabilities.

    PubMed

    Ogletree, Billy T; Brady, Nancy; Bruce, Susan; Dean, Evan; Romski, MaryAnn; Sylvester, Lorraine; Westling, David

    2017-05-17

    The principles of interprofessional collaborative practice (IPCP) are illustrated through the case of Mary, a child with severe disabilities. Mary's experiences from early childhood to young adulthood are highlighted by both optimal and less-than-ideal examples of clinical services and collaborative practice. The range of collaboration illustrates potential variations in service delivery. Thematic comments and resources are provided by professionals experienced with and committed to IPCP who represent the following four disciplines: occupational therapy, physical therapy, special education, and speech-language pathology. Although potentially challenging, IPCP is a dynamic practice methodology appropriate for speech-language pathologists and others serving persons with severe disabilities.

  1. M-ary suprathreshold stochastic resonance in multilevel threshold systems with signal-dependent noise

    NASA Astrophysics Data System (ADS)

    Cheng, Chaojun; Zhou, Bingchang; Gao, Xiao; McDonnell, Mark D.

    2017-08-01

    We investigate multilevel threshold systems with signal-dependent noise that transmit a common random input signal. We demonstrate the occurrence of M-ary suprathreshold stochastic resonance caused by the signal-dependent noise, and quantify the information enhancement that results relative to the absence of noise. We also find that in the case of M-ary threshold systems, the values of mutual information and signal-to-quantization-noise ratio are larger than the corresponding values in the case of binary threshold systems. These results are potentially useful for understanding the encoding mechanism of inner-ear hair cells and other biological sensory systems.

  2. MARIE Measurements and Model Predictions of Solar Modulation of Galactic Cosmic Rays at Mars

    NASA Technical Reports Server (NTRS)

    Saganti, P. B.; Cucinotta, F. A.; Zeitlin, C. J.; Cleghorn, T. F.; Hu, X.; Lee, K. T.

    2003-01-01

    Recent data from the MARIE (Martian Radiation Environment Experiment) instrument on board the 2001 Mars Odyssey spacecraft currently in Mars orbit are presented. It is shown that the short-term modulations of galactic cosmic rays (GCR) are well described by correlating the so lar modulation parameter, <1>, with Earth-based neutron monitor counts using a 85-day time lag and the NASA Models - HZETRN (High Z and Energy Transport) and QMSFRG (Quantum Multiple Scattering theory of nuclear Fragmentation). The dose rates observed by the MARIE instrument are within 10% of the model calculations.

  3. Charcot-Marie-Tooth Disease Type 1A: Influence of Body Mass Index on Nerve Conduction Studies and on the Charcot-Marie-Tooth Examination Score.

    PubMed

    Jerath, Nivedita U; Shy, Michael E

    2017-09-11

    Charcot-Marie-Tooth Disease type 1A (CMT1A) is caused by a duplication of the peripheral myelin protein gene 22 at chromosome 17p11.2-12. There is limited data regarding whether body mass index (BMI) affects electrophysiological or clinical data in those with CMT1A. Electrophysiological data, the Charcot-Marie-Tooth examination score (CMTES) and BMI from 101 patients with known CMT1A were obtained and analyzed. When controlling for age, a higher BMI does not affect ulnar motor nerve conduction studies in those with CMT1A, but rather components of the CMTES (loss of pinprick and motor strength in the lower extremities). BMI and clinical components of the CMTES are correlated, but it is uncertain which came first-whether the loss of lower extremity pinprick sensation and motor strength results in a higher BMI or if higher BMI results in these signs.

  4. A Rasch Analysis of the Charcot-Marie-Tooth Neuropathy Score (CMTNS) in a Cohort of Charcot-Marie-Tooth Type 1A Patients

    PubMed Central

    Guedj, Mickaël; Bertrand, Viviane; Foucquier, Julie; Jouve, Elisabeth; Commenges, Daniel; Proust-Lima, Cécile; Murphy, Niall P.; Blin, Olivier; Magy, Laurent; Cohen, Daniel; Attarian, Shahram

    2017-01-01

    The Charcot-Marie-Tooth Neuropathy Score (CMTNS) was developed as a main efficacy endpoint for application in clinical trials of Charcot-Marie-Tooth disease type 1A (CMT1A). However, the sensitivity of the CMTNS for measuring disease severity and progression in CMT1A patients has been questioned. Here, we applied a Rasch analysis in a French cohort of patients to evaluate the psychometrical properties of the CMTNS. Overall, our analysis supports the validity of the CMTNS for application to CMT1A patients though with some limitations such as certain items of the CMTNS being more suitable for moderate to severe forms of the disease, and some items being disordered. We suggest that additional items and/or categories be considered to better assess mild-to-moderate patients. PMID:28095456

  5. What can we learn from B{yields}a{sub 1}(1260)(b{sub 1}(1235)){pi}(K) decays?

    SciTech Connect

    Wang Wei; Li Runhui; Lue Caidian

    2008-10-01

    We investigate the B{yields}a{sub 1}(1260)(b{sub 1}(1235)){pi}(K) decays under the factorization scheme and find many discrepancies between theoretical predictions and the experimental data. In the tree-dominated processes, large contributions from color-suppressed tree diagrams are required in order to accommodate the large decay rates of B{sup -}{yields}a{sub 1}{sup 0}{pi}{sup -} and B{sup -}{yields}a{sub 1}{sup -}{pi}{sup 0}. For B{sup 0}{yields}(a{sub 1}{sup +},b{sub 1}{sup +})K{sup -} decays which are induced by b{yields}s transition, theoretical predictions on their decay rates are larger than the data by a factor of 2.8 and 5.5, respectively. Large electroweak penguins or some new mechanism are expected to explain the branching ratios of B{sup -}{yields}b{sub 1}{sup 0}K{sup -} and B{sup -}{yields}a{sub 1}{sup -}K{sup 0}. The soft-collinear effective theory has the potential to explain large decay rates of B{sup -}{yields}a{sub 1}{sup 0}{pi}{sup -} and B{sup -}{yields}a{sub 1}{sup -}{pi}{sup 0} via a large hard-scattering form factor {zeta}{sub J}{sup B{yields}}{sup a{sub 1}}. We will also show that, with proper charming penguins, predictions on the branching ratios of B{sup 0}{yields}(a{sub 1}{sup +},b{sub 1}{sup +})K{sup -} can also be consistent with the data.

  6. Civil Rights' Voice and Conscience: Thorough Preparation and Research are Dr. Mary Frances Berry's Formidable Tools.

    ERIC Educational Resources Information Center

    Black Issues in Higher Education, 1994

    1994-01-01

    In an interview, black civil rights leader Mary Frances Berry discusses the dilemmas and opportunities facing African Americans, women, and other minorities from her perspectives as observer and Washington insider. Issues addressed include African-American leadership, transforming knowledge into policy, Afrocentrism, and tensions with other…

  7. The Politics of Thinking About China: 1. Mary Berry on China. 2. Shanker Versus Berry

    ERIC Educational Resources Information Center

    Berry, Mary; Shanker, Albert

    1978-01-01

    Mary Berry's speech suggesting that America had much to learn from Chinese education prompted a sharply critical letter from Albert Shanker, head of the American Federation of Teachers. Parts of the speech and the subsequent exchange with Shanker are reprinted here. (LBH)

  8. Aspects of Community Healing: Experiences of the Sault Sainte Marie Tribe of Chippewa Indians.

    ERIC Educational Resources Information Center

    McBride, Beverly A.

    2003-01-01

    The Sault Sainte Marie tribe of Chippewa Indians (Michigan) facilitated community healing through a curriculum that raised awareness of harmful assimilation factors and the impact of oppression and reintroduced creation stories and the clan system to reclaim American Indian cultural identity. Thirty-two persons completed the first round of…

  9. Mary Miles Bibb: Education and Moral Improvement in the "Voice of the Fugitive."

    ERIC Educational Resources Information Center

    Tripp, Bernell E.

    An ardent antislavery supporter and teacher, Mary Elizabeth Miles Bibb (c.1820-1877) knew the significance of an education and the purpose it would serve, in the classroom and in the newsroom, in establishing a better life for blacks prior to the Civil War. In 1847, her antislavery involvement allowed her to meet her future husband, Henry Bibb,…

  10. Online Opportunist: Mary Ellen Icaza--Montgomery County Public Libraries, Rockville, MD

    ERIC Educational Resources Information Center

    Library Journal, 2004

    2004-01-01

    When Mary Ellen Icaza became Electronic Services Librarian at Montgomery County Public Libraries, she noticed that the readers' services information on the library web site was invisible, even to librarians. "And if staff can't find it," she says, "customers can't." She set out to help people find that material-and to turn a…

  11. Golden Girl: Mary Lai Reflects as She Marks Her 50th Anniversary.

    ERIC Educational Resources Information Center

    Iwanowski, Jay

    1996-01-01

    The career and administrative style of Mary M. Lai, who celebrates her 50th year as chief financial officer at Long Island University (New York), are discussed. Her perspectives on change in higher education and in the institution during that time, the administrator's role, current challenges for financial officers, and the college environment as…

  12. Summer Programs for Gifted Learners at the College of William and Mary.

    ERIC Educational Resources Information Center

    Peterson, Kristina; And Others

    1992-01-01

    The William and Mary Summer Enrichment Program for Gifted Learners serves students in the Williamsburg, Virginia, area from preschool through grade 10, while the Governor's School for Science and Technology serves high school juniors and seniors. A sample course in library skills for at risk verbally talented children (ages five through seven) is…

  13. MaRIE: A facility for time-dependent materials science at the mesoscale

    SciTech Connect

    Barnes, Cris William; Kippen, Karen Elizabeth

    2015-02-11

    To meet new and emerging national security issues the Laboratory is stepping up to meet another grand challenge—transitioning from observing to controlling a material’s performance. This challenge requires the best of experiment, modeling, simulation, and computational tools. MaRIE is the Laboratory’s proposed flagship experimental facility intended to meet the challenge.

  14. Response to Marie Paz Morales' "Influence of Culture and Language Sensitive Physics on Science Attitude Achievement"

    ERIC Educational Resources Information Center

    Cole, Mikel Walker

    2015-01-01

    This response to Marie Paz Morales' "Influence of culture and language sensitive physics on science attitude achievement" explores the ideas of culturally responsive pedagogy and critical literacy to examine some implications for culturally responsive science instruction implicit in the original manuscript. [For "Influence of…

  15. Response to Marie Paz Morales' ``Influence of culture and language sensitive physics on science attitude achievement''

    NASA Astrophysics Data System (ADS)

    Cole, Mikel Walker

    2015-12-01

    This response to Marie Paz Morales' "Influence of culture and language sensitive physics on science attitude achievement" explores the ideas of culturally responsive pedagogy and critical literacy to examine some implications for culturally responsive science instruction implicit in the original manuscript.

  16. Migrating to the City: Negotiating Gender and Race in Marie Arana's "Lima Nights"

    ERIC Educational Resources Information Center

    Heredia, Juanita

    2016-01-01

    This article examines Peruvian-American Marie Arana's second novel "Lima Nights" (2008) in which she represents Amazonian indigenous migrations to Lima, Peru during and after the Shining Path civil war years (1986-2006). As part of a generation of transnational US Latina authors in the post-2000 period, Arana recovers the image of the…

  17. World of John and Mary Smith: A Study of Quirk and Greenbaum's "University Grammar of English."

    ERIC Educational Resources Information Center

    Stephens, Kate

    This paper analyzes the "University Grammar of English" by Randolph Quirk and Sidney Greenbaum (1973) from the point of view of isolation of forms of language from meaning used to convey these forms, especially regarding gender differences and relations in the main characters, John and Mary Smith. It is suggested that females are underrepresented,…

  18. Making Socialists: Mary Bridges Adams and the Fight for Knowledge and Power, 1855-1939

    ERIC Educational Resources Information Center

    Weiler, Kathleen

    2012-01-01

    This article presents a review of "Making socialists: Mary Bridges Adams and the fight for knowledge and power, 1855-1939," by Jane Martin. Jane Martin has explored the history of late-nineteenth-century and early-twentieth century-British women educational activists in numerous publications over the past two decades. Her first book,…

  19. Neuromuscular Hip Dysplasia in Charcot-Marie-Tooth Disease Type 1A

    ERIC Educational Resources Information Center

    Bamford, Nigel S.; White, Klane K.; Robinett, Stephanie A.; Otto, Randolph K.; Gospe, Sidney M., Jr.

    2009-01-01

    Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders, affecting 36 in 100,000 people. CMT type 1A (hereditary motor and sensory neuropathy) is the most frequent form of this disease, affecting 60 to 80% of the CMT population, but its diagnosis may be delayed because of inconsistent clinical signs and…

  20. Nerve Excitability Properties in Charcot-Marie-Tooth Disease Type 1A

    ERIC Educational Resources Information Center

    Nodera, Hiroyuki; Bostock, Hugh; Kuwabara, Satoshi; Sakamoto, Takashi; Asanuma, Kotaro; Jia-Ying, Sung; Ogawara, Kazue; Hattori, Naoki; Hirayama, Masaaki; Kaji, Ryuji

    2004-01-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is commonly considered a prototype of a hereditary demyelinating polyneuropathy. Apart from the myelin involvement, there has been little information on axonal membrane properties in this condition. Taking advantage of the uniform nature of the disease process, we undertook the "in vivo" assessment of…