Science.gov

Sample records for maarja pik mari

  1. 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.

  2. PIK3CA in Colorectal Cancer

    PubMed Central

    Cathomas, Gieri

    2014-01-01

    PIK3CA, the catalytic subunit of PI3K, is mutated in many different tumors, including colorectal cancer (CRC). Mutations of PIK3CA have been reported in 10–20% of CRC, about 80% of mutations found in two hot spots in exon 9 and exon 20. In RAS wild-type CRC, PIK3CA mutations have been associated with a worse clinical outcome and with a negative prediction of a response to targeted therapy by anti-EGFR monoclonal antibodies. However, these findings have not been confirmed in all studies and subsequent more detailed analysis has revealed that these effects may be restricted to mutations in Exon 20. Finally, mutations in PIK3CA may be the long sought biomarker for successful adjuvant therapy with aspirin in patients with CRC. Therefore, PIK3CA mutations appear to be a promising predictive biomarker; however, further data are needed to conclusively define the impact of somatic mutations in the PIK3CA gene for the management of patients with CRC. PMID:24624362

  3. Essential Role for Schizosaccharomyces pombe pik1 in Septation

    PubMed Central

    Desautels, Michel; Hemmingsen, Sean M.

    2009-01-01

    Background Schizosaccharomyces pombe pik1 encodes a phosphatidylinositol 4-kinase, reported to bind Cdc4, but not Cdc4G107S. Principal Findings Gene deletion revealed that pik1 is essential. In cells with pik1 deleted, ectopic expression of a loss-of-function allele, created by fusion to a temperature-sensitive dihydrofolate reductase, allowed normal cell proliferation at 25°C. At 36°C, cells arrested with abnormally thick, misplaced or supernumerary septa, indicating a defect late in septation. In addition to being Golgi associated, ectopically expressed GFP-tagged Pik1 was observed at the medial cell plane late in cytokinesis. New alleles, created by site-directed mutagenesis, were expressed ectopically. Lipid kinase and Cdc4-binding activity assays were performed. Pik1D709A was kinase-dead, but bound Cdc4. Pik1R838A did not bind Cdc4, but was an active kinase. Genomic integration of these substitutions in S. pombe and complementation studies in Saccharomyces cerevisiae pik1-101 cells revealed that D709 is essential in both cases while R838 is dispensable. In S. pombe, ectopic expression of pik1 was dominantly lethal; while, pik1D709A,R838A was innocuous, pik1R838A was almost innocuous, and pik1D709A produced partial lethality and septation defects. The pik1 ectopic expression lethal phenotype was suppressed in cdc4G107S. Thus, D709 is essential for kinase activity and septation. Conclusions Pik1 kinase activity is required for septation. The Pik1 R838 residue is required for important protein-protein interactions, possibly with Cdc4. PMID:19587793

  4. Knockin of mutant PIK3CA activates multiple oncogenic pathways

    PubMed Central

    Gustin, John P.; Karakas, Bedri; Weiss, Michele B.; Abukhdeir, Abde M.; Lauring, Josh; Garay, Joseph P.; Cosgrove, David; Tamaki, Akina; Konishi, Hiroyuki; Konishi, Yuko; Mohseni, Morassa; Wang, Grace; Rosen, D. Marc; Denmeade, Samuel R.; Higgins, Michaela J.; Vitolo, Michele I.; Bachman, Kurtis E.; Park, Ben Ho

    2009-01-01

    The phosphatidylinositol 3-kinase subunit PIK3CA is frequently mutated in human cancers. Here we used gene targeting to “knock in” PIK3CA mutations into human breast epithelial cells to identify new therapeutic targets associated with oncogenic PIK3CA. Mutant PIK3CA knockin cells were capable of epidermal growth factor and mTOR-independent cell proliferation that was associated with AKT, ERK, and GSK3β phosphorylation. Paradoxically, the GSK3β inhibitors lithium chloride and SB216763 selectively decreased the proliferation of human breast and colorectal cancer cell lines with oncogenic PIK3CA mutations and led to a decrease in the GSK3β target gene CYCLIN D1. Oral treatment with lithium preferentially inhibited the growth of nude mouse xenografts of HCT-116 colon cancer cells with mutant PIK3CA compared with isogenic HCT-116 knockout cells containing only wild-type PIK3CA. Our findings suggest GSK3β is an important effector of mutant PIK3CA, and that lithium, an FDA-approved therapy for bipolar disorders, has selective antineoplastic properties against cancers that harbor these mutations. PMID:19196980

  5. 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. PMID:27184479

  6. Somatic Activating PIK3CA Mutations Cause Venous Malformation.

    PubMed

    Limaye, Nisha; Kangas, Jaakko; Mendola, Antonella; Godfraind, Catherine; Schlögel, Matthieu J; Helaers, Raphael; Eklund, Lauri; Boon, Laurence M; Vikkula, Miikka

    2015-12-01

    Somatic mutations in TEK, the gene encoding endothelial cell tyrosine kinase receptor TIE2, cause more than half of sporadically occurring unifocal venous malformations (VMs). Here, we report that somatic mutations in PIK3CA, the gene encoding the catalytic p110α subunit of PI3K, cause 54% (27 out of 50) of VMs with no detected TEK mutation. The hotspot mutations c.1624G>A, c.1633G>A, and c.3140A>G (p.Glu542Lys, p.Glu545Lys, and p.His1047Arg), frequent in PIK3CA-associated cancers, overgrowth syndromes, and lymphatic malformation (LM), account for >92% of individuals who carry mutations. Like VM-causative mutations in TEK, the PIK3CA mutations cause chronic activation of AKT, dysregulation of certain important angiogenic factors, and abnormal endothelial cell morphology when expressed in human umbilical vein endothelial cells (HUVECs). The p110α-specific inhibitor BYL719 restores all abnormal phenotypes tested, in PIK3CA- as well as TEK-mutant HUVECs, demonstrating that they operate via the same pathogenic pathways. Nevertheless, significant genotype-phenotype correlations in lesion localization and histology are observed between individuals with mutations in PIK3CA versus TEK, pointing to gene-specific effects. PMID:26637981

  7. 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.

  8. Society of Mary: Marianists

    ERIC Educational Resources Information Center

    Habjan, John

    2007-01-01

    The Society of Mary's ministry in education needs to be placed in the context of the Marianist family. The Marianist family is comprised of men and women who are religious brothers, sisters, and priests and vowed and non-vowed members of Marianist lay communities. The implementation of the Marianist mission is the result of the collaboration among…

  9. 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 of Anna Magdalena Bach";…

  10. 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.

  11. Frequent PIK3CA mutations in radial scars.

    PubMed

    Wolters, Katie L; Ang, Daphne; Warrick, Andrea; Beadling, Carol; Corless, Christopher L; Troxell, Megan L

    2013-12-01

    Radial scars are breast lesions of uncertain pathogenesis that are associated with a 2-fold increased risk of breast cancer compared with that in controls. Activating point mutations in PIK3CA are found in 25% to 30% of invasive breast cancers; however, they have not previously been investigated in radial scars. We sought to evaluate radial scars for known activating point mutations commonly seen in invasive breast cancer. Sixteen surgical cases containing 22 radial scars were identified from pathology archives. Lesional tissue was macrodissected from unstained paraffin sections; genomic DNA was then extracted and screened for a panel of known hotspot mutations using polymerase chain reaction and mass spectroscopy analysis. Of the 22 radial scars, 14 (63.6%) had PIK3CA mutations (10 with H1047R mutations, 2 G1049R mutations, 1 E542K, 1 E545K). The remaining 8 lesions were wild type for all of the screened genes. Of the radial scars without epithelial atypia, 9/16 (56.3%) had PIK3CA mutations; furthermore, 5/6 (83.3%) radial scars with atypia had mutations detected. In this study, the frequency of PIK3CA mutations was notably higher than the 25% to 30% mutation frequency of invasive breast cancer. This finding raises interesting questions as to the role of PIK3CA mutations in breast cancer development. Additional larger studies are indicated to confirm and extend these observations in understanding the pathogenesis of radial scars and their relationship to breast cancer. PMID:24193002

  12. 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.

  13. Whatever Happened to Mary Ellen?

    ERIC Educational Resources Information Center

    Lazoritz, Stephen

    1990-01-01

    The case of Mary Ellen, whose maltreatment as a child began the organized response to child abuse in the United States, is reviewed. The paper emphasizes Mary Ellen's rescue from her stepmother, her life after intervention, and her meaningful and productive life as a wife and mother. (JDD)

  14. Charcot-Marie-Tooth disease

    MedlinePlus

    Charcot-Marie-Tooth disease is a group of disorders passed down through families that affect the nerves outside the brain and ... Charcot-Marie-Tooth is one of the most common nerve-related disorders passed down through families (inherited). Changes to at least ...

  15. Clinicopathological Significance of Elevated PIK3CA Expression in Gastric Cancer

    PubMed Central

    Jang, Si-Hyong; Kim, Kyung-Ju; Oh, Mee-Hye; Lee, Ji-Hye; Lee, Hyun Ju; Cho, Hyun Deuk; Han, Sun Wook; Son, Myoung Won

    2016-01-01

    Purpose PIK3CA is often mutated in a variety of malignancies, including colon, gastric, ovary, breast, and brain tumors. We investigated PIK3CA expression in gastric cancer and explored the relationships between the PIK3CA expression level and clinicopathological features as well as survival of the patients. Materials and Methods We examined PIK3CA expression in a tissue microarray of 178 gastric adenocarcinomas by immunohisto-chemistry and reviewed patients' medical records. Results In our study, 112 of the 178 gastric cancer patients displayed positive PIK3CA expression. Overexpression of PIK3CA was correlated with low grade differentiation (P=0.001), frequent lymphatic invasion (P=0.032), and high T stage (P=0.040). Patients with positive PIK3CA staining were more likely to display worse overall survival rate than those with negative PIK3CA staining, as determined by Kaplan-Meier survival analysis with log-rank test (P=0.047) and a univariate analysis using the Cox proportional hazard model (hazard ratio=1.832, P=0.051). Conclusions Elevated PIK3CA expression was significantly correlated with tumor invasiveness, tumor phenotypes, and poor patient survival. PMID:27433393

  16. 33 CFR 162.117 - St. Marys River, Sault Ste. Marie, Michigan.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 33 Navigation and Navigable Waters 2 2013-07-01 2013-07-01 false St. Marys River, Sault Ste. Marie... SECURITY (CONTINUED) PORTS AND WATERWAYS SAFETY INLAND WATERWAYS NAVIGATION REGULATIONS § 162.117 St. Marys River, Sault Ste. Marie, Michigan. (a) The area. The waters of the St. Marys River and lower...

  17. 33 CFR 162.117 - St. Marys River, Sault Ste. Marie, Michigan.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 2 2012-07-01 2012-07-01 false St. Marys River, Sault Ste. Marie... SECURITY (CONTINUED) PORTS AND WATERWAYS SAFETY INLAND WATERWAYS NAVIGATION REGULATIONS § 162.117 St. Marys River, Sault Ste. Marie, Michigan. (a) The area. The waters of the St. Marys River and lower...

  18. 33 CFR 162.117 - St. Marys River, Sault Ste. Marie, Michigan.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 33 Navigation and Navigable Waters 2 2014-07-01 2014-07-01 false St. Marys River, Sault Ste. Marie... SECURITY (CONTINUED) PORTS AND WATERWAYS SAFETY INLAND WATERWAYS NAVIGATION REGULATIONS § 162.117 St. Marys River, Sault Ste. Marie, Michigan. (a) The area. The waters of the St. Marys River and lower...

  19. 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. PMID:27301098

  20. Cape St. Mary

    NASA Technical Reports Server (NTRS)

    2007-01-01

    Another of the best examples of spectacular cross-bedding in Victoria crater are the outcrops at Cape St. Mary, which is an approximately 15 m (45 foot) high promontory located along the western rim of Victoria crater and near the beginning of the rover's traverse around the rim. Like the Cape St. Vincent images, these Pancam super-resolution images have allowed scientists to discern that the rocks at Victoria Crater once represented a large dune field that migrated across this region.

    This is a Mars Exploration Rover Opportunity Panoramic Camera image mosaic acquired on sol 1213 (June 23, 2007), and was constructed from a mathematical combination of 32 different blue filter (480 nm) images.

  1. Pik3ip1 modulates cardiac hypertrophy by inhibiting PI3K pathway.

    PubMed

    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

  2. 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

  3. Marie-unna hereditary hypotrichosis.

    PubMed

    Srinivas, Sahana M; Hiremagalore, Ravi

    2014-10-01

    Marie-Unna type of hereditary hypotrichosis is a rare autosomal dominant disorder that has a distinctive type of hair loss pattern that varies with child's age. It is characterized by sparse or absent hair at birth with regrowth of coarse, wiry twisted hair from childhood, followed by progressive loss on approaching puberty. We report a 12-year-old male child with characteristic clinical features suggestive of hereditary hypotrichosis of Marie-Unna type. PMID:25368478

  4. Ernst Julius Öpik, Solar Variability and Climate Change

    NASA Astrophysics Data System (ADS)

    Sterken, C.

    This paper covers some aspects of the life and work of the Estonian astronomer Ernst Öpik (1893--1985), who contributed to a very wide range of astronomical disciplines, and whose publications span more than 70 years. He worked in Estonia, the Soviet Union, the United States, Germany and Northern Ireland. His visions on the role of solar variability in global climate change are emphasized, and his opinions on modelling in science are explained, in addition to his views about scientific refereeing and publishing.

  5. 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. PMID:26915040

  6. 75 FR 38718 - Safety Zone; Sault Sainte Marie 4th of July Fireworks, St. Mary's River, Sault Sainte Marie, MI

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-06

    ... SECURITY Coast Guard 33 CFR Part 165 RIN 1625-AA00 Safety Zone; Sault Sainte Marie 4th of July Fireworks... the Sault Sainte Marie 4th of July Fireworks display, July ] 4, 2010. This temporary safety zone is... with the Sault Sainte Marie 4th of July Fireworks display. The fireworks display is planned to...

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

    PubMed

    Kim, Seung Tae; Lira, Maruja; 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

    2015-11-24

    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

  8. 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

  9. PIK3CA mutations predict recurrence in localized microsatellite stable colon cancer

    PubMed Central

    Manceau, Gilles; Marisa, Laetitia; Boige, Valérie; Duval, Alex; Gaub, Marie-Pierre; Milano, Gérard; Selves, Janick; Olschwang, Sylviane; Jooste, Valérie; le Legrain, Michè; Lecorre, Delphine; Guenot, Dominique; Etienne-Grimaldi, Marie-Christine; Kirzin, Sylvain; Martin, Laurent; Lepage, Come; Bouvier, Anne-Marie; Laurent-Puig, Pierre

    2015-01-01

    PIK3CA, which encodes the p110α catalytic subunit of PI3Kα, is one of the most frequently altered oncogenes in colon cancer (CC), but its prognostic value is still a matter of debate. Few reports have addressed the association between PIK3CA mutations and survival and their results are controversial. In the present study, we aimed to clarify the prognostic impact of PIK3CA mutations in stage I–III CC according to mismatch repair status. Fresh frozen tissue samples from two independent cohorts with a total of 826 patients who underwent curative surgical resection of CC were analyzed for microsatellite instability and screened for activating point mutations in exon 9 and 20 of PIK3CA by direct sequencing. Overall, 693 tumors (84%) exhibited microsatellite stability (MSS) and 113 samples (14%) harbored PIK3CA mutation. In the retrospective training cohort (n = 433), patients with PIK3CA-mutated MSS tumors (n = 47) experienced a significant increased 5-year relapse-free interval compared with PIK3CA wild-type MSS tumors (n = 319) in univariate analysis (94% vs. 68%, Log-rank P = 0. 0003) and in multivariate analysis (HR = 0.12; 95% confidence interval, 0.029–0.48; P = 0.0027). In the prospective validation cohort (n = 393), the favorable prognostic impact of PIK3CA mutations in MSS tumors (n = 327) was confirmed (83% vs. 67%, Log-rank P = 0.04). Our study showed that PIK3CA mutations are associated with a good prognosis in patients with MSS stage I–III CC. PMID:25641861

  10. Mary Tape, An Outspoken Woman. Primary Source.

    ERIC Educational Resources Information Center

    OAH Magazine of History, 2001

    2001-01-01

    Provides reproductions of primary documents pertaining to Mary Tape, a Chinese immigrant in San Francisco who fought to have her children admitted to public school, including a letter from Mary Tape to the Board of Education and an article about Mary Tape that appeared in the "Morning Call" (23 November 1892). (CMK)

  11. 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…

  12. 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 ...

  13. Mount St. Mary's College. Exemplars.

    ERIC Educational Resources Information Center

    Iannozzi, Maria

    This report describes the efforts of Mount St. Mary's College (California) to extend the benefits of a strong, traditional baccalaureate program to an underserved population of women in an urban region, including substantial numbers of minority and first-generation college students. To help realize its service mission and increase access to…

  14. 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…

  15. Targeting therapeutic liabilities engendered by PIK3R1 mutations for cancer treatment.

    PubMed

    Cheung, Lydia Wt; Mills, Gordon B

    2016-02-01

    The regulatory subunit of PI3K, p85α (encoded by PIK3R1), binds, stabilizes and inhibits the PI3K p110 catalytic subunit. Functional characterization of PIK3R1 mutations has identified not only hypomorphs with reduced inhibition of p110, but also hypomorphs and dominant negative mutants that disrupt a novel regulatory role of p85α on PTEN or neomorphs that activate unexpected signaling pathways. The diverse phenotypic spectrum of these PIK3R1 driver mutations underscores the need for different treatment strategies targeting tumors harboring these mutations. This article describes the functional consequences of the spectrum of PIK3R1 driver mutations and therapeutic liabilities they may engender. PMID:26807692

  16. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer.

    PubMed

    Vasudevan, Krishna M; Barbie, David A; Davies, Michael A; Rabinovsky, Rosalia; McNear, Chontelle J; Kim, Jessica J; Hennessy, Bryan T; Tseng, Hsiuyi; Pochanard, Panisa; Kim, So Young; Dunn, Ian F; Schinzel, Anna C; Sandy, Peter; Hoersch, Sebastian; Sheng, Qing; Gupta, Piyush B; Boehm, Jesse S; Reiling, Jan H; Silver, Serena; Lu, Yiling; Stemke-Hale, Katherine; Dutta, Bhaskar; Joy, Corwin; Sahin, Aysegul A; Gonzalez-Angulo, Ana Maria; Lluch, Ana; Rameh, Lucia E; Jacks, Tyler; Root, David E; Lander, Eric S; Mills, Gordon B; Hahn, William C; Sellers, William R; Garraway, Levi A

    2009-07-01

    Dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway occurs frequently in human cancer. PTEN tumor suppressor or PIK3CA oncogene mutations both direct PI3K-dependent tumorigenesis largely through activation of the AKT/PKB kinase. However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3. SGK3 undergoes PI3K- and PDK1-dependent activation in PIK3CA mutant cancer cells. Thus, PI3K may promote cancer through both AKT-dependent and AKT-independent mechanisms. Knowledge of differential PI3K/PDK1 signaling could inform rational therapeutics in cancers harboring PIK3CA mutations. PMID:19573809

  17. Multiple forms of p55PIK, a regulatory subunit of phosphoinositide 3-kinase, are generated by alternative initiation of translation.

    PubMed Central

    Xia, X; Serrero, G

    1999-01-01

    A cDNA encoding p55PIK, one of the regulatory subunits of phosphoinositide (phosphatidylinositol) 3-kinase, was cloned from a cDNA library derived from the mouse mammary epithelial cell line C57MG. The cDNA coding for full-length p55PIK was transiently expressed in COS-7 cells. Western blot analysis of p55PIK expression using a specific antibody against p55PIK revealed that multiple protein products with different molecular masses were detected in COS-7 cell extracts. Experiments presented here demonstrate that multiple forms of p55PIK detected in COS-7 cells were produced by alternative initiation of translation. We also show that at least two in-frame start codons (AUG#2 and AUG#5) in p55PIK mRNA are used in COS-7 cells for the initiation of translation of p55PIK into proteins of 54 kDa and 50 kDa respectively. p55PIK mRNA was also alternatively translated into two proteins in PC cells, a mouse teratoma cell line, indicating that the alternative initiation of translation of p55PIK is not restricted to COS-7 cells. Results from immunoprecipitation and Western blot analysis showed that two forms (54 kDa and 50 kDa protein species) of p55PIK were detected in C57MG cells. Interestingly, when C57MG cells were treated with insulin, only p55PIK, but not p50PIK, bound to insulin receptor substrate-1 protein, providing evidence that different forms of p55PIKs may have specific distinct roles in signal transduction pathways. PMID:10417350

  18. Mutation of the PIK3CA gene in ovarian and breast cancer.

    PubMed

    Campbell, Ian G; Russell, Sarah E; Choong, David Y H; Montgomery, Karen G; Ciavarella, Marianne L; Hooi, Christine S F; Cristiano, Briony E; Pearson, Richard B; Phillips, Wayne A

    2004-11-01

    Phosphatidylinositol 3'-kinases are lipid kinases with important roles in neoplasia. Recently, a very high frequency of somatic mutations in PIK3CA has been reported among a large series of colorectal cancers. However, the relevance of PIK3CA mutation in other cancer types remains unclear because of the limited number of tumors investigated. We have screened a total of 284 primary human tumors for mutations in all coding exons of PIK3CA using a combination of single stranded conformational polymorphism and denaturing high-performance liquid chromatography analysis. Among 70 primary breast cancers, 40% (28 of 70) harbored mutations in PIK3CA, making it the most common mutation described to date in this cancer type. Mutations were not associated with histologic subtype, estrogen receptor status, grade or presence of tumor in lymph nodes. Among the primary epithelial ovarian cancers only 11 of 167 (6.6%) contain somatic mutations, but there was a clear histologic subtype bias in their distribution. Only 2 of 88 (2.3%) of serous carcinomas had PIK3CA mutations compared with 8 of 40 (20.0%) endometrioid and clear cell cancers, which was highly significant (P = 0.001). In contrast, PIK3CA gene amplification (>7-fold) was common among all histologic subtypes (24.5%) and was inversely associated with the presence of mutations. Overall, PIK3CA mutation or gene amplification was detected in 30.5% of all ovarian cancers and 45% of the endometrioid and clear cell subtypes. Our study is the first direct evidence that PIK3CA is an oncogene in ovarian cancer and greatly extends recent findings in breast cancer. PMID:15520168

  19. Novel method for PIK3CA mutation analysis: locked nucleic acid--PCR sequencing.

    PubMed

    Ang, Daphne; O'Gara, Rebecca; Schilling, Amy; Beadling, Carol; Warrick, Andrea; Troxell, Megan L; Corless, Christopher L

    2013-05-01

    Somatic mutations in PIK3CA are commonly seen in invasive breast cancer and several other carcinomas, occurring in three hotspots: codons 542 and 545 of exon 9 and in codon 1047 of exon 20. We designed a locked nucleic acid (LNA)-PCR sequencing assay to detect low levels of mutant PIK3CA DNA with attention to avoiding amplification of a pseudogene on chromosome 22 that has >95% homology to exon 9 of PIK3CA. We tested 60 FFPE breast DNA samples with known PIK3CA mutation status (48 cases had one or more PIK3CA mutations, and 12 were wild type) as identified by PCR-mass spectrometry. PIK3CA exons 9 and 20 were amplified in the presence or absence of LNA-oligonucleotides designed to bind to the wild-type sequences for codons 542, 545, and 1047, and partially suppress their amplification. LNA-PCR sequencing confirmed all 51 PIK3CA mutations; however, the mutation detection rate by standard Sanger sequencing was only 69% (35 of 51). Of the 12 PIK3CA wild-type cases, LNA-PCR sequencing detected three additional H1047R mutations in "normal" breast tissue and one E545K in usual ductal hyperplasia. Histopathological review of these three normal breast specimens showed columnar cell change in two (both with known H1047R mutations) and apocrine metaplasia in one. The novel LNA-PCR shows higher sensitivity than standard Sanger sequencing and did not amplify the known pseudogene. PMID:23541593

  20. Mutation distributions and clinical correlations of PIK3CA gene mutations in breast cancer.

    PubMed

    Dirican, Ebubekir; Akkiprik, Mustafa; Özer, Ayşe

    2016-06-01

    Breast cancer (BCa) is the most common cancer and the second cause of death among women. Phosphoinositide 3-kinase (PI3K) signaling pathway has a crucial role in the cellular processes such as cell survival, growth, division, and motility. Moreover, oncogenic mutations in the PI3K pathway generally involve the activation phosphatidylinositol-4,5-bisphosphate 3-kinase-catalytic subunit alpha (PIK3CA) mutation which has been identified in numerous BCa subtypes. In this review, correlations between PIK3CA mutations and their clinicopathological parameters on BCa will be described. It is reported that PIK3CA mutations which have been localized mostly on exon 9 and 20 hot spots are detected 25-40 % in BCa. This relatively high frequency can offer an advantage for choosing the best treatment options for BCa. PIK3CA mutations may be used as biomarkers and have been major focus of drug development in cancer with the first clinical trials of PI3K pathway inhibitors currently in progress. Screening of PIK3CA gene mutations might be useful genetic tests for targeted therapeutics or diagnosis. Increasing data about PIK3CA mutations and its clinical correlations with BCa will help to introduce new clinical applications in the near future. PMID:26921096

  1. 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.

  2. 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.

  3. 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

  4. 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

    2016-01-01

    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

  5. KRAS, BRAF and PIK3CA Status in Squamous Cell Anal Carcinoma (SCAC)

    PubMed Central

    Giannini, Massimo; Freier, Eva; Tamberi, Stefano; Scarpi, Emanuela; Passardi, Alassandro; Zoli, Wainer; Ragazzini, Angela; Amadori, Dino; Frassineti, Giovanni Luca

    2014-01-01

    Anti-EGFR therapy appears to be a potential treatment option for squamous cell anal carcinoma (SCAC). KRAS mutation is a rare event in SCAC, indicating the absence of the principal mechanism of resistance to this type of therapy. However, no information is available from the literature regarding the status of BRAF or PIK3CA in this cancer type. We analysed KRAS, BRAF and PIK3CA status in SCAC patients in relation to the clinical-pathological characteristics of patients and to the presence of the human papilloma virus (HPV). One hundred and three patients were treated with the Nigro scheme for anal cancer from March 2001 to August 2012. Fifty patients were considered for the study as there was insufficient paraffin-embedded tumour tissue to perform molecular analysis the remaining 53. DNA was extracted from paraffin-embedded sections. KRAS, BRAF and PIK3CA gene status and HPV genotype were evaluated by pyrosequencing. KRAS and BRAF genes were wild-type in all cases. Conversely, PIK3CA gene was found to be mutated in 11 (22%) cases. In particular, 8 mutations occurred in exon 9 and 3 in exon 20 of the PIK3CA gene. These findings suggest that SCAC could potentially respond to an anti-EGFR drug. PIK3CA mutation may be involved in the process of carcinogenesis in some cases of SCAC. PMID:24642661

  6. Mutation of the PIK3CA gene as a prognostic factor in patients with colorectal cancer

    PubMed Central

    STEC, RAFAŁ; SEMENIUK-WOJTAŚ, ALEKSANDRA; CHARKIEWICZ, RADOSŁAW; BODNAR, LUBOMIR; KORNILUK, JAN; SMOTER, MARTA; CHYCZEWSKI, LECH; NIKLIŃSKI, JACEK; SZCZYLIK, CEZARY

    2015-01-01

    Colorectal cancer (CRC) is one of the most common cancers worldwide, with ~700,000 mortalities occurring due to CRC in 2012. The treatment options are effective in a small percentage of patients, and it is important to identify specific biomarkers in order to determine patients for whom the available therapies will be beneficial. It has been hypothesised that the PIK3CA gene mutation may affect the response to therapy of patients with metastatic CRC. In the present study, primary tumour specimens were collected from 156 patients with CRC who were treated in the Military Institute of Medicine in Warsaw (Warsaw, Poland). Codons 12 and 13 of exon 1 of KRAS, exons 11 and 15 of BRAF and exons 9 and 20 of PIK3CA were analysed for mutation using direct sequencing. The prognostic value of each mutation and the clinical and pathological variables of these tumours were estimated. The results revealed that PIK3CA mutations were present in 15 patients (9.6%), of whom seven (46.7%) possessed mutations in codon 9 and eight (53.3%) possessed mutations in codon 20. Mutation in the PIK3CA gene was detected in six patients with KRAS gene mutations, which accounted for 40% of PIK3CA-mutated tumours, and in one patient with BRAF mutations, which accounted for 6.6% of PIK3CA-mutated tumours. No significant differences were identified between the overall survival (OS) rates of patients with PIK3CA mutations (median OS, 56.7 months) and those with wild-type PIK3CA genes (median OS, 47.6 months) (P=0.1270). Univariate analysis identified that the following prognostic factors affected the OS rate in the current patient cohort: Gender, female patients survived for 57.5 months compared with 39.3 months for male patients (P=0.0111); and lymph node involvement grade, as survival of patients without lymph node metastases was 61.4 months compared with 45.4 months in patients presenting with metastases (P=0.0122). The findings of the present analysis indicate that PIK3CA mutation status is not a

  7. 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.

  8. Analysis of PIK3CA Mutations and Activation Pathways in Triple Negative Breast Cancer

    PubMed Central

    Muroni, Maria Rosaria; Sanges, Francesca; Sotgiu, Giovanni; Ena, Sara; Pira, Giovanna; Murgia, Luciano; Manca, Alessandra; Uras, Maria Gabriela; Sarobba, Maria Giuseppina; Urru, Silvana; De Miglio, Maria Rosaria

    2015-01-01

    Background Triple Negative Breast Cancer (TNBC) accounts for 12–24% of all breast carcinomas, and shows worse prognosis compared to other breast cancer subtypes. Molecular studies demonstrated that TNBCs are a heterogeneous group of tumors with different clinical and pathologic features, prognosis, genetic-molecular alterations and treatment responsivity. The PI3K/AKT is a major pathway involved in the regulation of cell survival and proliferation, and is the most frequently altered pathway in breast cancer, apparently with different biologic impact on specific cancer subtypes. The most common genetic abnormality is represented by PIK3CA gene activating mutations, with an overall frequency of 20–40%. The aims of our study were to investigate PIK3CA gene mutations on a large series of TNBC, to perform a wider analysis on genetic alterations involving PI3K/AKT and BRAF/RAS/MAPK pathways and to correlate the results with clinical-pathologic data. Materials and Methods PIK3CA mutation analysis was performed by using cobas® PIK3CA Mutation Test. EGFR, AKT1, BRAF, and KRAS genes were analyzed by sequencing. Immunohistochemistry was carried out to identify PTEN loss and to investigate for PI3K/AKT pathways components. Results PIK3CA mutations were detected in 23.7% of TNBC, whereas no mutations were identified in EGFR, AKT1, BRAF, and KRAS genes. Moreover, we observed PTEN loss in 11.3% of tumors. Deregulation of PI3K/AKT pathways was revealed by consistent activation of pAKT and p-p44/42 MAPK in all PIK3CA mutated TNBC. Conclusions Our data shows that PIK3CA mutations and PI3K/AKT pathway activation are common events in TNBC. A deeper investigation on specific TNBC genomic abnormalities might be helpful in order to select patients who would benefit from current targeted therapy strategies. PMID:26540293

  9. Feasibility of Targeting PIK3CA Mutations in Head and Neck Squamous Cell Carcinoma.

    PubMed

    Theurer, Julie A; Stecho, William; Yoo, John; Kwan, Keith; Wehrli, Bret; Harry, Vimla; Black, Morgan; Pinto, Nicole; Winquist, Eric; Palma, David; Richter, Suzanne; Barrett, John W; Danielle MacNeil, S; Fung, Kevin; Howlett, Christopher J; Nichols, Anthony C

    2016-01-01

    PIK3CA is the only frequently-mutated, directly druggable oncogene in head and neck squamous cell carcinoma (HNSCC). However, it is unclear if a molecularly-driven intervention trial can be launched successfully, particularly within a single-institution setting secondary to the infrastructure necessary for mutation detection, mutation prevalence, and patient willingness to participate. This study aimed to evaluate 1) local frequency of PIK3CA activating mutations in HNSCC, 2) timeliness of our mutation-profiling clinical pathway, and 3) patients' willingness to enroll in a novel neoadjuvant drug trial. Tissue biopsies of 25 consecutive cases of HNSCC were tested for activating PIK3CA mutations at three mutational hotspots by real-time polymerase chain reaction. Mutations prevalence and number of working days accrued in determining PIK3CA mutational status were calculated. In addition, 30 HNSCC patients were surveyed prospectively regarding their willingness to participate in a hypothetical drug trial. Survey data were summarized descriptively. 4 of 25 (16 %) tumors harbored a PIK3CA activating mutation, including one at codon E542K, two at codon E545K/D, and one at codon H1047R. On average, this result was obtained in approximately 15 working days (range, 9-24 working days). The majority of patients surveyed (70 %) indicated their willingness to participate in a targeted PIK3CA trial. This study provides evidence that within a single institution, PIK3CA activating mutations can be detected with expected frequency, with sufficient timeliness and sufficient patient interest to mount a targeted intervention trial that may lead to improved tumor response in selected HNSCC patients. PMID:26271341

  10. 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

  11. Pik3c3 deletion in pyramidal neurons results in loss of synapses, extensive gliosis and progressive neurodegeneration

    PubMed Central

    Wang, Liangli; Budolfson, Katie; Wang, Fan

    2010-01-01

    The lipid kinase PIK3C3 (also known as VPS34) regulates multiple aspects of endo-membrane trafficking processes. PIK3C3 is widely expressed by neurons in the central nervous system (CNS), and its catalytic product PI3P is enriched in dendritic spines. Here we generated a line of conditional mutant mouse in which Pik3c3 is specifically deleted in hippocampal and in small subsets of cortical pyramidal neurons using the CaMKII-Cre transgene. We found that Pik3c3-deficiency initially causes loss of dendritic spines accompanied with reactive gliosis, which is followed by progressive neuronal degeneration over a period of several months. Layers III and IV cortical neurons are more susceptible to Pik3c3-deletion than hippocampal neurons. Furthermore, in aged conditional Pik3c3 mutant animals, there are extensive gliosis and severe secondary loss of wildtype neurons. Our analyses show that Pik3c3 is essential for CNS neuronal homeostasis and Pik3c3flox/flox;CaMKII-Cre mouse is a useful model for studying pathological changes in progressive forebrain neurodegeneration. PMID:20955765

  12. The mammalian class 3 PI3K (PIK3C3) is required for early embryogenesis and cell proliferation.

    PubMed

    Zhou, Xiang; Takatoh, Jun; Wang, Fan

    2011-01-01

    The Pik3c3 gene encodes an 887 amino acid lipid kinase, phosphoinositide-3-kinase class 3 (PIK3C3). PIK3C3 is known to regulate various intracellular membrane trafficking events. However, little is known about its functions during early embryogenesis in mammals. To investigate the function of PIK3C3 in vivo, we generated Pik3c3 null mice. We show here that Pik3c3 heterozygous are normal and fertile. In contrast, Pik3c3 homozygous mutants are embryonic lethal and die between E7.5 and E8.5 of embryogenesis. Mutant embryos are poorly developed with no evidence of mesoderm formation, and suffer from severely reduced cell proliferations. Cell proliferation defect is also evident in vitro, where mutant blastocysts in culture fail to give rise to typical colonies formed by inner cell mass. Electron microscopic analysis revealed that epiblast cells in mutant embryos appear normal, whereas the visceral endoderm cells contain larger vesicles inside the lipid droplets. Finally, we provide evidence that mTOR signaling is drastically reduced in Pik3c3 null embryos, which could be a major contributor to the observed proliferation and embryogenesis defects. PMID:21283715

  13. 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…

  14. 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…

  15. Somatic mutation in PIK3CA is a late event in cervical carcinogenesis

    PubMed Central

    Verlaat, Wina; Snijders, Peter JF; van Moorsel, Marinda IH; Bleeker, Maaike; Rozendaal, Lawrence; Sie, Daoud; Ylstra, Bauke; Meijer, Chris JLM; Steenbergen, Renske DM

    2015-01-01

    Abstract Somatic mutations in cervical intraepithelial neoplasia (CIN) are largely unknown. Here, we profiled 35 cervical carcinomas and 23 CIN grade 2/3 (CIN2/3) for mutations in 48 cancer‐related genes using a Next Generation Sequencing‐based cancer panel. PIK3CA exon 9 was the most frequently mutated locus in cervical carcinoma and the only mutated locus detected in CIN2/3. These PIK3CA exon 9 mutation findings were verified in a large, independent series (n = 647) covering all stages of cervical carcinogenesis using high resolution melting‐guided Sanger sequencing. PIK3CA exon 9 mutation frequency was 37.1% (13/35; 95%CI 21.2–54.0%) in cervical carcinoma, and 2.4% (5/209; 95%CI 0.5–4.7%) in CIN3. No PIK3CA exon 9 mutations were detected in CIN2 (0/144), CIN1 (0/154) and normal cervix (0/105). In a third series of 46 CIN2/3 lesions from women with a known 5‐year history of preceding high‐risk human papillomavirus (hrHPV) infection, detection of PIK3CA exon 9 mutation was confined to 2 (5.4%; 95%CI 0.0–13.2%) CIN3 lesions with preceding hrHPV infection ≥5 years, and was absent in those with a short duration (<5 years) of preceding hrHPV infection. In conclusion, somatic mutation in PIK3CA represents a late event during cervical carcinogenesis, detected in a substantial subset of cervical carcinoma, but only in a minority of CIN3.

  16. Prevalence of PIK3CA mutations and the SNP rs17849079 in Arab breast cancer patients

    PubMed Central

    Karakas, Bedri; Colak, Dilek; Kaya, Namik; Ghebeh, Hazem; Al-Qasem, Abeer; Hendrayani, Fawziah; Toulimat, Mohamed; Al-Tweigeri, Taher; Park, Ben Ho; Aboussekhra, Abdelilah

    2013-01-01

    Carcinomas initiate and progress due to genetic and epigenetic alterations in epithelial cells. However, recently, these alterations have also been reported in stromal fibroblasts. The gain-of-function mutations in the PI3K p110 catalytic subunit (PIK3CA) have been identified in many cancers with a current global incidence of 26% (18–40%) in breast carcinomas. We analyzed the mutational frequency of PIK3CA of three hotspots (exons 1, 9, and 20) in 81 primary invasive breast cancers (BC) and 25 cultured breast cancer-associated fibroblast (CAF) samples by Sanger sequencing in Arab breast cancer patients. Associations between the incidence of any PIK3CA mutation and several clinicopathologic characteristics were assessed using chi-square tests for categorical or t test for continuous variables. Furthermore, survival curves were estimated using the Kaplan–Meier method with the log rank test to evaluate the significance of their differences. We identified a total of 21 PIK3CA missense mutations with a frequency of 25.9%. The majority of the mutations, 17 out of 21 (81%), were in exon 20 (p.His1047Arg, p.His1047Lys, p.Thr1025Ala, p.Gly1049Arg, p.Asp1056Asn) while the remainder, 4 out of 21 (19%) were in exon 9 (p.Glu545Lys). PIK3CA mutations were significantly associated with lower grade and hormone receptor positivity. Although there was a favorable trend in overall survival for patients whose tumor harbored PIK3CA mutations, the difference was not statistically significant (P = 0.10). However, we did not detect any somatic mutations in CAFs. Furthermore, we have shown a high prevalence (8.2-fold) of a silent variant (SNP, rs17849079) in the Arab breast cancer population compared with disease-free individuals. PMID:23982433

  17. Prevalence of PIK3CA mutations and the SNP rs17849079 in Arab breast cancer patients.

    PubMed

    Karakas, Bedri; Colak, Dilek; Kaya, Namik; Ghebeh, Hazem; Al-Qasem, Abeer; Hendrayani, Fawziah; Toulimat, Mohamed; Al-Tweigeri, Taher; Park, Ben Ho; Aboussekhra, Abdelilah

    2013-10-01

    Carcinomas initiate and progress due to genetic and epigenetic alterations in epithelial cells. However, recently, these alterations have also been reported in stromal fibroblasts. The gain-of-function mutations in the PI3K p110 catalytic subunit (PIK3CA) have been identified in many cancers with a current global incidence of 26% (18-40%) in breast carcinomas. We analyzed the mutational frequency of PIK3CA of three hotspots (exons 1, 9, and 20) in 81 primary invasive breast cancers (BC) and 25 cultured breast cancer-associated fibroblast (CAF) samples by Sanger sequencing in Arab breast cancer patients. Associations between the incidence of any PIK3CA mutation and several clinicopathologic characteristics were assessed using chi-square tests for categorical or t test for continuous variables. Furthermore, survival curves were estimated using the Kaplan-Meier method with the log rank test to evaluate the significance of their differences. We identified a total of 21 PIK3CA missense mutations with a frequency of 25.9%. The majority of the mutations, 17 out of 21 (81%), were in exon 20 (p.His1047Arg, p.His1047Lys, p.Thr1025Ala, p.Gly1049Arg, p.Asp1056Asn) while the remainder, 4 out of 21 (19%) were in exon 9 (p.Glu545Lys). PIK3CA mutations were significantly associated with lower grade and hormone receptor positivity. Although there was a favorable trend in overall survival for patients whose tumor harbored PIK3CA mutations, the difference was not statistically significant (P = 0.10). However, we did not detect any somatic mutations in CAFs. Furthermore, we have shown a high prevalence (8.2-fold) of a silent variant (SNP, rs17849079) in the Arab breast cancer population compared with disease-free individuals. PMID:23982433

  18. PIK3CA mutations and EGFR overexpression predict for lithium sensitivity in human breast epithelial cells

    PubMed Central

    Higgins, Michaela J; Beaver, Julia A; Wong, Hong yuen; Gustin, John P; Lauring, Josh D; Garay, Joseph P; Konishi, Hiroyuki; Mohseni, Morassa; Wang, Grace M; Cidado, Justin; Jelovac, Danijela; Cosgrove, David P; Tamaki, Akina; Park, Ben Ho

    2011-01-01

    A high frequency of somatic mutations has been found in breast cancers within the gene encoding the catalytic p110α subunit of PI3K, PIK3CA. Using isogenic human breast epithelial cells, we have previously demonstrated that oncogenic PIK3CA “hotspot” mutations predict for response to the toxic effects of lithium. However, other somatic genetic alterations occur within this pathway in breast cancers, and it is possible that these changes may also predict for lithium sensitivity. We overexpressed the epidermal growth factor receptor (EGFR) into the non-tumorigenic human breast epithelial cell line MCF-10A, and compared these cells to isogenic cell lines previously created via somatic cell gene targeting to model Pten loss, PIK3CA mutations, and the invariant AKT1 mutation, E17K. EGFR overexpressing clones were capable of cellular proliferation in the absence of EGF and were sensitive to lithium similar to the results previously seen with cells harboring PIK3CA mutations. In contrast, AKT1 E17K cells and PTEN−/− cells displayed resistance or partial sensitivity to lithium, respectively. Western blot analysis demonstrated that lithium sensitivity correlated with significant decreases in both PI3K and MAPK signaling that were observed only in EGFR overexpressing and mutant PIK3CA cell lines. These studies demonstrate that EGFR overexpression and PIK3CA mutations are predictors of response to lithium, whereas Pten loss and AKT1 E17K mutations do not predict for lithium sensitivity. Our findings may have important implications for the use of these genetic lesions in breast cancer patients as predictive markers of response to emerging PI3K pathway inhibitors. PMID:21124076

  19. 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.

  20. Charcot-Marie-Tooth disease

    PubMed Central

    Sivera, Rafael; Vílchez, Juan Jesús; Martínez-Rubio, Dolores; Chumillas, María José; Vázquez, Juan Francisco; Muelas, Nuria; Bataller, Luis; Millán, José María; Palau, Fancesc; Espinós, Carmen

    2013-01-01

    Objectives: To determine the genetic distribution and the phenotypic correlation of an extensive series of patients with Charcot-Marie-Tooth disease in a geographically well-defined Mediterranean area. Methods: A thorough genetic screening, including most of the known genes involved in this disease, was performed and analyzed in this longitudinal descriptive study. Clinical data were analyzed and compared among the genetic subgroups. Results: Molecular diagnosis was accomplished in 365 of 438 patients (83.3%), with a higher success rate in demyelinating forms of the disease. The CMT1A duplication (PMP22 gene) was the most frequent genetic diagnosis (50.4%), followed by mutations in the GJB1 gene (15.3%), and in the GDAP1 gene (11.5%). Mutations in 13 other genes were identified, but were much less frequent. Sixteen novel mutations were detected and characterized phenotypically. Conclusions: The relatively high frequency of GDAP1 mutations, coupled with the scarceness of MFN2 mutations (1.1%) and the high proportion of recessive inheritance (11.6%) in this series exemplify the particularity of the genetic distribution of Charcot-Marie-Tooth disease in this region. PMID:24078732

  1. 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. PMID:26353837

  2. HOTAIR Promotes Proliferation, Migration, and Invasion of Ovarian Cancer SKOV3 Cells Through Regulating PIK3R3

    PubMed Central

    Dong, Lijun; Hu, Lina

    2016-01-01

    Background The aim of this study was to determine the effect on proliferation, migration, and invasion after silencing HOTAIR in ovarian cancer SKOV3 cells, and to elucidate the potential mechanism. Material/Methods We analyzed the mRNA expression level of HOTAIR and PIK3R3 in ovarian cancer SKOV3, OVCAR3, and A2780 cell lines. We analyzed the mRNA expression level of HOTAIR and PIK3R3 in ovarian SKOV3 after transection with miR-214 or miR-217. We analyzed the mRNA and protein expression level of PIK3R3 when silencing HOTAIR. We analyzed the expression of HOTAIR when silencing PIK3R3. We analyzed the proliferation, migration and invasion in ovarian cancer SKOV3 after silencing HOTAIR or PIK3R3. Results The expression of HOTAIR and PIK3R3 in ovarian SKOV3 and OVCAR3 was increased compared with A2780 cells (P<0.05). The mRNA level of HOTAIR and PIK3R3 in ovarian cancer SKOV3 cells was decreased when transected with miR-214 or miR-217 compared to negative control (p<0.05). The mRNA and protein level of PIK3R3 was decreased when HOTAIR was silenced and the mRNA level of HOTAIR was decreased when PIK3R3 was silenced (p<0.05). The proliferation, migration and invasion was decreased in ovarian SKOV3 when HOTAIR or PIK3R3 was silenced (p<0.05). Conclusions HOTAIR can promote proliferation, migration, and invasion in ovarian SKOV3 cells as a competing endogenous RNA. PMID:26826873

  3. A PIK3C3-ankyrin-B-dynactin pathway promotes axonal growth and multiorganelle transport.

    PubMed

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

    2014-12-22

    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

  4. Blocking p55PIK signaling inhibits proliferation and induces differentiation of leukemia cells.

    PubMed

    Wang, G; Deng, Y; Cao, X; Lai, S; Tong, Y; Luo, X; Feng, Y; Xia, X; Gong, J; Hu, J

    2012-11-01

    p55PIK, a regulatory subunit of phosphatidylinositol 3-kinases, promotes cell cycle progression by interacting with cell cycle modulators such as retinoblastoma protein (Rb) via its unique amino-terminal 24 amino-acid residue (N24). Overexpression of N24 specifically inhibits these interactions and leads to cell cycle arrest. Herein, we describe the generation of a fusion protein (Tat transactivator protein (TAT)-N24) that contains the protein transduction domain and N24, and examined its effects on the proliferation and differentiation of leukemia cells. TAT-N24 not only blocks cell proliferation but remarkably induces differentiation of leukemia cells in vitro and in vivo. Systemically administered TAT-N24 also significantly decreases growth of leukemia cell tumors in animal models. Furthermore, overexpression of p55PIK in leukemia cells leads to increased proliferation; however, TAT-N24 blocks this effect and concomitantly induces differentiation. There is significant upregulation of p55PIK mRNA and protein expression in leukemia cells from patients. TAT-N24 inhibits cell cycle progression and induces differentiation of bone marrow cells derived from patients with several different types of leukemia. These results show that cell-permeable N24 peptide induces leukemia cell differentiation and suggest that p55PIK may be a novel drug target for the treatment of hematopoetic malignancies. PMID:22722333

  5. Conditional knockout of pik3c3 causes a murine muscular dystrophy.

    PubMed

    Reifler, Aaron; Li, Xingli; Archambeau, Ashley J; McDade, Joel R; Sabha, Nesrin; Michele, Daniel E; Dowling, James J

    2014-06-01

    Abnormalities in phosphoinositide metabolism are an emerging theme in human neurodegenerative disease. Myotubular myopathy is a prototypical disorder of phosphoinositide dysregulation that is characterized by profound muscle pathology and weakness and that is caused by mutations in MTM1, which encodes a phosphatase that targets 3-position phosphoinositides, including phosphatidylinositol 3-phosphate. Although the association between MTM1 and muscle disease has become increasingly clarified, the normal role(s) of phosphatidylinositol 3-phosphate metabolism in muscle development and homeostasis remain poorly understood. To begin to address the function of phosphatidylinositol 3-phosphate in skeletal muscle, we focused on the primary kinase responsible for its production, and created a muscle-specific conditional knockout of the class III phosphatidylinositol 3-kinase, Pik3c3. Muscle-specific deletion of Pik3c3 did not disturb embryogenesis or early postnatal development, but resulted in progressive disease characterized by reduced activity and death by 2 months of age. Histopathological analysis demonstrated changes consistent with a murine muscular dystrophy. Examination for cellular mechanism(s) responsible for the dystrophic phenotype revealed significant alterations in the autophagolysosomal pathway with mislocation of known dystrophy proteins to the lysosomal compartment. In all, we present the first analysis of Pik3c3 in skeletal muscle, and report a novel association between deletion of Pik3c3 and muscular dystrophy. PMID:24726497

  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. Relationship of PIK3CA mutation and pathway activity with antiproliferative response to aromatase inhibition

    PubMed Central

    2014-01-01

    Introduction PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α) somatic mutations are the most common genetic alteration in breast cancer (BC). Their prognostic value and that of the phosphatidylinositol 3-kinase (PI3K) pathway in BC remains only partly defined. The effect of PIK3CA mutations and alterations of the PI3K pathway on the antiproliferative response to aromatase inhibitor treatment was determined. Methods The Sequenom MassARRAY System was used to determine the presence of 20 somatic mutations across the PIK3CA gene in 85 oestrogen receptor–positive (ER+) BC patients treated with 2 weeks of anastrozole before surgery. Whole-genome expression profiles were used to interrogate gene signatures (GSs) associated with the PI3K pathway. Antiproliferative activity was assessed by the change in Ki67 staining between baseline and surgery. Three GSs representing the PI3K pathway were assessed (PIK3CA-GS (Loi), PI3K-GS (Creighton) and PTEN-loss-GS (Saal)). Results In our study sample, 29% of tumours presented with either a hotspot (HS, 71%) or a nonhotspot (non-HS, 29%) PIK3CA mutation. Mutations were associated with markers of good prognosis such as progesterone receptor positivity (PgR+) (P = 0.006), low grade (P = 0.028) and luminal A subtype (P = 0.039), with a trend towards significance with degree of ER positivity (P = 0.051) and low levels of Ki67 (P = 0.051). Non-HS mutations were associated with higher PgR (P = 0.014) and ER (P < 0.001) expression than both wild-type (WT) and HS-mutated samples, whereas neither biomarker differed significantly between WT and HS mutations or between HS and non-HS mutations. An inverse correlation was found between the Loi signature and both the Creighton and Saal signatures, and a positive correlation was found between the latter signatures. Lower pretreatment Ki67 levels were observed in mutation compared with WT samples (P = 0.051), which was confirmed in an

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

    PubMed

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

    2016-02-23

    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 Pten∆ 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 Pten∆ versus PIK3CAH1047R tumors. Thus, Pten∆ and PIK3CAH1047R tumors exhibit discernable differences that may impact tumorigenesis and response to therapy. PMID:26814435

  10. 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

  11. Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA

    PubMed Central

    Luks, Valerie L.; Kamitaki, Nolan; Vivero, Matthew P.; Uller, Wibke; Rab, Rashed; Bovée, Judith V.M.G.; Rialon, Kristy L.; Guevara, Carlos J.; Alomari, Ahmad I.; Greene, Arin K.; Fishman, Steven J.; Kozakewich, Harry P.W.; Maclellan, Reid A.; Mulliken, John B.; Rahbar, Reza; Spencer, Samantha A.; Trenor, Cameron C.; Upton, Joseph; Zurakowski, David; Perkins, Jonathan A.; Kirsh, Andrew; Bennett, James T; Dobyns, William B; Kurek, Kyle C.; Warman, Matthew L.; McCarroll, Steven A.; Murillo, Rudy

    2015-01-01

    Objectives To test the hypothesis that somatic PIK3CA mutations would be found in patients with more common disorders including isolated lymphatic malformation (LM) and Klippel-Trenaunay syndrome (KTS). Study design We used next generation sequencing, droplet digital PCR (ddPCR), and single molecule molecular inversion probes (smMIPs) to search for somatic PIK3CA mutations in affected tissue from patients seen at Boston Children’s Hospital who had an isolated LM (n=17), KTS (n=21), fibro-adipose vascular anomaly (FAVA; n=8), or congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (CLOVES; n = 33), the disorder for which we first identified somatic PIK3CA mutations. We also screened 5 of the more common PIK3CA mutations in a second cohort of patients with LM (n=31) from Seattle Children’s Hospital. Results Most individuals from Boston Children’s Hospital who had isolated LM (16/17) or LM as part of a syndrome, such as KTS (19/21), FAVA (4/8), and CLOVES (30/32) were somatic mosaic for PIK3CA mutations, with 5 specific PIK3CA mutations accounting for ~ 80% of cases. Seventy-four percent of patients with LM from Seattle Children’s Hospital also were somatic mosaic for 1 of 5 specific PIK3CA mutations. Many affected tissue specimens from both cohorts contained fewer than 10% mutant cells. Conclusions Somatic PIK3CA mutations are the most common cause of isolated lymphatic malformations and disorders in which lymphatic malformation is a component feature. Five PIK3CA mutations account for most cases. The search for causal mutations requires sampling of affected tissues and techniques that are capable of detecting low-level somatic mosaicism, because the abundance of mutant cells in a malformed tissue can be low. PMID:25681199

  12. 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.

  13. Ernst Öpik's Fundamental Ideas on the Structure of Red Giants

    NASA Astrophysics Data System (ADS)

    Pustylnik, I.

    As early as in 1932 Estonian astronomer E. Öpik in his pioneering investigation indicated that the only source of stellar radiative energy capable of sustaining the observed stellar luminosities for billions of years must be the process of nuclear fusion transforming in stellar cores hydrogen into helium, carbon and so forth up to iron. He was the first to introduce in 1938 the so-called compound unmixed stellar models with stellar convective core consisting of helium and hydrogen envelope in radiative equilibrium lying on the top of it. Contrary to the universally adopted view of A. Eddington who firmly believed that rotationally induced convection would inevitably lead to full mixing up of the stellar matter, calculations of E. Öpik confirmed the viability of compound models and indicated that upon the exhaustion of hydrogen fuel the core will start contracting whereas the hydrogen envelope will expand. In this way the structural differences between the giant and main sequence stars were interpreted and in broad features stellar evolution along the H-R diagram explained (for earlier discussions see, for instance, J. Einasto and M. Joeveer 1975, J. Einasto 1994). E. Öpik was ahead of F. Hoyle and K. Schwarzschild who reached similar conclusions only 15 years afterwards. In our report we analyze various implications of E. Öpik's research dedicated to the internal structure of red giants for the treatment of the advanced stages of stellar evolution. It took almost half a century before the priority of this discovery by the Estonian astrophysicist found a deserved recognition. We discuss the reasons behind it and summarize briefly also other fundamental accomplishments of E. Öpik from the pre-war period in Tartu observatory where he founded Tartu school of astrophysics and stellar astronomy.

  14. PIK3CA mutations can initiate pancreatic tumorigenesis and are targetable with PI3K inhibitors

    PubMed Central

    Payne, S N; Maher, M E; Tran, N H; Van De Hey, D R; Foley, T M; Yueh, A E; Leystra, A A; Pasch, C A; Jeffrey, J J; Clipson, L; Matkowskyj, K A; Deming, D A

    2015-01-01

    Aberrations in the phosphoinositide 3-kinase (PI3K) signaling pathway have a key role in the pathogenesis of numerous cancers by altering cell growth, metabolism, proliferation and apoptosis. Interest in targeting the PI3K signaling cascade continues, as new agents are being clinically evaluated. PIK3CA mutations result in a constitutively active PI3K and are present in a subset of pancreatic cancers. Here we examine mutant PIK3CA-mediated pancreatic tumorigenesis and the response of PIK3CA mutant pancreatic cancers to dual PI3K/mammalian target of rapamycin (mTOR) inhibition. Two murine models were generated expressing a constitutively active PI3K within the pancreas. An increase in acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasms (PanINs) was identified. In one model these lesions were detected as early as 10 days of age. Invasive pancreatic ductal adenocarcinoma developed in these mice as early as 20 days of age. These cancers were highly sensitive to treatment with dual PI3K/mTOR inhibition. In the second model, PanINs and invasive cancer develop with a greater latency owing to a lesser degree of PI3K pathway activation in this murine model. In addition to PI3K pathway activation, increased ERK1/2 signaling is common in human pancreatic cancers. Phosphorylation of ERK1/2 was also investigated in these models. Phosphorylation of ERK1/2 is demonstrated in the pre-neoplastic lesions and invasive cancers. This activation of ERK1/2 is diminished with dual PI3K/mTOR inhibition. In summary, PIK3CA mutations can initiate pancreatic tumorigenesis and these cancers are particularly sensitive to dual PI3K/mTOR inhibition. Future studies of PI3K pathway inhibitors for patients with PIK3CA mutant pancreatic cancers are warranted. PMID:26436951

  15. PI3K is negatively regulated by PIK3IP1, a novel p110 interacting protein

    SciTech Connect

    Zhu, Zhenqi; He, Xin; Johnson, Carla; Stoops, John; Eaker, Amanda E.; Stoffer, David S.; Bell, Aaron; Zarnegar, Reza; DeFrances, Marie C. . E-mail: defrancesmc@upmc.edu

    2007-06-22

    Signaling initiated by Class Ia phosphatidylinositol-3-kinases (PI3Ks) is essential for cell proliferation and survival. We discovered a novel protein we call PI3K interacting protein 1 (PIK3IP1) that shares homology with the p85 regulatory PI3K subunit. Using a variety of in vitro and cell based assays, we demonstrate that PIK3IP1 directly binds to the p110 catalytic subunit and down modulates PI3K activity. Our studies suggest that PIK3IP1 is a new type of PI3K regulator.

  16. "Mary Hartman, Mary Hartman"; A New Genre of Prosocial Programming, or Just Another Soap Opera?

    ERIC Educational Resources Information Center

    Surlin, Stuart H.; Maloof, Mary C.

    This paper discusses the wide appeal, and the effect on the viewing audience, of traditional television soap operas. It reports on a comparison of role interactions, topics discussed by the characters, and types of topics and problems presented on the television program "Mary Hartman, Mary Hartman" with those presented on two traditional soap…

  17. Charcot-Marie-Tooth disease

    PubMed Central

    Manganelli, Fiore; Nolano, Maria; Pisciotta, Chiara; Provitera, Vincenzo; Fabrizi, Gian M.; Cavallaro, Tiziana; Stancanelli, Annamaria; Caporaso, Giuseppe; Shy, Michael E.

    2015-01-01

    Objective: To evaluate, by skin biopsy, dermal nerve fibers in 31 patients with 3 common Charcot-Marie-Tooth (CMT) genotypes (CMT1A, late-onset CMT1B, and CMTX1), and rarer forms of CMT caused by mutations in RAB7 (CMT2B), TRPV4 (CMT2C), and GDAP1 (AR-CMT2K) genes. Methods: We investigated axonal loss by quantifying Meissner corpuscles and intrapapillary myelinated endings and evaluated morphometric changes in myelinated dermal nerve fibers by measuring fiber caliber, internodal, and nodal gap length. Results: The density of both Meissner corpuscles and intrapapillary myelinated endings was reduced in skin samples from patients with CMT1A and all the other CMT genotypes. Nodal gaps were larger in all the CMT genotypes though widening was greater in CMT1A. Perhaps an altered communication between axons and glia may be a common feature for multiple forms of CMT. Internodal lengths were shorter in all the CMT genotypes, and patients with CMT1A had the shortest internodes of all our patients. The uniformly shortened internodes in all the CMT genotypes suggest that mutations in both myelin and axon genes may developmentally impede internode formation. The extent of internodal shortening and nodal gap widening are likely both important in determining nerve conduction velocities in CMT. Conclusions: This study extends the information gained from skin biopsies on morphologic abnormalities in various forms of CMT and provides insights into potential pathomechanisms of axonal and demyelinating CMT. PMID:26362287

  18. 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.

  19. PIK3C2G copy number is associated with clinical outcomes of colorectal cancer patients treated with oxaliplatin

    PubMed Central

    Li, Ajian; Chen, Hui; Lin, Moubin; Zhang, Chenbo; Tang, Erjiang; Peng, Jian; Wei, Qing; Li, Huaguang; Yin, Lu

    2015-01-01

    Purpose: To investigate whether the copy number of PIK3C2G is associated with clinical outcomes for stage III colorectal cancer (CRC) patients treated with oxaliplatin-based chemotherapy. Methods: A total of 142 CRC patients who received first-line oxaliplatin-based chemotherapy after curative surgery in Ruijin Hospital and The Tenth People’s Hospital were recruited in this study. Patients were enrolled between June 2006 and December 2011, with follow-up to January 2014. Quantitative real-time PCR method was used to detect the copy number of PIK3C2G. Cox proportional hazards model and Kaplan-Meier curves were used to analyze the association between PIK3C2G copy number and clinical outcome. Results: In patients with stage III disease, low copy number of PIK3C2G was associated with increased risk of both recurrence (HR, 2.44, 95% CI, 1.33-4.47, P=0.004) and death (HR, 2.89, 95% CI, 1.49-5.60, P=0.002). Multivariate analysis also indicated that low PIK3C2G copy number was a significant and independent predictor of OS and RFS of stage III CRC. Conclusions: PIK3C2G is capable of predicting the recurrence and overall survival of stage III CRC patients receiving oxaliplatin-based therapy. PMID:25785104

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

    PubMed Central

    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.

    2016-01-01

    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.

  1. Cancer-specific mutations in PIK3CA are oncogenic in vivo

    PubMed Central

    Bader, Andreas G.; Kang, Sohye; Vogt, Peter K.

    2006-01-01

    The PIK3CA gene, coding for the catalytic subunit p110α of class IA phosphatidylinositol 3-kinases (PI3Ks), is frequently mutated in human cancer. Mutated p110α proteins show a gain of enzymatic function in vitro and are oncogenic in cell culture. Here, we show that three prevalent mutants of p110α, E542K, E545K, and H1047R, are oncogenic in vivo. They induce tumors in the chorioallantoic membrane of the chicken embryo and cause hemangiosarcomas in the animal. These tumors are marked by increased angiogenesis and an activation of the Akt pathway. The target of rapamycin inhibitor RAD001 blocks tumor growth induced by the H1047R p110α mutant. The in vivo oncogenicity of PIK3CA mutants in an avian species strongly suggests a critical role for these mutated proteins in human malignancies. PMID:16432179

  2. PIK3CA-AKT pathway mutations in micropapillary breast carcinoma.

    PubMed

    Flatley, Ellen; Ang, Daphne; Warrick, Andrea; Beadling, Carol; Corless, Christopher L; Troxell, Megan L

    2013-07-01

    Micropapillary carcinoma of the breast is associated with increased rates of lymph node metastasis and lymphovascular invasion. While activating point mutations in PIK3CA (encoding phosphatidylinositol-3-kinase catalytic subunit) or AKT1 are found in 25% to 30% of invasive ductal carcinomas, the mutational profile of invasive micropapillary carcinomas has not been characterized in detail. Micropapillary carcinomas, concurrent metastatic and precursor breast lesions from 19 patients were identified. Lesional tissue was punched from paraffin-tissue blocks, and genomic DNA was extracted and screened for a large panel of known hotspot mutations using multiplex polymerase chain reaction and mass-spectroscopy analysis (643 mutations in 53 genes). Hotspot point mutations were identified in 35% (7/20) of micropapillary breast carcinomas, including PIK3CA exons 7, 9 and 20 hotspots, as well as the AKT1 plekstrin homology domain mutation (E17K); mutations in TP53 and KRAS were each found in a single patient. In 6 patients, micropapillary and non-micropapillary components of the same tumor were separately tested, yielding concordant results in five; one had a wild type micropapillary component, but a PIK3CA mutation in the invasive ductal component. Concurrent lymph node metastases were mostly wild type (2/8 mutant). Accompanying ductal carcinoma in situ had point mutations in 45% (5/11), mostly concordant with invasive carcinoma; however, mutational status of other breast proliferative lesions was generally discordant with accompanying carcinoma. The rate of PIK3CA mutations in this series of micropapillary carcinomas is similar to invasive ductal carcinomas; however, there may be an enrichment of AKT1 mutations (10%). The non-micropapillary components and precursor lesions occasionally had different mutations. PMID:23352210

  3. 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

  4. Somatic PIK3CA mutations as a driver of sporadic venous malformations

    PubMed Central

    Castel, Pau; Carmona, F. Javier; Grego-Bessa, Joaquim; Berger, Michael F.; Viale, Agnès; Anderson, Kathryn V.; Bague, Silvia; Scaltriti, Maurizio; Antonescu, Cristina R.; Baselga, Eulàlia; Baselga, José

    2016-01-01

    Venous malformations (VM) are vascular malformations characterized by enlarged and distorted blood vessel channels. VM grow over time and cause substantial morbidity because of disfigurement, bleeding, and pain, representing a clinical challenge in the absence of effective treatments (Nguyen et al., 2014; Uebelhoer et al., 2012). Somatic mutations may act as drivers of these lesions, as suggested by the identification of TEK mutations in a proportion of VM (Limaye et al., 2009). We report that activating PIK3CA mutations gives rise to sporadic VM in mice, which closely resemble the histology of the human disease. Furthermore, we identified mutations in PIK3CA and related genes of the PI3K (phosphatidylinositol 3-kinase)/AKT pathway in about 30% of human VM that lack TEK alterations. PIK3CA mutations promote downstream signaling and proliferation in endothelial cells and impair normal vasculogenesis in embryonic development. We successfully treated VM in mouse models using pharmacological inhibitors of PI3Kα administered either systemically or topically. This study elucidates the etiology of a proportion of VM and proposes a therapeutic approach for this disease. PMID:27030594

  5. Acquired PIK3CA amplification causes resistance to selective phosphoinositide 3-kinase inhibitors in breast cancer.

    PubMed

    Huw, L-Y; O'Brien, C; Pandita, A; Mohan, S; Spoerke, J M; Lu, S; Wang, Y; Hampton, G M; Wilson, T R; Lackner, M R

    2013-01-01

    Agents targeting the PI3K/mTOR signaling axis have shown promise in early-phase clinical trials and are currently being studied in later stages of clinical development in multiple indications. Experience with other targeted agents suggests that clinical responses may be short-lived because of acquired resistance to therapy. Here, we report preclinical modeling of acquired resistance in a HER2-positive, PIK3CA mutant breast cancer cell line, KPL-4. We identified a heretofore-unreported mechanism of resistance, specifically high-level amplification of the mutant allele of PIK3CA, which resulted in a marked upregulation of PI3K signaling, enabling resistant cells to regain proliferative capacity at clinically relevant concentrations of the PI3K inhibitor, GDC-0941. We show that knockdown of the amplified PIK3CA mutant allele in these cells by small interfering RNA restored pathway signaling and sensitivity to PI3K inhibition at levels comparable to parental cells. These novel preclinical findings suggest that, in addition to assessment of other previously reported mechanisms of resistance, evaluation of PI3K copy number variation should be integrated into the exploratory analysis of biopsies obtained at disease progression. PMID:24366379

  6. 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

  7. Somatic PIK3CA mutations as a driver of sporadic venous malformations.

    PubMed

    Castel, Pau; Carmona, F Javier; Grego-Bessa, Joaquim; Berger, Michael F; Viale, Agnès; Anderson, Kathryn V; Bague, Silvia; Scaltriti, Maurizio; Antonescu, Cristina R; Baselga, Eulàlia; Baselga, José

    2016-03-30

    Venous malformations (VM) are vascular malformations characterized by enlarged and distorted blood vessel channels. VM grow over time and cause substantial morbidity because of disfigurement, bleeding, and pain, representing a clinical challenge in the absence of effective treatments (Nguyenet al, 2014; Uebelhoeret al, 2012). Somatic mutations may act as drivers of these lesions, as suggested by the identification ofTEKmutations in a proportion of VM (Limayeet al, 2009). We report that activatingPIK3CAmutations gives rise to sporadic VM in mice, which closely resemble the histology of the human disease. Furthermore, we identified mutations inPIK3CAand related genes of the PI3K (phosphatidylinositol 3-kinase)/AKT pathway in about 30% of human VM that lackTEKalterations.PIK3CAmutations promote downstream signaling and proliferation in endothelial cells and impair normal vasculogenesis in embryonic development. We successfully treated VM in mouse models using pharmacological inhibitors of PI3Kα administered either systemically or topically. This study elucidates the etiology of a proportion of VM and proposes a therapeutic approach for this disease. PMID:27030594

  8. UCN sources at external beams of thermal neutrons. An example of PIK reactor

    NASA Astrophysics Data System (ADS)

    Lychagin, E. V.; Mityukhlyaev, V. A.; Muzychka, A. Yu.; Nekhaev, G. V.; Nesvizhevsky, V. V.; Onegin, M. S.; Sharapov, E. I.; Strelkov, A. V.

    2016-07-01

    We consider ultracold neutron (UCN) sources based on a new method of UCN production in superfluid helium (4He). The PIK reactor is chosen as a perspective example of application of this idea, which consists of installing 4He UCN source in the beam of thermal or cold neutrons and surrounding the source with moderator-reflector, which plays the role of cold neutron (CN) source feeding the UCN source. CN flux in the source can be several times larger than the incident flux, due to multiple neutron reflections from the moderator-reflector. We show that such a source at the PIK reactor would provide an order of magnitude larger density and production rate than an analogous source at the ILL reactor. We estimate parameters of 4He source with solid methane (CH4) or/and liquid deuterium (D2) moderator-reflector. We show that such a source with CH4 moderator-reflector at the PIK reactor would provide the UCN density of ~1·105 cm-3, and the UCN production rate of ~2·107 s-1. These values are respectively 1000 and 20 times larger than those for the most intense UCN user source. The UCN density in a source with D2 moderator-reflector would reach the value of ~2·105 cm-3, and the UCN production rate would be equal ~8·107 s-1. Installation of such a source in a beam of CNs would slightly increase the density and production rate.

  9. PIK3CA somatic mutations in breast cancer: Mechanistic insights from Langevin dynamics simulations

    PubMed Central

    Mankoo, Parminder K.; Sukumar, Saraswati; Karchin, Rachel

    2011-01-01

    Somatic mutations in PIK3CA (phosphati-dylinositol-3 kinase, catalytic subunit, alpha isoform) are reported in breast and other human cancers to concentrate at hotspots within its kinase and helical domains. Most of these mutations cause kinase gain of function in vitro and are associated with oncogenicity in vivo. However, little is known about the mechanisms driving tumor development. We have performed computational structural studies on a homology model of wildtype PIK3CA plus recurrent H1047R, H1047L, and P539R mutations, located in the kinase and helical domains, respectively. The time evolution of the structures show that H1047R/L mutants exhibit a larger area of the catalytic cleft between the kinase N- and C-lobes compared with the wildtype that could facilitate the entrance of substrates. This larger area might yield enhanced substrate-to-product turnover associated with oncogenicity. In addition, the H1047R/L mutants display increased kinase activation loop mobility, compared with the wildtype. The P539R mutant forms more hydrogen bonds and salt-bridge interactions than the wildtype, properties that are associated with enhanced thermostability. Mutant-specific differences in the catalytic cleft and activation loop behavior suggest that structure-based mutant-specific inhibitors can be designed for PIK3CA-positive breast cancers. PMID:18951408

  10. 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

  11. 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.

  12. 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

  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

    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. PMID:25953087

  14. 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.

  15. 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…

  16. PIK3CA mutation / PTEN expression status predicts response of colon cancer cells to the EGFR inhibitor cetuximab

    PubMed Central

    Jhawer, Minaxi; Goel, Sanjay; Wilson, Andrew J.; Montagna, Cristina; Ling, Yi-He; Byun, Do-Sun; Nasser, Shannon; Arango, Diego; Shin, Joongho; Klampfer, Lidija; Augenlicht, Leonard H.; Soler, Roman Perez; Mariadason, John M.

    2014-01-01

    Cetuximab is a monoclonal antibody that targets the human epidermal growth factor receptor (EGFR). Although approved for use in EGFR over-expressing advanced colorectal cancer, recent studies have demonstrated a lack of association between EGFR over-expression and cetuximab response, requiring the identification of novel biomarkers predictive of response to this agent. To do so, 22 colon cancer cell lines were screened for cetuximab response in-vitro and sensitive and resistant lines identified. In sensitive cell lines cetuximab induced a G0/G1 arrest without inducing apoptosis. Notably, cetuximab sensitive but not resistant cell lines were preferentially responsive to EGF-stimulated growth. While neither EGFR protein/mRNA expression nor gene copy number correlated with cetuximab response, examination of the mutation status of signaling components downstream of EGFR demonstrated that cells lines with activating PIK3CA mutations or loss of PTEN expression (PTEN null) were more resistant to cetuximab than PIK3CA wild type/PTEN expressing cell lines (14±5.0% versus 38.5±6.4% growth inhibition, mean ± SEM, p=0.008). Consistently, PIK3CA mutant isogenic HCT116 cells showed increased resistance to cetuximab compared to PIK3CA wild type controls. Furthermore, cell lines that were PIK3CA mutant/PTEN null and Ras/BRAF mutant were highly resistant to cetuximab compared to those without dual mutations / PTEN loss (10.8±4.3% versus 38.8±5.9% growth inhibition, respectively, p=0.002), indicating constitutive and simultaneous activation of the Ras and PIK3CA pathways confers maximal resistance to this agent. A priori screening of colon tumors for PTEN expression status and PIK3CA and Ras/BRAF mutation status could help stratify patients likely to benefit from this therapy. PMID:18339877

  17. Abnormal expression of PTEN and PIK3CA in pemetrexed-resistant human pancreatic cancer cell line Patu8988.

    PubMed

    Shi, X; Gu, H T; Lin, S B; Zhang, Y; Yang, J; Qian, C J

    2016-01-01

    The aim of this study was to investigate the expression of PTEN and PIK3CA in the pemetrexed-resistant human pancreatic cancer cell line Patu8988, and to evaluate their effects on the biological behavior of pancreatic cancer cells. PTEN and PIK3CA gene and protein expressions were detected by reverse transcriptase polymerase chain reaction (RT-PCR) and western blot, respectively, in a pemetrexed-resistant pancreatic cancer cell line and in the parent strain of the pancreatic cancer cells. The discrepancies between the two types of cell lines were detected by a transwell test. RT-PCR and western blot analyses revealed that PTEN and PIK3CA were overexpressed in the pemetrexed-resistant pancreatic cancer cell line. PTEN and PIK3CA were shown to be upregulated by 89 and 76% (western blot), respectively, in the pemetrexed-resistant cell line, compared to the normal pancreatic cancer cell line. The migratory and invasive abilities of the pemetrexed-resistant pancreatic cancer cell were significantly reduced compared to those of the parent strain (P < 0.05; transwell assay). Both PTEN and PIK3CA expression was abnormally enhanced in the pemetrexed-resistant cell line Patu8988; the co-existence of high levels of PTEN and PIK3CA in the pemetrexed-resistant pancreatic cancer line cells induced a significant decrease in their migratory and invasive capacities. This suggested that the mechanism of pemetrexed resistant may be affected by PTEN and PIK3CA, and that these may alter the biological behavior of cancer cells. PMID:27525871

  18. Comparison of KRAS and PIK3CA gene status between primary tumors and paired metastases in colorectal cancer

    PubMed Central

    He, Qiong; Xu, Qi; Wu, Wei; Chen, Lei; Sun, Weijing; Ying, Jieer

    2016-01-01

    Purpose In metastatic or recurrent colorectal cancer (MRCRC), the concordance of Kirsten rat sarcoma viral oncogene homolog (KRAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation status between the primary tumors and metastases is still controversial. The purpose of this study was to evaluate the association between KRAS and PIK3CA mutational status and various clinicopathologic features, and compare their genotype in primary tumors with that of the paired metastatic tumors. Method We compared the mutation status of KRAS and PIK3CA between the primary tumors and the paired metastases of 59 MRCRC patients with available tissues (resection or biopsy). The presence of KRAS and PIK3CA mutations were determined by direct sequencing analysis. Results Seventeen patients (28.8%) had the KRAS mutation and 46 patients (80.0%) had the PIK3CA mutation when considering both the primary and metastatic sites. KRAS mutation was observed in ten primary tumors and eleven related metastases (16.9% vs 18.6%), while PIK3CA mutation was found in 26 primary tumors and 32 related metastases (44.1% vs 54.2%). KRAS status was concordant between primary and metastatic sites in 45 patients (76.3%, kappa =0.157), while the concordance of PIK3CA status was only found in 25 patients (42.4%, kappa =−0.141). The PIK3CA status discordance rate was significantly higher in 40 patients undergoing metachronous resection of primary tumor or metastasis, compared with that in 19 patients with synchronous resection of primary tumor or metastasis (67.5% [27/40] vs 36.8% [7/19]; P=0.026). Conclusion Our results demonstrate that low concordance of KRAS and high discordance of PIK3CA mutational status exist between the primary tumors and paired metastasis, and these findings remind us to have second thoughts about the need to evaluate metastatic tumors separately rather than only based on the primary tumor data when targeted therapy is considered. PMID:27143928

  19. Response of Head and Neck Squamous Cell Carcinoma Cells Carrying PIK3CA Mutations to Select Targeted Therapies

    PubMed Central

    Wirtz, Eric D; Hoshino, Daisuke; Maldonado, Anthony T; Tyson, Darren R; Weaver, Alissa M

    2015-01-01

    Importance The PIK3CA mutation is one of the most common mutations in Head and Neck Squamous Cell Carcinoma (HNSCC). Through this research we attempt to elicit the role of oncogene dependence and effects of targeted therapy on this PIK3CA mutation. Objectives 1) To determine the role of oncogene dependence on one of the more common and targetable oncogenes in HNSCC – PIK3CA; 2) To evaluate the consequence of this oncogene on the effectiveness of newly developed targeted therapies. Study Design In vitro study. Setting Academic research laboratory. Participants Cell culture based study assessing the viability of PIK3CA mutated head and neck cell lines when treated with targeted therapy. Exposures PIK3CA mutated head and neck cell lines were treated with 17-AAG, GDC-0941, trametinib, and BEZ-235. Main Outcome and Measures Assessment of cell viability of HNSCC cell lines characterized for PIK3CA mutations or SCC25 cells engineered to express the PIK3CA hotspot mutations E545K or H1047R Results Surprisingly, in engineered cell lines, the hotspot E545K and H1047R mutations conferred decreased, rather than increased, sensitivity as measured by IC50 when treated with the respective HSP90, PI3K, and MEK inhibitors, 17-AAG, GDC-0941, and trametinib, compared to the SCC25 control cell lines. When treated with BEZ-235, H1047R-expressing cell lines showed increased sensitivity to inhibition compared to control while those expressing E545K showed slightly increased sensitivity of unclear significance. Conclusions and Relevance 1) The PIK3CA mutations within our engineered cell model did not lead to enhanced oncogene-dependent cell death when treated with direct inhibition of the PI3K enzyme yet did show increased sensitivity compared to control with dual PI3K/mTOR inhibition. 2) Oncogene addiction to PIK3CA hot spot mutations, if it occurs, is likely to evolve in vivo molecular changes that remain to be identified. Additional study is required to develop new model systems and

  20. 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…

  1. 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 emancipation based on a…

  2. 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,…

  3. 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…

  4. PIK3CA(H1047R)- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling.

    PubMed

    Cheng, H; Liu, P; Ohlson, C; Xu, E; Symonds, L; Isabella, A; Muller, W J; Lin, N U; Krop, I E; Roberts, T M; Winer, E P; Arteaga, C L; Zhao, J J

    2016-06-01

    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 PIK3CA(H1047R). Induction of PIK3CA(H1047R) 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 phosphatidylinositol-3-kinase (PI3K)/AKT signaling but attenuation of Her2/Her3 signaling, and this can be reversed by deinduction of PIK3CA(H1047R) expression. Strikingly, although these Her2(+) PIK3CA(H1047R)-initiated primary mammary tumors are refractory to HER2-targeted therapy, all tumors responded to inactivation of the oncogenic PIK3CA(H1047R), 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

  5. PIK3CA mutation uncouples tumor growth and Cyclin D1 regulation from MEK/ERK and mutant KRAS signaling

    PubMed Central

    Halilovic, Ensar; She, Qing-Bai; Ye, Qing; Pagliarini, Raymond; Sellers, William R.; Solit, David B.; Rosen, Neal

    2010-01-01

    Mutational activation of KRAS is a common event in human tumors. Identification of the key signaling pathways downstream of mutant KRAS is essential for our understanding of how to pharmacologically target these cancers in patients. We show that PD0325901, a small molecule MEK inhibitor, decreases MEK/ERK pathway signaling, and destabilizes Cyclin D1, resulting in significant anti-cancer activity in a subset of KRAS mutant tumors in vitro and in vivo. Mutational activation of PIK3CA, which commonly co-occurs with KRAS mutation, provides resistance to MEK inhibition through reactivation of AKT signaling. Genetic ablation of the mutant PIK3CA allele in MEK inhibitor-resistant cells restores MEK pathway sensitivity, and re-expression of mutant PIK3CA reinstates the resistance, highlighting the importance of this mutation in resistance to therapy in human cancers. In KRAS mutant tumors, PIK3CA mutation restores Cyclin D1 expression and G1/S cell cycle progression so that they are no longer dependent on KRAS and MEK/ERK signaling. Furthermore, the growth of KRAS mutant tumors with coexistent PIK3CA mutations in vivo is profoundly inhibited with combined pharmacologic inhibition of MEK and AKT. These data suggest that tumors with both KRAS and PI3K mutations are unlikely to respond to inhibition of the MEK pathway alone but will require effective inhibition of both MEK and PI3K/AKT pathway signaling. PMID:20699365

  6. 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

  7. Suppression of CD4+ T lymphocyte activation in vitro and experimental encephalomyelitis in vivo by the phosphatidyl inositol 3-kinase inhibitor PIK-75.

    PubMed

    Acosta, Y Y; Montes-Casado, M; Aragoneses-Fenoll, L; Dianzani, U; Portoles, P; Rojo, J M

    2014-01-01

    Class IA phosphatidyl inositol-3 kinases (PI3-K) are important targets in cancer therapy and are essential to immune responses, particularly through costimulation by CD28 and ICOS. Thus, small PI3-K inhibitors are likely candidates to immune intervention. PIK-75 is an efficient inhibitor of the PI3-K p110alpha catalytic subunits that suppresses tumor growth, and its effects on immune and autoimmune responses should be studied. Here, we describe the effect of PIK-75 on different immune parameters in vitro and in vivo. PIK-75 at concentrations commonly used in vitro (≥0.1 μM) inhibited T and B cell activation by Concanavalin A and LPS, respectively, and survival of non-stimulated spleen cells. In naive CD4+ T lymphocytes, PIK-75 induced apoptosis of resting or activated cells that was prevented by caspase inhibitors. At low nanomolar concentrations (≤10 nM), PIK-75 inhibited naive CD4+ T cell proliferation, and IL-2 and IFN-gamma production induced by anti-CD3 plus anti-CD28. In activated CD4+ T blasts costimulated by ICOS, PIK-75 (less than 10 nM) inhibited IFN-gamma, IL-17A, or IL-21 secretion. Furthermore, PIK-75 (20 mg/kg p.o.) suppressed clinical symptoms in ongoing experimental autoimmune encephalomyelitis (EAE) and inhibited MOG-specific responses in vitro. Thus, PIK-75 is an efficient suppressor of EAE, modulating lymphocyte function and survival. PMID:24674679

  8. Activation of p53-Dependent Growth Suppression in Human Cells by Mutations in PTEN or PIK3CA▿

    PubMed Central

    Kim, Jung-Sik; Lee, Carolyn; Bonifant, Challice L.; Ressom, Habtom; Waldman, Todd

    2007-01-01

    In an effort to identify genes whose expression is regulated by activated phosphatidylinositol 3-kinase (PI3K) signaling, we performed microarray analysis and subsequent quantitative reverse transcription-PCR on an isogenic set of PTEN gene-targeted human cancer cells. Numerous p53 effectors were upregulated following PTEN deletion, including p21, GDF15, PIG3, NOXA, and PLK2. Stable depletion of p53 led to reversion of the gene expression program. Western blots revealed that p53 was stabilized in HCT116 PTEN−/− cells via an Akt1-dependent and p14ARF-independent mechanism. Stable depletion of PTEN in untransformed human fibroblasts and epithelial cells also led to upregulation of p53 and senescence-like growth arrest. Simultaneous depletion of p53 rescued this phenotype, enabling PTEN-depleted cells to continue proliferating. Next, we tested whether oncogenic PIK3CA, like inactivated PTEN, could activate p53. Retroviral expression of oncogenic human PIK3CA in MCF10A cells led to activation of p53 and upregulation of p53-regulated genes. Stable depletion of p53 reversed these PIK3CA-induced expression changes and synergized with oncogenic PIK3CA in inducing anchorage-independent growth. Finally, targeted deletion of an endogenous allele of oncogenic, but not wild-type, PIK3CA in a human cancer cell line led to a reduction in p53 levels and a decrease in the expression of p53-regulated genes. These studies demonstrate that activation of PI3K signaling by mutations in PTEN or PIK3CA can lead to activation of p53-mediated growth suppression in human cells, indicating that p53 can function as a brake on phosphatidylinositol (3,4,5)-triphosphate-induced mitogenesis during human cancer pathogenesis. PMID:17060456

  9. Antitumoral Efficacy of the Protease Inhibitor Gabexate Mesilate in Colon Cancer Cells Harbouring KRAS, BRAF and PIK3CA Mutations

    PubMed Central

    Brandi, Giovanni; Tavolari, Simona; De Rosa, Francesco; Di Girolamo, Stefania; Agostini, Valentina; Barbera, Maria Aurelia; Frega, Giorgio; Biasco, Guido

    2012-01-01

    The employment of anti-epidermal growth factor receptor (EGFR) antibodies represents a backbone of the therapeutic options for the treatment of metastatic colorectal cancer (mCRC). However, this therapy is poorly effective or ineffective in unselected patients. Mutations in KRAS, BRAF and PIK3CA genes have recently emerged as the best predictive factors of low/absent response to EGFR-targeted therapy. Due to the need for efficacious treatment options for mCRC patients bearing these mutations, in this short report we examined the antitumoral activity of the protease inhibitor gabexate mesilate, alone and in combination with the anti-EGFR monoclonal antibody cetuximab, in a panel of human CRC cell lines harbouring a different expression pattern of wild-type/mutated KRAS, BRAF and PIK3CA genes. Results obtained showed that gabexate mesilate significantly inhibited the growth, invasive potential and tumour-induced angiogenesis in all the CRC cells employed in this study (including those ones harbouring dual KRAS/PIK3CA or BRAF/PIK3CA mutation), while cetuximab affected these parameters only in CRC cells with KRAS, BRAF and PIK3CA wild-type. Notably, the antitumoral efficacy of gabexate mesilate and cetuximab in combination was found to be not superior than that observed with gabexate mesilate as single agent. Overall, these preliminary findings suggest that gabexate mesilate could represent a promising therapeutic option for mCRC patients, particularly for those harbouring KRAS, BRAF and PIK3CA mutations, either as mono-therapy or in addition to standard chemotherapy regimens. Further studies to better elucidate gabexate mesilate mechanism of action in CRC cells are therefore warranted. PMID:22911782

  10. PIK3CA Amplification Is Common in Left Side-Tubular Adenomas but Uncommon Sessile Serrated Adenomas Exclusively with KRAS Mutation

    PubMed Central

    Lee, Hyunsu; Lee, Jae-Ho; Kim, Dae-Kwang; Choi, In-Jang; Hwang, Ilseon; Kang, Yu-Na; Kim, Shin

    2015-01-01

    Colorectal cancer is a heterogeneous disorder than arises via multiple distinct pathways, from tubular adenomas (TAs) and sessile serrated adenomas (SSAs), which are clinically, morphologically, and molecularly different. We examined PIK3CA amplification in colorectal precancerous legions, including TAs and SSAs. DNA was isolated from paired normal and tumoral tissues in 64 TAs and 32 SSAs. PIK3CA amplification, KRAS mutation, and BRAF mutation were analyzed by real-time PCR and pyrosequencing. PIK3CA amplification was found in 25% of TAs and 9.4% of SSAs, respectively. KRAS and BRAF mutations were mutually exclusive in both TAs and SSAs. In TAs, PIK3CA amplification was associated with left side and it was mutually exclusive with KRAS mutation. These results suggest that PIK3CA amplification may be early and important event in colorectal carcinogenesis and may drive the development of left-side TAs independently with KRAS mutation. PMID:26019684

  11. PIK3CA gene alterations in bladder cancer are frequent and associate with reduced recurrence in non-muscle invasive tumors.

    PubMed

    Dueñas, Marta; Martínez-Fernández, Mónica; García-Escudero, Ramón; Villacampa, Felipe; Marqués, Miriam; Saiz-Ladera, Cristina; Duarte, José; Martínez, Victor; Gómez, M José; Martín, M Luisa; Fernández, Manoli; Castellano, Daniel; Real, Francisco X; Rodriguez-Peralto, Jose L; De La Rosa, Federico; Paramio, Jesús M

    2015-07-01

    Bladder cancer (BC) is the fifth most common cancer in the world, being the non-muscle invasive tumors (NMIBC) the most frequent. NMIBC shows a very high frequency of recurrence and, in certain cases, tumor progression. The phosphatidylinositol 3-kinase (PI3K) pathway, which controls cell growth, tumorigenesis, cell invasion and drug response, is frequently activated in numerous human cancers, including BC, in part through alterations of PIK3CA gene. However, the significance of PIK3CA gene alterations with respect to clinicopathological characteristics, and in particular tumor recurrence and progression, remains elusive. Here, we analyzed the presence of mutations in FGFR3 and PIK3CA genes and copy number alterations of PIK3CA gene in bladder tumor and their correspondent paired normal samples from 87 patients. We observed an extremely high frequency of PIK3CA gene alterations (mutations, copy gains, or both) in tumor samples, affecting primarily T1 and T2 tumors. A significant number of normal tissues also showed mutations and copy gains, being coincident with those found in the corresponding tumor sample. In low-grade tumors PIK3CA mutations associated with FGFR3 mutations. Alterations in PIK3CA gene resulted in increased Akt activity in tumors. Interestingly, the presence of PIK3CA gene alterations, and in particular gene mutations, is significantly associated with reduced recurrence of NMIBC patients. Importantly, the presence of FGFR3 mutations may influence the clinical outcome of patients bearing alterations in PIK3CA gene, and increased recurrence was associated to FGFR3 mutated, PIK3CA wt tumors. These findings may have high relevance in terms of using PI3K-targeted therapies for BC treatment. PMID:24347284

  12. PIK3CA promotes proliferation and motility but is unassociated with lymph node metastasis or prognosis in esophageal squamous cell carcinoma.

    PubMed

    Zheng, Shutao; Yang, Chenchen; Lu, Mang; Liu, Qing; Liu, Tao; Dai, Fang; Gao, Xiangpeng; Sheyhidin, Ilyar; Lu, Xiaomei

    2016-07-01

    The PIK3CA mutation has been extensively reported in the setting of cancers; however, the clinicopathological significance of PIK3CA expression has rarely been discussed in esophageal squamous cell carcinoma. In the present study, to confirm the significance of PIK3CA expression in association with metastasis and prognosis, which has been somewhat controversial in esophageal squamous cell carcinoma (ESCC), the relationship between clinicopathological features of ESCC and PIK3CA expression was analyzed using immunohistochemistry with a tissue microarray. Meanwhile, as additional verification and an ethnic control, another independent small cohort of Kazakh ESCC were analyzed by immunohistochemistry. To investigate the pilot role of PIK3CA in ESCC cells, ESCC cell lines ECa109 and EC9706 were transiently transfected with specific siRNA against PIK3CA. The silencing effect was detected by Western blot. Cell proliferation was examined using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay; apoptosis and the cell cycles were analyzed by flow cytometry. Furthermore, the migratory and invasive ability were evaluated by wound healing and transwell invasion assay, respectively. Expression of PIK3CA was significantly higher in ESCC than in paired normal controls and was ethnicity independent; no statistically significant difference was observed between PIK3CA expression and sex, age, depth of invasion, tumor differentiation, lymph node metastasis, or prognosis. Proliferation, migration, and invasion were all markedly reduced after knockout of PIK3CA. Moreover, the cell cycle was arrested at the S phase, and the apoptosis rate was significantly increased, suggesting that PIK3CA plays a key role in promoting the proliferation and motility of ESCC cells. PMID:27001433

  13. 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

  14. Activating Mutations in PIK3CA Lead to Widespread Modulation of the Tyrosine Phosphoproteome

    PubMed Central

    Blair, Brian G.; Pinto, Sneha M.; Nirujogi, Raja S.; Jelinek, Christine A.; Malhotra, Radhika; Kim, Min-Sik; Park, Ben Ho; Pandey, Akhilesh

    2015-01-01

    The human oncogene PIK3CA is frequently mutated in human cancers. Two hotspot mutations in PIK3CA, E545K and H1047R, have been shown to regulate widespread signaling events downstream of AKT, leading to increased cell proliferation, growth, survival, and motility. We used quantitative mass spectrometry to profile the global phosphotyrosine proteome of isogenic knock-in cell lines containing these activating mutations, where we identified 824 unique phosphopeptides. Although it is well understood that these mutations result in hyperactivation of the serine/threonine kinase AKT, we found a surprisingly widespread modulation of tyrosine phosphorylation levels of proteins in the mutant cells. In the tyrosine kinome alone, 29 tyrosine kinases were altered in their phosphorylation status. Many of the regulated phosphosites that we identified were located in the kinase domain or the canonical activation sites, indicating that these kinases and their downstream signaling pathways were activated. Our study demonstrates that there is frequent and unexpected cross-talk that occurs between tyrosine signaling pathways and serine/threonine signaling pathways activated by the canonical PI3K-AKT axis. PMID:26267517

  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. 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).

  17. 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

  18. Biphasic papillary and lobular breast carcinoma with PIK3CA and IDH1 mutations.

    PubMed

    Ang, Daphne; VanSandt, Amanda M; Beadling, Carol; Warrick, Andrea; West, Robert B; Corless, Christopher L; Troxell, Megan L

    2012-12-01

    Morphologic "special types" of breast carcinomas have been recognized for many years, and their molecular and genetic properties have not been specifically studied until recently. Lobular carcinoma lacks functional E-cadherin expression but shares molecular similarities with low-grade invasive ductal carcinomas. Papillary carcinoma is relatively rare, and molecular features are just being elucidated. We report a case of concurrent invasive lobular and papillary carcinoma, the latter with extensive nodal involvement. Multiplex screening for activating point mutations identified different point mutations in the distinct morphologic components: lobular PIK3CA H1047R, papillary; PIK3CA Q546P, and IDH1 R132H. These molecular data favor coincidental "collision tumors" over clonal evolution. The IDH1 R132H point mutation is common in gliomas and acute myelogenous leukemia, but this has not been previously reported in breast carcinoma. The characterization of activating point mutations in morphologic special types of breast carcinoma may suggest avenues amenable to targeted therapy. PMID:23111200

  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. PMID:26592080

  20. 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

  1. MARIE Results: Implications for a Mars Mission

    NASA Astrophysics Data System (ADS)

    Zeitlin, C.; Cucinotta, F.; Cleghorn, T.

    The MARIE instrument onboard the 2001 Mars Odyssey spacecraft operated in Mars orbit from March 13, 2002, and October 28, 2003. The time period matches fairly well with the expected duration of a surface stay for NASA's present design for a crewed Mars mission. Based on MARIE data and model calculations using the NASA-JSC transport code HZETRN, it is expected that a crewmember on a mission of 1000 days duration would receive a dose equivalent of about 800 mSv from the Galactic Cosmic Radiation. The dose equivalent is received at a higher rate during the transits from Earth to Mars and back than it is on the surface. The major reason for this is that, in free space, radiation impinges from all directions, whereas on the surface of a planet (or other large body), half of the solid angle is shielded by the planet, resulting in a factor of two dose reduction. During the stay on Mars, additional shielding -- particularly against Solar Particle Events (SPE) -- will be provided by the Martian atmosphere. The contribution to total dose equivalent from SPE is unpredictable. During the period in which MARIE data were obtained, the solar cycle was declining from the 2001 maximum, and several SPEs were observed. Averaged by month, SPE contributions to dose equivalent were as high as 30% of the total, with some months being entirely free of SPEs. Even the maximum 30% increase is almost certainly an overestimate of what would be experienced by an actual crew, since MARIE is far less shielded (by design) than an interplanetary spacecraft would be. This does not preclude the possibility of SPEs with a ``harder'' energy spectrum, in which high fluxes of very penetrating particles can be produced. Though rare, such events have been observed, and must be considered when designing the spacecraft and its shielding properties. In addition to the MARIE data, we will also discuss the state of research on the biological effects of heavy ion irradiation. An active program is underway at the

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

    NASA Video Gallery

    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 ...

  3. 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

  4. Molecular evaluation of PIK3CA gene mutation in breast cancer: determination of frequency, distribution pattern and its association with clinicopathological findings in Indian patients.

    PubMed

    Ahmad, Firoz; Badwe, Anuya; Verma, Geeta; Bhatia, Simi; Das, Bibhu Ranjan

    2016-07-01

    Somatic mutations in the PIK3CA gene are common in breast cancer and represent a clinically useful marker for prognosis and therapeutic target. Activating mutations in the PI3K p110 catalytic subunit (PIK3CA) have been identified in 18-40 % of breast carcinomas. In this study, we evaluated PIK3CA mutation in 185 Indian breast cancer patients by direct DNA sequencing. PIK3CA mutations were observed in 23.2 % (43/185) of breast tumor samples. PIK3CA mutations were more frequent exon 30 (76.8 %) than in exon 9 (23.2 %). Mutations were mostly clustered within two hotspot region between nucleotides 1624 and 1636 or between 3129 and 3140. Sequencing analysis revealed four different missense mutations at codon 542 and 545 (E542K, E545K, E545A and E545G) in the helical domain and two different amino acid substitutions at codon 1047 (H1047R and H1047L) in the kinase domain. None of the cases harbored concomitant mutations at multiple codons. PIK3CA mutations were more frequent in older patients, smaller size tumors, ductal carcinomas, grade II tumors, lymph node-positive tumors and non-DCIS tumors; however, none of the differences were significant. In addition, PIK3CA mutations were common in ER+, PR+ and HER2+ cases (30 %), and a comparatively low frequency were noted in triple-negative tumors (13.6 %). In conclusion, to our knowledge, this is the largest study to evaluate the PIK3CA mutation in Indian breast cancer patients. The frequency and distribution pattern of PIK3CA mutations is similar to global reports. Furthermore, identification of molecular markers has unique strengths and can provide insights into the pathogenic process of breast carcinomas. PMID:27282497

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

    PubMed Central

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

    2015-01-01

    Background Information 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. Results 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. Conclusions Taken together, our results indicated for the first time that miR‐490‐5p functions as a tumour suppressor in renal carcinoma by targeting PIK3CA. Significance Our findings suggest that miR‐490‐5p may be a potential gene therapy target for the treatment of renal cell carcinoma. PMID:26559013

  6. 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.

  7. 33 CFR 117.653 - St. Mary's Falls Canal.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 1 2012-07-01 2012-07-01 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 of the International Railway bridge, mile...

  8. 33 CFR 117.653 - St. Mary's Falls Canal.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 33 Navigation and Navigable Waters 1 2011-07-01 2011-07-01 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 of the International Railway bridge, mile...

  9. 1. Photocopied August 1978. GENERAL VIEW OF THE ST. MARY'S ...

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

    1. Photocopied August 1978. GENERAL VIEW OF THE ST. MARY'S RAPIDS AND THE INTERNATIONAL BRIDGE, C. 1910. THE OLD CHANDLER-DUNBAR (GOVERNMENT) HYDROELECTRIC PLANT IS VISIBLE ON THE LEFT. (573) - Michigan Lake Superior Power Company, Portage Street, Sault Ste. Marie, Chippewa County, MI

  10. 33 CFR 117.373 - St. Marys River.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false St. Marys River. 117.373 Section 117.373 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Georgia § 117.373 St. Marys River. See § 117.329,...

  11. 33 CFR 117.373 - 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. 117.373 Section 117.373 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Georgia § 117.373 St. Marys River. See § 117.329,...

  12. 33 CFR 117.373 - St. Marys River.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 1 2012-07-01 2012-07-01 false St. Marys River. 117.373 Section 117.373 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Georgia § 117.373 St. Marys River. See § 117.329,...

  13. 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.

  14. 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

    ... Explosives, St. Marys River, Sault Sainte Marie, MI AGENCY: Coast Guard, DHS. ACTION: Temporary final rule... effective with actual notice for purposes of enforcement beginning 5 a.m. April 23, 2010 through 10 p.m... 5 p.m., Monday through Friday, except Federal holidays. FOR FURTHER INFORMATION CONTACT: If you...

  15. Reverse Phase Protein Array profiling of oropharyngeal cancer and significance of PIK3CA mutations in HPV-associated head and neck cancer

    PubMed Central

    Sewell, Andrew; Brown, Brandee; Biktasova, Asel; Mills, Gordon B.; Lu, Yiling; Tyson, Darren R.; Issaeva, Natalia; Yarbrough, Wendell G.

    2014-01-01

    Purpose HPV-associated (HPV+) oropharyngeal squamous cell carcinomas (OPSCC) have different molecular and biological characteristics and clinical behavior compared to HPV-negative (HPV−) OPSCC. PIK3CA mutations are more common in HPV(+)OPSCC. To define molecular differences and tumor subsets, protein expression and phosphorylation were compared between HPV(+) and HPV(−) OPSCC and between tumors with and without PIK3CA mutations. Experimental design Expression of 137 total and phosphorylated proteins was evaluated by reverse phase protein array(RPPA) in 29 HPV(+) and 13 HPV(−)prospectively collected OPSCCs. 47 OPSCCs were tested for hotspot activating mutations in PIK3CA and AKT. Activation of PIK3CA downstream targets and sensitivity to pathway inhibitors were determined in HPV(+) head and neck cancer cells overexpressing wild-type or mutant PIK3CA. Results Analyses revealed forty-one differentially expressed proteins between HPV(+) and HPV(−) OPSCC categorized into functional groups: DNA repair, cell cycle, apoptosis, PI3K/AKT/mTOR, and receptor kinase pathways. All queried DNA repair proteins were significantly upregulated in HPV(+) samples. 8 of 33 HPV(+) and 0 of 14 HPV(−) tumors contained activating PIK3CA mutations. Despite all activating PIK3CA mutations occurring in HPV(+) samples, HPV(+) tumors had lower mean levels of activated AKT and downstream AKT target phosphorylation. Ectopic expression of mutant PIK3CA in HPV(+) cells increase dmTOR, but not AKT activity. HPV E6/E7 overexpression inhibited AKT phosphorylation in HPV-negative cells. Mutant PIK3CA overexpressing cells were more sensitive to a dual PI3K/mTOR inhibitor compared to an AKT inhibitor. Conclusions Protein expression analyses suggest that HPV(+) and HPV(−) OPSCC differentially activate DNA repair, cell cycle, apoptosis, PI3K/AKT/mTOR, and receptor kinase pathways. PIK3CA mutations are more common in HPV(+) OPSCC and are associated with activation of mTOR, but not AKT. These data

  16. Oncogenic activation of the PI3-kinase p110β isoform via the tumor-derived PIK3Cβ(D1067V) kinase domain mutation.

    PubMed

    Pazarentzos, E; Giannikopoulos, P; Hrustanovic, G; St John, J; Olivas, V R; Gubens, M A; Balassanian, R; Weissman, J; Polkinghorn, W; Bivona, T G

    2016-03-01

    Activation of the phosphoinositide 3-kinase (PI3K) pathway occurs widely in human cancers. Although somatic mutations in the PI3K pathway genes PIK3CA and PTEN are known to drive PI3K pathway activation and cancer growth, the significance of somatic mutations in other PI3K pathway genes is less clear. Here, we establish the signaling and oncogenic properties of a recurrent somatic mutation in the PI3K p110β isoform that resides within its kinase domain (PIK3Cβ(D1067V)). We initially observed PIK3Cβ(D1067V) by exome sequencing analysis of an EGFR-mutant non-small cell lung cancer (NSCLC) tumor biopsy from a patient with acquired erlotinib resistance. On the basis of this finding, we hypothesized that PIK3Cβ(D1067V) might function as a novel tumor-promoting genetic alteration, and potentially an oncogene, in certain cancers. Consistent with this hypothesis, analysis of additional tumor exome data sets revealed the presence of PIK3Cβ(D1067V) at low frequency in other patient tumor samples (including renal cell carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, melanoma, thyroid carcinoma and endometrial carcinoma). Functional studies revealed that PIK3Cβ(D1067V) promoted PI3K pathway signaling, enhanced cell growth in vitro, and was sufficient for tumor formation in vivo. Pharmacologic inhibition of PIK3Cβ with TGX-221 (isoform-selective p110β inhibitor) specifically suppressed growth in patient-derived renal-cell carcinoma cells with endogenous PIK3Cβ(D1067V) and in NIH-3T3 and human EGFR-mutant lung adenocarcinoma cells engineered to express this mutant PI3K. In the EGFR-mutant lung adenocarcinoma cells, expression of PIK3Cβ(D1067V) also promoted erlotinib resistance. Our data establish a novel oncogenic form of PI3K, revealing the signaling and oncogenic properties of PIK3Cβ(D1067V) and its potential therapeutic relevance in cancer. Our findings provide new insight into the genetic mechanisms underlying PI3K pathway activation in

  17. 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

  18. MicroRNA-126 inhibits proliferation and metastasis by targeting pik3r2 in prostate cancer

    PubMed Central

    SONG, LEI; XIE, XUBIO; YU, SHAOJIE; PENG, FENGHUA; PENG, LONGKAI

    2016-01-01

    The dysregulation of miR-126 has been reported to correlate with the progression of several cancer types. The present study demonstrated that miR-126 was significantly downregulated in prostate cancer (PCa) tissues compared with normal prostate tissues. In vitro and in vivo studies indicated that forced overexpression of miR-126 significantly suppressed the proliferation of PCa cell lines. Additionally, a Transwell assay showed that enhanced expression of miR-126 inhibited metastasis in PCa in vitro. Furthermore, pik3r2 was confirmed to be a direct target of miR-126 in PCa. It was also shown that pik3r2 was upregulated in PCa tissues and this inversely correlated with miR-126 in PCa tissues. In conclusion, these results revealed that aberrant expression of miR-126 promoted the progression of PCa and may serve as a novel therapeutic biomarker for PCa. PMID:26677064

  19. PIK3CA-Related Overgrowth Spectrum (PROS): Diagnostic and Testing Eligibility Criteria, Differential Diagnosis, and Evaluation

    PubMed Central

    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.

    2015-01-01

    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

  20. 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

  1. 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. PMID:15749150

  2. 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

  3. Intrinsic Subtypes, PIK3CA Mutation, and the Degree of Benefit From Adjuvant Trastuzumab in the NSABP B-31 Trial

    PubMed Central

    Pogue-Geile, Katherine L.; Song, Nan; Jeong, Jong-Hyeon; Gavin, Patrick G.; Kim, Seong-Rim; Blackmon, Nicole L.; Finnigan, Melanie; Rastogi, Priya; Fehrenbacher, Louis; Mamounas, Eleftherios P.; Swain, Sandra M.; Wickerham, D. Lawrence; Geyer, Charles E.; Costantino, Joseph P.; Wolmark, Norman; Paik, Soonmyung

    2015-01-01

    Purpose Considerable molecular heterogeneity exists among human epidermal growth factor receptor 2 (HER2) –positive breast cancer regarding gene expression and mutation profiling. Evidence from preclinical, clinical neoadjuvant, and metastatic clinical trials suggested that PIK3CA mutational status and PAM50 intrinsic subtype of a tumor were markers of response to anti-HER2 therapies. We evaluated the predictive value of these two biomarkers in the adjuvant setting using archived tumor blocks from National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31. Patients and Methods Expression data for 49 genes using the nCounter platform were used to generate PAM50 intrinsic subtypes for 1,578 archived tumor blocks from patients in the B-31 trial. Six PIK3CA hotspot mutations were examined by mass spectrometry of the primer extension products in a randomly selected subset (n = 671). We examined the heterogeneity of trastuzumab treatment effect across different subsets defined by each marker using Cox regression and disease-free survival as the end point. Results Seven hundred forty-one (47.0%) of 1,578 tumors were classified as HER2-enriched (HER2E) subtype, and 166 (24.7%) of 671 tumors had PIK3CA mutations. Hazard ratios (HRs) for trastuzumab in HER2E and other subtypes were 0.44 (95% CI, 0.34 to 0.58; P < .001) and 0.47 (95% CI, 0.35 to 0.62; P < .001), respectively (interaction P = .67). HRs for trastuzumab in PIK3CA wild-type and mutated tumors were 0.51 (95% CI, 0.37 to 0.71; P < .001) and 0.44 (95% CI, 0.24 to 0.82; P = .009), respectively (interaction P = .64). Conclusion Unlike results seen in the metastatic and neoadjuvant clinical trials, PIK3CA and PAM50 intrinsic subtypes were not predictive biomarkers for adjuvant trastuzumab in NSABP B-31. These data suggest that results from the metastatic and neoadjuvant setting may not be always applicable to the adjuvant setting. PMID:25559813

  4. 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 ...

  5. 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.

  6. Students Speak With Vacuum Chamber Project Manager Mary Cerimele

    NASA Video Gallery

    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...

  7. 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.

  8. 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)

  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. 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

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. Inhibition of PI3K Pathway Reduces Invasiveness and Epithelial-to-Mesenchymal Transition in Squamous Lung Cancer Cell Lines Harboring PIK3CA Gene Alterations.

    PubMed

    Bonelli, Mara A; Cavazzoni, Andrea; Saccani, Francesca; Alfieri, Roberta R; Quaini, Federico; La Monica, Silvia; Galetti, Maricla; Cretella, Daniele; Caffarra, Cristina; Madeddu, Denise; Frati, Caterina; Lagrasta, Costanza Annamaria; Falco, Angela; Rossetti, Pietro; Fumarola, Claudia; Tiseo, Marcello; Petronini, Pier Giorgio; Ardizzoni, Andrea

    2015-08-01

    A prominent role in the pathogenesis of squamous cell carcinoma of the lung (SQCLC) has been attributed to the aberrant activation of the PI3K signaling pathway, due to amplification or mutations of the p110α subunit of class I phosphatidylinositol 3-kinase (PIK3CA) gene. The aim of our study was to determine whether different genetic alterations of PIK3CA affect the biologic properties of SQCLC and to evaluate the response to specific targeting agents in vitro and in vivo. The effects of NVP-BEZ235, NVP-BKM120, and NVP-BYL719 on two-dimensional/three-dimensional (2D/3D) cellular growth, epithelial-to-mesenchymal transition, and invasiveness were evaluated in E545K or H1047R PIK3CA-mutated SQCLC cells and in newly generated clones carrying PIK3CA alterations, as well as in a xenograft model. PIK3CA mutated/amplified cells showed increased growth rate and enhanced migration and invasiveness, associated with an increased activity of RhoA family proteins and the acquisition of a mesenchymal phenotype. PI3K inhibitors reverted this aggressive phenotype by reducing metalloproteinase production, RhoA activity, and the expression of mesenchymal markers, with the specific PI3K inhibitors NVP-BKM120 and NVP-BYL719 being more effective than the dual PI3K/mTOR inhibitor NVP-BEZ235. A xenograft model of SQCLC confirmed that PIK3CA mutation promotes the acquisition of a mesenchymal phenotype in vivo and proved the efficacy of its specific targeting drug NVP-BYL719 in reducing the growth and the expression of mesenchymal markers in xenotransplanted tumors. These data indicate that PIK3CA mutation/amplification may represent a good predictive feature for the clinical application of specific PI3K inhibitors in SQCLC patients. PMID:26013318

  16. The sad and tragic life of Typhoid Mary.

    PubMed

    Brooks, J

    1996-03-15

    As society grapples with contemporary moral questions raised by the barring of HIV-infected people from jobs and even crossing some national borders, it is probably useful to re-examine the case of Typhoid Mary. The case of Mary Mallon shows how an earlier age resolved the conflict that arises when society's right to protect itself from unnecessary exposure to disease impinges on the liberty of individual citizens. PMID:8634973

  17. The sad and tragic life of Typhoid Mary.

    PubMed Central

    Brooks, J

    1996-01-01

    As society grapples with contemporary moral questions raised by the barring of HIV-infected people from jobs and even crossing some national borders, it is probably useful to re-examine the case of Typhoid Mary. The case of Mary Mallon shows how an earlier age resolved the conflict that arises when society's right to protect itself from unnecessary exposure to disease impinges on the liberty of individual citizens. PMID:8634973

  18. Cholangicarcinoma Presenting as a Sister Mary Joseph Nodule

    PubMed Central

    Rangegowda, Devaraja; Vyas, Tanmay; Grover, Shrruti; Joshi, YK; Sharma, Chhagan; Sahney, Amrish

    2016-01-01

    Sister Mary Joseph nodules represent metastatic cancer of the umbilicus. More than half of these cases are attributable to gastrointestinal malignancies including gastric, colonic, and pancreatic cancer. In addition, gynecologic (ovarian, uterine cancer), unknown primary tumors, and, rarely, bladder or respiratory malignancies may cause umbilical metastasis. We report the case of a Sister Mary Joseph nodule originating from a hilar cholangiocarcinoma. Umbilical nodules should prompt clinical evaluation, as these tumors are usually associated with poor prognosis. PMID:27144207

  19. 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.

  20. 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.

  1. A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA+ oral cancers

    PubMed Central

    Yamaguchi, Kosuke; Iglesias-Bartolomé, Ramiro; Wang, Zhiyong; Callejas-Valera, Juan Luis; Amornphimoltham, Panomwat; Molinolo, Alfredo A.; Cohen, Ezra E.; Califano, Joseph A.; Lippman, Scott M.; Luo, Ji; Gutkind, J. Silvio

    2016-01-01

    mTOR inhibition has emerged as a promising strategy for head and neck squamous cell carcinomas (HNSCC) treatment. However, most targeted therapies ultimately develop resistance due to the activation of adaptive survival signaling mechanisms limiting the activity of targeted agents. Thus, co-targeting key adaptive mechanisms may enable more effective cancer cell killing. Here, we performed a synthetic lethality screen using shRNA libraries to identify druggable candidates for combinatorial signal inhibition. We found that the ERK pathway was the most highly represented. Combination of rapamycin with trametinib, a MEK1/2 inhibitor, demonstrated strong synergism in HNSCC-derived cells in vitro and in vivo, including HNSCC cells expressing the HRAS and PIK3CA oncogenes. Interestingly, cleaved caspase-3 was potently induced by the combination therapy in PIK3CA+ cells in vitro and tumor xenografts. Moreover, ectopic expression of PIK3CA mutations into PIK3CA− HNSCC cells sensitized them to the pro-apoptotic activity of the combination therapy. These findings indicate that co-targeting the mTOR/ERK pathways may provide a suitable precision strategy for HNSCC treatment. Moreover, PIK3CA+ HNSCC are particularly prone to undergo apoptosis after mTOR and ERK inhibition, thereby providing a potential biomarker of predictive value for the selection of patients that may benefit from this combination therapy. PMID:26882569

  2. Mutational analysis of PI3K/AKT and RAS/RAF pathway activation in malignant salivary gland tumours with a new mutation of PIK3CA.

    PubMed

    Shalmon, B; Drendel, M; Wolf, M; Hirshberg, A; Cohen, Y

    2016-06-01

    The phosphoinositide 3-kinase (PIK3)/v-akt murine thymoma (AKT) oncogene pathway and the RAS/RAF pathway are involved in regulating the signalling of multiple biological processes, including apoptosis, metabolism, cell proliferation, and cell growth. Mutations in the genes within these pathways are frequently found in several tumours. The aim of this study was to investigate the frequency of mutations in the PIK3CA, BRAF, and KRAS genes in cases of malignant salivary gland tumours. Mutational analysis of the PIK3CA, KRAS, and BRAF genes was performed by direct sequencing of material from 21 patients with malignant salivary gland tumours who underwent surgery between 1992 and 2001. No mutations were found in the KRAS exon 2, BRAF exon 15, or PIK3CA exon 9 genes. However, an unpublished mutation of the PIK3CA gene in exon 20 (W1051 stop mutation) was found in one case of adenocarcinoma NOS. The impact of this mutation on the biological behaviour of the tumour has yet to be explored, however the patient with adenocarcinoma NOS harbouring this mutation has survived for over 20 years following surgery despite a high stage at presentation. Further studies with more homogeneous patient cohorts are needed to address whether this mutation reflects a different clinical presentation and may benefit from targeted treatment strategies. PMID:26811072

  3. [Rehabilitation of Charcot-Marie-Tooth Disease].

    PubMed

    Tajima, Fumihiro; Nakamura, Takeshi; Nishimura, Yukihide; Arakawa, Hideki; Kawasaki, Takashi; Ogawa, Takahiro; Nishiyama, Kazunari

    2016-01-01

    Charcot-Marie-Tooth disease (CMT) is one of the most commonly inherited neuromuscular diseases causing progressive muscle weakness; contracture; deformity in the feet, legs, and hands; and impairments of ambulation and handgrip. Reduced physical ability can be attributed not only to the disease but also to physical deconditioning. Previously, most physicians in the field of rehabilitation were anxious about the hypothesis of overwork weakness in CMT, and did not conduct intensive exercise programs for patients with CMT. However, recent studies have reported that progressive resistance strengthening programs for lower extremities are feasible, safe, beneficial, and improve exercise intolerance and undue fatigue in patients with CMT. Although the improvement in exercise tolerance may be partly due to the reversal of deconditioning effect of related sedentary lifestyle, progressive resistance training and physical fitness can improve walking function, activities of daily living, and subjective perception of pain and fatigue in patients with CMT. To increase the daily physical function, some studies described the potential benefits of ankle-foot orthoses (AFOs); however, no control study supported it. So far, the training programs on CMT have been dependent on the exercise programs for able-bodied individuals. To increase the effects of rehabilitation, optimal programs that combine the training protocol and AFO strategies will have to be designed for patients with CMT. PMID:26764300

  4. [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. PMID:26764296

  5. Inhibition of PIK3 signaling pathway members by the ovotoxicant 4-vinylcyclohexene diepoxide in rats.

    PubMed

    Keating, Aileen F; Fernandez, Shannon M; Mark-Kappeler, Connie J; Sen, Nivedita; Sipes, I Glenn; Hoyer, Patricia B

    2011-04-01

    4-Vinylcyclohexene diepoxide (VCD), an occupational chemical that specifically destroys primordial and small primary follicles in the ovaries of rats and mice, is thought to target an oocyte-expressed tyrosine kinase receptor, Kit. This study compared the temporal effect of VCD on protein distribution of KIT and its downstream PIK3-activated proteins, AKT and FOXO3. Postnatal Day 4 Fischer 344 rat ovaries were cultured in control media ± VCD (30 μM) for 2-8 days (d2-d8). KIT, AKT, phosphorylated AKT, FOXO3, and pFOXO3 protein levels were assessed by Western blotting and/or immunofluorescence staining with confocal microscopy. Phosphorylated AKT was decreased (P < 0.05) in oocyte nuclei in primordial (39% decrease) and small primary (37% decrease) follicles within 2 days of VCD exposure. After d4, VCD reduced (P < 0.05) oocyte staining for KIT (primordial, 44% decrease; small primary, 39% decrease) and FOXO3 (primordial, 40% decrease; small primary, 36% decrease) protein. Total AKT and pFOXO3 were not affected by VCD at any time. Akt1 mRNA, as measured by quantitative RT-PCR, was reduced (P < 0.05) by 23% on d4 of VCD exposure, but returned to control levels on d6 and d8. VCD exposure reduced Foxo3a mRNA by 26% on d6 (P < 0.05) and by 23% on d8 (P < 0.1). These results demonstrate that the earliest observed effect of VCD is an inhibition of phosphorylation and nuclear localization of AKT in the oocyte of primordial and small primary follicles. This event is followed by reductions in KIT and FOXO3 protein subcellular distribution prior to changes in mRNA. Thus, these findings further support that VCD induces ovotoxicity by directly targeting the oocyte through posttranslational inhibition of KIT-mediated signaling components. PMID:21076081

  6. Sorafenib enhances the therapeutic efficacy of rapamycin in colorectal cancers harboring oncogenic KRAS and PIK3CA

    PubMed Central

    Evers, B. Mark

    2012-01-01

    Activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling is associated with tumorigenesis and metastasis of colorectal cancer (CRC). The mammalian target of rapamycin (mTOR) kinase, a downstream effector of PI3K/Akt signaling, regulates tumorigenesis and metastasis of CRCs, indicating that mTOR inhibition may have therapeutic potential. Notwithstanding, many cancers, including CRC, demonstrate resistance to the antitumorigenic effects of rapamycin. In this study, we show that inhibition of mTORC1 with rapamycin leads to feedback activation of PI3K/Akt and Ras-MAPK signaling, resulting in cell survival and possible contribution to rapamycin resistance. Combination with the multikinase inhibitor, sorafenib, abrogates rapamycin-induced activation of PI3K/Akt and Ras-MAPK signaling pathways. Combination of rapamycin with sorafenib synergistically inhibits proliferation of CRC cells. CRCs harboring coexistent KRAS and PIK3CA mutations are partially sensitive to either rapamycin or sorafenib monotherapy, but highly sensitive to combination treatment with rapamycin and sorafenib. Combination with sorafenib enhances therapeutic efficacy of rapamycin on induction of apoptosis and inhibition of cell-cycle progression, migration and invasion of CRCs. We demonstrate efficacy and safety of concomitant treatment with rapamycin and sorafenib at inhibiting growth of xenografts from CRC cells with coexistent mutations in KRAS and PIK3CA. The efficacy and tolerability of combined treatment with rapamycin and sorafenib provides rationale for use in treating CRC patients, particularly those with tumors harboring coexistent KRAS and PIK3CA mutations. Abbreviations:CIcombination indexCRCcolorectal cancerIHCimmunohistochemistryMAPKmitogen activated protein kinasemTORmammalian target of rapamycinPI3Kphosphatidylinositol 3-kinase. PMID:22696593

  7. The Prognostic Value of Microsatellite Instability, KRAS, BRAF and PIK3CA Mutations in Stage II Colon Cancer Patients

    PubMed Central

    Vogelaar, F Jeroen; N van Erning, Felice; Reimers, Marlies S; van der Linden, Hans; Pruijt, Hans; C van den Brule, Adriaan J; Bosscha, Koop

    2015-01-01

    In the era of personalized cancer medicine, identifying mutations within patient tumors plays an important role in defining high-risk stage II colon cancer patients. The prognostic role of BRAF V600E mutation, microsatellite instability (MSI) status, KRAS mutation and PIK3CA mutation in stage II colon cancer patients is not settled. We retrospectively analyzed 186 patients with stage II colon cancer who underwent an oncological resection but were not treated with adjuvant chemotherapy. KRAS mutations, PIK3CA mutation, V600E BRAF mutation and MSI status were determined. Survival analyses were performed. Mutations were found in the patients with each mutation in the following percentages: 23% (MSI), 35% (KRAS), 19% (BRAF) and 11% (PIK3CA). A trend toward worse overall survival (OS) was seen in patients with an MSI (5-year OS 74% versus 82%, adjusted hazard ratio [HR] 1.8, 95% confidence interval [CI] 0.6–4.9) and a KRAS-mutated tumor (5-year OS 77% versus 82%, adjusted HR 1.7, 95% CI 0.8–3.5). MSI and BRAF-mutated tumors tended to correlate with poorer disease-free survival (DFS) (5-year DFS 60% versus 78%, adjusted HR 1.6, 95% CI 0.5–2.1 and 5-year DFS 57% versus 77%, adjusted HR 1.1, 95% CI 0.4–2.6 respectively). In stage II colon cancer patients not treated with adjuvant chemotherapy, BRAF mutation and MSI status both tended to have a negative prognostic effect on disease-free survival. KRAS and MSI status also tended to be correlated with worse overall survival. PMID:26716438

  8. Analytical complex at the PIK reactor for studying the supra-atomic structure and dynamics of materials by neutron scattering

    SciTech Connect

    Lebedev, V. M. Lebedev, V. T.; Ivanova, I. N.; Orlova, D. N.

    2011-12-15

    A project of the center for studying reactor materials and solving problems of materials science is presented which will be equipped with the following neutron instruments: a small-angle Membrana diffractometer, a spin-echo spectrometer, and a time-of-flight spectrometer. It is proposed to irradiate materials in the PIK reactor core and use neutron-scattering tools to analyze the structure and dynamics of these materials and investigate radiative defects in the complete experimental cycle (initial material-irradiation-strength tests, thermal loads, and other effects) using materials science techniques.

  9. EGFR, COX2, p-AKT expression and PIK3CA mutation in distal extrahepatic bile duct carcinoma.

    PubMed

    Moon, Ahrim; Chin, Susie; Kim, Hee Kyung; Kwak, Jeong Ja; Koh, Eun Suk; Kim, Youn Wha; Jang, Kee-Taek

    2016-01-01

    Distal extrahepatic bile duct (EBD) carcinoma is a rare but highly aggressive malignant neoplasm. Some in vitro studies have shown that EGFR and PI3K-Akt pathway play an important role in the carcinogenesis of bile duct carcinoma. The aim of the present study is to investigate the expression of EGFR, p-AKT, and COX-2 and the mutation of PIK3CA in distal EBD carcinoma and evaluate the association with clinicopathological factors. Ninety cases of distal extrahepatic bile duct (EBD) carcinoma specimens were studied. Immunohistochemistry (IHC) using antibodies against EGFR, p-AKT, and COX-2 was performed on TMA blocks. The PIK3CA mutation was evaluated using the PNAClamp Detection Kit from DNA samples extracted from formalin fixed, paraffin embedded tissue. EGFR expression of distal EBD carcinomas was 61.9%, 26.2%, 6.0% and 6.0% in the negative, weakly positive, moderately positive, and strongly positive groups, respectively. Positive EGFR expression showed significant relationships with high T stage (p = 0.024). In Kaplan-Meier analysis, EGFR expression was associated with shorter cancer-specific overall survival (p = 0.005). Multivariate analysis also showed that moderate or strong (2+ or 3+) EGFR expression was a significant prognostic factor in distal EBD carcinoma: HR 5.286; p = 0.001. Ninety cases of EBD carcinoma tissue were analysed for hotspot mutations (exon 9 and 20) in the PIK3CA gene. Only one mutation was detected: a missense mutation of H1047 at exon 20. The expression levels of p-AKT and COX-2 showed no association with any clinicopathological parameters, including survival rate. Moderate and strong EGFR expressions demonstrate a direct link to poor prognosis. Although further study is warranted to understand the clinicopathological significance, our finding suggests EGFR is a useful prognostic marker of patients with distal EBD carcinoma. A low prevalence of PIK3CA mutation exists in the distal EBD carcinoma of Korean patients, indicating that

  10. 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.

  11. The analysis of PIK3CA mutations in gastric carcinoma and metanalysis of literature suggest that exon-selectivity is a signature of cancer type

    PubMed Central

    2010-01-01

    Background PIK3CA is one of the genes most frequently mutated in human cancers and it is a potential target for personalized therapy. The aim of this study was to assess the frequency and type of PIK3CA mutations in gastric carcinoma and compare them with their clinical pathological correlates. Methods We analysed 264 gastric cancers, including 39 with microsatellite instability (MSI), for mutations in the two PIK3CA hotspots in exons 9 and 20 by direct sequencing of DNA obtained from microdissected cancer cells. Results The cases harbouring mutations were 42 (16%). All were heterozygous missense single base substitutions; the most common was H1047R (26/42; 62%) in exon 20 and the second was Q546K (4/42; 9.5%) in exon 9. All the mutated MSI cases (8/39) carried the H1047R mutation. No other association between PI3KCA mutations and their clinical pathological covariates was found. A metanalysis of the mutations occurring in the same regions presented in 27 publications showed that ratio between exon 20 and exon 9 prevalences was 0.6 (95% CI: 0.5 -0.8) for colon, 1.6 (95% CI: 1.1 -2.3) for breast, 2.7 (95% CI: 1.6 -4.9) for gastric and 4.1 (95% CI: 1.9 -10.3) for endometrial cancer. Conclusions The overall prevalence of PIK3CA mutations implies an important role for PIK3CA in gastric cancer. The lack of association with any clinical-pathological condition suggests that mutations in PIK3CA occur early in the development of cancer. The metanalysis showed that exon-selectivity is an important signature of cancer type reflecting different contexts in which tumours arise. PMID:20398348

  12. MYC-xing it up with PIK3CA mutation and resistance to PI3K inhibitors: summit of two giants in breast cancers.

    PubMed

    Dey, Nandini; Leyland-Jones, Brian; De, Pradip

    2015-01-01

    Approximately 35% of breast cancers exhibit PIK3CA activating mutation. Since PIK3CA hotspot mutation is the most frequently mutated gene in human breast cancers and primarily overlaps in HER2+ as well as ER+ breast cancers, the subset of patients bearing PIK3CA activating mutation does not get fullest benefit from either anti-HER2 or anti-hormonal agents. Literature also suggests that these patients may have chemotherapy resistance. Indeed, multiple clinical trials are currently evaluating the efficacy of over 30 drugs targeting different nodal points in the PI3K-AKT-mTOR pathway in breast and other cancers. However, to date, responses of solid tumors to PI3K pathway inhibitor monotherapy remains modest with an accompanied rapid emergences of drug resistance. MYC elevation represents one of the potential modes of actions by which breast tumors develop resistance to the PI3K pathway-specific targeted therapies. As products of oncogenes, both MYC and PIK3CA are well-established onco-proteins which contribute to breast oncogenesis. However, their similarities out number their dissimilarities in the context of their specific oncogenic cellular signals. In this review we will describe the specific cellular signals initiated following alteration in the MYC gene and PIK3CA gene in breast cancers. We will interrogate how MYC gene alterations influence the action of PI3K pathway targeted drugs in the context of PIK3CA mutation towards the development PI3K inhibitor induced drug-resistance in breast cancers. PMID:25628917

  13. MYC-xing it up with PIK3CA mutation and resistance to PI3K inhibitors: summit of two giants in breast cancers

    PubMed Central

    Dey, Nandini; Leyland-Jones, Brian; De, Pradip

    2015-01-01

    Approximately 35% of breast cancers exhibit PIK3CA activating mutation. Since PIK3CA hotspot mutation is the most frequently mutated gene in human breast cancers and primarily overlaps in HER2+ as well as ER+ breast cancers, the subset of patients bearing PIK3CA activating mutation does not get fullest benefit from either anti-HER2 or anti-hormonal agents. Literature also suggests that these patients may have chemotherapy resistance. Indeed, multiple clinical trials are currently evaluating the efficacy of over 30 drugs targeting different nodal points in the PI3K-AKT-mTOR pathway in breast and other cancers. However, to date, responses of solid tumors to PI3K pathway inhibitor monotherapy remains modest with an accompanied rapid emergences of drug resistance. MYC elevation represents one of the potential modes of actions by which breast tumors develop resistance to the PI3K pathway-specific targeted therapies. As products of oncogenes, both MYC and PIK3CA are well-established onco-proteins which contribute to breast oncogenesis. However, their similarities out number their dissimilarities in the context of their specific oncogenic cellular signals. In this review we will describe the specific cellular signals initiated following alteration in the MYC gene and PIK3CA gene in breast cancers. We will interrogate how MYC gene alterations influence the action of PI3K pathway targeted drugs in the context of PIK3CA mutation towards the development PI3K inhibitor induced drug-resistance in breast cancers. PMID:25628917

  14. 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. PMID:26832731

  15. mTOR Co-Targeting in Cetuximab Resistance in Head and Neck Cancers Harboring PIK3CA and RAS Mutations

    PubMed Central

    Wang, Zhiyong; Martin, Daniel; Molinolo, Alfredo A.; Patel, Vyomesh; Iglesias-Bartolome, Ramiro; Sol Degese, Maria; Vitale-Cross, Lynn; Gutkind, J. Silvio

    2014-01-01

    Background Cetuximab, a monoclonal blocking antibody against the epidermal growth factor receptor EGFR, has been approved for the treatment of squamous cell carcinomas of the head and neck (HNSCC). However, only few patients display long-term responses, prompting the search for cetuximab resistance mechanisms and new therapeutic options enhancing cetuximab effectiveness. Methods Cetuximab-sensitive HNSCC cells were retro-engineered to express PIK3CA and RAS oncogenes. These cells and HNSCC cells harboring endogenous PIK3CA and RAS oncogenes were xenografted into mice (n = 10 per group) and studied for their biochemical, antitumor, antiangiogenic, and antilymphangiogenic responses to cetuximab and mTOR targeting agents. All P values are two-sided. Results Cetuximab treatment of PIK3CA- and RAS-expressing HNSCC xenografts promoted an initial antitumor response, but all tumors relapsed within few weeks. In these tumors, cetuximab did not decrease the activity of mTOR, a downstream signaling target of EGFR, PIK3CA, and RAS. The combined administration of cetuximab and mTOR inhibitors exerted a remarkably increased antitumor activity, particularly in HNSCC cells that are resistant to cetuximab as a single agent. Indeed, cotargeting mTOR together with cetuximab caused a rapid tumor collapse of both PIK3CA- and RAS-expressing HNSCC xenografts (P < .001), concomitant with reduced proliferation (P < .001) and lymphangiogenesis (P < .001). Conclusion The presence of PIK3CA and RAS mutations and other alterations affecting the mTOR pathway activity in HNSCC could be exploited to predict the potential resistance to cetuximab, and to select the patients that may benefit the most from the concomitant administration of cetuximab and PI3K and/or mTOR inhibitors as a precision molecular therapeutic option for HNSCC patients. PMID:25099740

  16. Molecular and Functional Characterization of Three Different Postzygotic Mutations in PIK3CA-Related Overgrowth Spectrum (PROS) Patients: Effects on PI3K/AKT/mTOR Signaling and Sensitivity to PIK3 Inhibitors

    PubMed Central

    Forte, Giovanna; Bagnulo, Rosanna; Stella, Alessandro; Lastella, Patrizia; Cutrone, Mario; Benedicenti, Francesco; Susca, Francesco C.; Patruno, Margherita; Varvara, Dora; Germani, Aldo; Chessa, Luciana; Laforgia, Nicola; Tenconi, Romano; Simone, Cristiano; Resta, Nicoletta

    2015-01-01

    Background PIK3CA-related overgrowth spectrum (PROS) include a group of disorders that affect only the terminal portion of a limb, such as type I macrodactyly, and conditions like fibroadipose overgrowth (FAO), megalencephaly-capillary malformation (MCAP) syndrome, congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies (CLOVES) syndrome and Hemihyperplasia Multiple Lipomatosis (HHML). Heterozygous postzygotic PIK3CA mutations are frequently identified in these syndromes, while timing and tissue specificity of the mutational event are likely responsible for the extreme phenotypic variability observed. Methods We carried out a combination of Sanger sequencing and targeted deep sequencing of genes involved in the PI3K/AKT/mTOR pathway in three patients (1 MCAP and 2 FAO) to identify causative mutations, and performed immunoblot analyses to assay the phosphorylation status of AKT and P70S6K in affected dermal fibroblasts. In addition, we evaluated their ability to grow in the absence of serum and their response to the PI3K inhibitors wortmannin and LY294002 in vitro. Results and Conclusion Our data indicate that patients’ cells showed constitutive activation of the PI3K/Akt pathway. Of note, PI3K pharmacological blockade resulted in a significant reduction of the proliferation rate in culture, suggesting that inhibition of PI3K might prove beneficial in future therapies for PROS patients. PMID:25915946

  17. 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. PMID:27369359

  18. 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.

  19. 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.

  20. 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

  1. Combined inhibition of MEK and Aurora A kinase in KRAS/PIK3CA double-mutant colorectal cancer models.

    PubMed

    Davis, S Lindsey; Robertson, Kelli M; Pitts, Todd M; Tentler, John J; Bradshaw-Pierce, Erica L; Klauck, Peter J; Bagby, Stacey M; Hyatt, Stephanie L; Selby, Heather M; Spreafico, Anna; Ecsedy, Jeffrey A; Arcaroli, John J; Messersmith, Wells A; Tan, Aik Choon; Eckhardt, S Gail

    2015-01-01

    Aurora A kinase and MEK inhibitors induce different, and potentially complementary, effects on the cell cycle of malignant cells, suggesting a rational basis for utilizing these agents in combination. In this work, the combination of an Aurora A kinase and MEK inhibitor was evaluated in pre-clinical colorectal cancer models, with a focus on identifying a subpopulation in which it might be most effective. Increased synergistic activity of the drug combination was identified in colorectal cancer cell lines with concomitant KRAS and PIK3CA mutations. Anti-proliferative effects were observed upon treatment of these double-mutant cell lines with the drug combination, and tumor growth inhibition was observed in double-mutant human tumor xenografts, though effects were variable within this subset. Additional evaluation suggests that degree of G2/M delay and p53 mutation status affect apoptotic activity induced by combination therapy with an Aurora A kinase and MEK inhibitor in KRAS and PIK3CA mutant colorectal cancer. Overall, in vitro and in vivo testing was unable to identify a subset of colorectal cancer that was consistently responsive to the combination of a MEK and Aurora A kinase inhibitor. PMID:26136684

  2. Combined inhibition of MEK and Aurora A kinase in KRAS/PIK3CA double-mutant colorectal cancer models

    PubMed Central

    Davis, S. Lindsey; Robertson, Kelli M.; Pitts, Todd M.; Tentler, John J.; Bradshaw-Pierce, Erica L.; Klauck, Peter J.; Bagby, Stacey M.; Hyatt, Stephanie L.; Selby, Heather M.; Spreafico, Anna; Ecsedy, Jeffrey A.; Arcaroli, John J.; Messersmith, Wells A.; Tan, Aik Choon; Eckhardt, S. Gail

    2015-01-01

    Aurora A kinase and MEK inhibitors induce different, and potentially complementary, effects on the cell cycle of malignant cells, suggesting a rational basis for utilizing these agents in combination. In this work, the combination of an Aurora A kinase and MEK inhibitor was evaluated in pre-clinical colorectal cancer models, with a focus on identifying a subpopulation in which it might be most effective. Increased synergistic activity of the drug combination was identified in colorectal cancer cell lines with concomitant KRAS and PIK3CA mutations. Anti-proliferative effects were observed upon treatment of these double-mutant cell lines with the drug combination, and tumor growth inhibition was observed in double-mutant human tumor xenografts, though effects were variable within this subset. Additional evaluation suggests that degree of G2/M delay and p53 mutation status affect apoptotic activity induced by combination therapy with an Aurora A kinase and MEK inhibitor in KRAS and PIK3CA mutant colorectal cancer. Overall, in vitro and in vivo testing was unable to identify a subset of colorectal cancer that was consistently responsive to the combination of a MEK and Aurora A kinase inhibitor. PMID:26136684

  3. PIK3CA rs7640662 (C/G) single nucleotide polymorphism lacks association with breast cancer cases in Persians

    PubMed Central

    Mir, Atefeh; Sadegh, Mahdiyeh Harati; Ahmadinia, Zahra

    2015-01-01

    Phosphatidylinositol-3-kinase (PI3K) is a group of enzymes involved in cellular growth, proliferation, differentiation, cell motility, intracellular trafficking, and survival that play very important roles in developing breast cancer. PIK3CA is a gene that encodes α catalytic subunit of this enzyme. A common polymorphism of PIK3CA, rs7640662 (C/G), was analyzed, and its association to breast cancer cases was determined. In this study, DNA was extracted from peripheral blood samples of 278 women suffering from breast cancer and 128 healthy women. Tetra-primer amplification refractory mutation system polymerase chain reaction (T-ARMS-PCR) method was performed to genotype rs7640662. P values and ODD ratios were measured using SPSS. P value less than 0.05 and ODD ratios more than 1 were considered as significant. All ODD ratios were less than 1, and P values were more than 0.05 showing that rs7640662 (C/G) and breast cancer are not significantly associated. However, the genotypes observed in the Persian population, as an ancient population living in the Middle East, was significantly different from the genotypes reported by HapMap for Asian populations. As a conclusion, rs7640662 was not associated with the risk of breast cancer in a Persian population; however, it was observed that heterozygote (GC) is the most common genotypes in both case and control samples. PMID:25838920

  4. Clinicopathologic Significance of HNF-1β, AIRD1A, and PIK3CA Expression in Ovarian Clear Cell Carcinoma

    PubMed Central

    Ye, Shuang; Yang, Jiaxin; You, Yan; Cao, Dongyan; Huang, Huifang; Wu, Ming; Chen, Jie; Lang, Jinghe; Shen, Keng

    2016-01-01

    Abstract Ovarian clear cell carcinoma (CCC) is a distinct histologic subtype with relatively poor survival. No prognostic or predictive molecular marker is currently available. Recent studies have shown that AT-rich interactive domain 1A (ARID1A) and phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutations are common genetic changes in ovarian CCC. Hepatocyte nuclear factor-1β (HNF-1β) expression has been proven to be highly sensitive and specific for clear cell histology. However, the correlations between these biomarkers and clinicopathologic variables and survival outcomes are controversial. The immunohistochemical analysis for HNF-1β, ARID1A, and PIK3CA was performed on a tissue microarray (TMA) consisting of 130 cases of ovarian CCC (237 tissue blocks) linked with clinical information. The immunostaining results were interpreted in a manner consistent with previous publications. The associations between biomarker expression and clinical and prognostic features were examined. All statistical analyses were conducted using 2-sided tests, and a value of P < 0.05 was considered significant. HNF-1β was expressed in 92.8% of all primary ovarian tumors, while the loss of ARID1A and PIK3CA was noted in 56.2% and 45.0%, respectively. Early-stage tumors tended to have high levels of HNF-1β immunoreactivity and expression of ARID1A (P = 0.02 and P = 0.03). Most patients (76.9%, 20/26) with concurrent endometriosis stained negative for ARID1A (P = 0.02). No relation was found between PIK3CA expression and clinical features. Low-level HNF-1β expression and loss of ARID1A were more commonly observed in patients with tumor recurrence (P = 0.02 and P < 0.001). Antibody expression was not associated with platinum-based chemotherapy response. Patients with negative ARID1A expression had worse survival outcome in terms of both overall survival (OS) and progression-free survival (PFS) (P = 0.03 and P = 0.01, respectively). On

  5. Sister Mary Joseph nodule-A case report with review of literature

    PubMed Central

    Dar, Ishrat Hussain; Kamili, Mqtasid Ahmed; Dar, Showkat Hussain; Kuchaai, Faiz Ahmed

    2009-01-01

    Sister Mary Joseph nodule or Sister Mary Joseph Sign refers to a palpable nodule bulging into the umbilicus as a result of metastasis of a malignant cancer in the pelvis or abdomen. A rare case of Sister Mary Joseph nodule, manifesting as ascites, cachexia and bleeding per rectum, is presented without any primary tumor despite extensive search for the same. PMID:21772912

  6. 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... Movement Reporting System Areas and Reporting Points § 161.45 Vessel Traffic Service St. Marys River. (a) The VTS area consists of the navigable waters of the St. Marys River and lower Whitefish Bay from...

  7. 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... Movement Reporting System Areas and Reporting Points § 161.45 Vessel Traffic Service St. Marys River. (a) The VTS area consists of the navigable waters of the St. Marys River and lower Whitefish Bay from...

  8. 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... Movement Reporting System Areas and Reporting Points § 161.45 Vessel Traffic Service St. Marys River. (a) The VTS area consists of the navigable waters of the St. Marys River and lower Whitefish Bay from...

  9. The PI3K regulatory subunit gene PIK3R1 is under direct control of androgens and repressed in prostate cancer cells

    PubMed Central

    Munkley, Jennifer; Livermore, Karen E.; McClurg, Urszula L.; Kalna, Gabriela; Knight, Bridget; McCullagh, Paul; McGrath, John; Crundwell, Malcolm; Leung, Hing Y.; Robson, Craig N.; Harries, Lorna W.; Rajan, Prabhakar; Elliott, David J.

    2015-01-01

    Androgen receptor (AR) signalling and the PI3K pathway mediate survival signals in prostate cancer, and have been shown to regulate each other by reciprocal negative feedback, such that inhibition of one activates the other. Understanding the reciprocal regulation of these pathways is important for disease management as tumour cells can adapt and survive when either single pathway is inhibited pharmacologically. We recently carried out genome-wide exon-specific profiling of prostate cancer cells to identify novel androgen-regulated transcriptional events. Here we interrogated this dataset for novel androgen-regulated genes associated with the PI3K pathway. We find that the PI3K regulatory subunits PIK3R1 (p85α) and PIK3R3 (p55γ) are direct targets of the AR which are rapidly repressed by androgens in LNCaP cells. Further characterisation revealed that the PIK3CA p110α catalytic subunit is also indirectly regulated by androgens at the protein level. We show that PIK3R1 mRNA is significantly under-expressed in prostate cancer (PCa) tissue, and provide data to suggest a context-dependent regulatory mechanism whereby repression of the p85α protein by the AR results in destabilisation of the PI3K p110α catalytic subunit and downstream PI3K pathway inhibition that functionally affects the properties of prostate cancer cells. PMID:26501081

  10. Activating Mutations in PIK3CB Confer Resistance to PI3K Inhibition and Define a Novel Oncogenic Role for p110β.

    PubMed

    Nakanishi, Yoshito; Walter, Kimberly; Spoerke, Jill M; O'Brien, Carol; Huw, Ling Y; Hampton, Garret M; Lackner, Mark R

    2016-03-01

    Activation of the PI3K pathway occurs commonly in a wide variety of cancers. Experience with other successful targeted agents suggests that clinical resistance is likely to arise and may reduce the durability of clinical benefit. Here, we sought to understand mechanisms underlying resistance to PI3K inhibition in PTEN-deficient cancers. We generated cell lines resistant to the pan-PI3K inhibitor GDC-0941 from parental PTEN-null breast cancer cell lines and identified a novel PIK3CB D1067Y mutation in both cell lines that was recurrent in cancer patients. Stable expression of mutant PIK3CB variants conferred resistance to PI3K inhibition that could be overcome by downstream AKT or mTORC1/2 inhibitors. Furthermore, we show that the p110β D1067Y mutant was highly activated and induced PIP3 levels at the cell membrane, subsequently promoting the localization and activation of AKT and PDK1 at the membrane and driving PI3K signaling to a level that could withstand treatment with proximal inhibitors. Finally, we demonstrate that the PIK3CB D1067Y mutant behaved as an oncogene and transformed normal cells, an activity that was enhanced by PTEN depletion. Collectively, these novel preclinical and clinical findings implicate the acquisition of activating PIK3CB D1067 mutations as an important event underlying the resistance of cancer cells to selective PI3K inhibitors. PMID:26759240

  11. A Functional Variant at miR-520a Binding Site in PIK3CA Alters Susceptibility to Colorectal Cancer in a Chinese Han Population

    PubMed Central

    Ding, Lifang; Jiang, Zao; Chen, Qiaoyun; Qin, Rong; Fang, Yue

    2015-01-01

    An increasing body of evidence has indicated that polymorphisms in the miRNA binding site of target gene can alter the ability of miRNAs to bind their target genes and modulate the risk of cancer. We aimed to investigate the association between a miR-520a binding site polymorphism rs141178472 in the PIK3CA 3′-UTR and the risk of colorectal cancer (CRC) in a Chinese Han population. The polymorphism rs141178472 was analyzed in a case-control study, including 386 CRC patients and 394 age- and sex-matched controls; the relationship between the polymorphism and the risk of colorectal cancer was examined. Individuals carrying the rs141178472 CC genotype or C allele had an increased risk of developing CRC (CC versus TT, OR (95% CI): 1.716 (1.084–2.716), P = 0.022; C versus T, OR (95% CI): 1.258 (1.021–1.551), P = 0.033). Furthermore, the expression of PIK3CA was detected in the peripheral blood mononucleated cell of CRC patients, suggesting that mRNA levels of PIK3CA might be associated with SNP rs141178472. These findings provide evidence that a miR-520a binding site polymorphism rs141178472 in the PIK3CA 3′-UTR may play a role in the etiology of CRC. PMID:25834816

  12. De novo PIK3R1 gain-of-function with recurrent sinopulmonary infections, long-lasting chronic CMV-lymphadenitis and microcephaly.

    PubMed

    Kuhlen, Michaela; Hönscheid, Andrea; Loizou, Loizos; Nabhani, Schafiq; Fischer, Ute; Stepensky, Polina; Schaper, Jörg; Klapper, Wolfram; Siepermann, Meinolf; Schuster, Friedhelm; Meisel, Roland; Borkhardt, Arndt

    2016-01-01

    PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1) gain-of-function has recently been described in patients with recurrent sinopulmonary infections, chronic CMV-/EBV-infections, lymphoproliferation, and hypogammaglobulinemia. Here we report a 15-year-old boy with treatment refractory CMV lymphadenitis, severe combined immunodeficiency, microcephaly and a severe developmental defect of Th17 cells. To avoid poor outcome, hematopoietic stem cell transplantation (HSCT) was performed. Subsequently, whole exome sequencing revealed a de novo heterozygous G-to-C mutation (chr5: 5:67,589,663: G>C) at the splice donor site of the PIK3R1 gene. Our data suggest that PIK3R1 gain-of-function leads to developmental defects in helper and regulatory T-cell subsets, the latter expanding the immunological features of PIK3R1 gain-of-function. T-cell subsets play a critical role in the regulation of immune response against infectious agents and of autoimmunity and thus may be particularly accountable for the clinical phenotype of affected patients. PMID:26529633

  13. 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 "Post" were special…

  14. Restructuring the system will benefit all. Interview by Mary Grayson.

    PubMed

    Roberts, C C

    1992-08-20

    Carolyn Roberts, president and CEO of Copley Health Systems Inc., Morrisville, VT, is the new chairman-elect designate of the American Hospital Association. In an exclusive interview with Hospitals Editor Mary Grayson, she shares her perspectives on health care reform, restructuring the delivery system, and the role of trustees. PMID:1644407

  15. 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)

  16. Mary Tyler Moore Helps Launch NIH MedlinePlus Magazine

    MedlinePlus

    ... Javascript on. Among those attending the NIH MedlinePlus magazine launch on Capitol Hill were (l-r) NIH Director Dr. Elias Zerhouni, Rep. Ralph Regula (R-OH), Mary Tyler Moore, former Rep. Paul Rogers, and NLM ... issue of NIH MedlinePlus magazine. In September, the FNLM was fortunate to have ...

  17. 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…

  18. SOURCE WATER CONTROL WITHIN THE MARY MURPHY MINE

    EPA Science Inventory

    The Mary Murphy mine is located in Chaffee County, Colorado, approximately 12 miles southwest from Buena Vista in the San Isabel National Forest.. The mine drains water from multiple portals into Chalk Creek; this mine water contains elevated levels of zinc and cadmium which exce...

  19. 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.

  20. 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

  1. 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. PMID:25535874

  2. 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…

  3. 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…

  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. 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 making of…

  6. 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 Missouri,…

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

    ERIC Educational Resources Information Center

    Sinclair, Anne

    2004-01-01

    In her response to Mary Reichling's article "Intersections: Form, Feeling, and Isomorphism, Anne Sinclair believes that the exploration of form, feeling, and isomorphism in the writings of Susanne Langer accomplishes its goal to examine and elucidate aspects of these concepts. Sinclair finds several of the ideas presented very engaging. Musical…

  9. Agnes Mary Clerke: Ever-popular historian of astronomy

    NASA Astrophysics Data System (ADS)

    Brück, M.

    In her day, Agnes Mary Clerke (1842-1907) was the English-speaking world's most highly regarded writer on the rapidly developing science of astrophysics. This account outlines how, without any formal education but with a deep interest in learning, this remarkable woman rose to the admired position she still holds as a leading historian of astronomy and astrophysics.

  10. 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…

  11. 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…

  12. 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…

  13. Taselisib (GDC-0032), a Potent β-Sparing Small Molecule Inhibitor of PI3K, Radiosensitizes Head and Neck Squamous Carcinomas Containing Activating PIK3CA Alterations

    PubMed Central

    Zumsteg, Zachary S.; Morse, Natasha; Krigsfeld, Gabriel; Gupta, Gaorav; Higginson, Daniel S.; Lee, Nancy Y.; Morris, Luc; Ganly, Ian; Shiao, Stephan L.; Powell, Simon N.; Chung, Christine H.; Scaltriti, Maurizio; Baselga, José

    2016-01-01

    Purpose Activating PIK3CA genomic alterations are frequent in head and neck squamous cell carcinoma (HNSCC), and there is an association between phosphoinositide 3-kinase (PI3K) signaling and radioresistance. Hence, we investigated the therapeutic efficacy of inhibiting PI3K with GDC-0032, a PI3K inhibitor with potent activity against p110α, in combination with radiation in HNSCC. Experimental Design The efficacy of GDC-0032 was assessed in vitro in 26 HNSCC cell lines with crystal violet proliferation assays, and changes in PI3K signaling were measured by Western blot analysis. Cytotoxicity and radiosensitization were assessed with Annexin V staining via flow cytometry and clonogenic survival assays, respectively. DNA damage repair was assessed with immunofluorescence for γH2AX foci, and cell cycle analysis was performed with flow cytometry. In vivo efficacy of GDC-0032 and radiation was assessed in xenografts implanted into nude mice. Results GDC-0032 inhibited potently PI3K signaling and displayed greater antiproliferative activity in HNSCC cell lines with PIK3CA mutations or amplification, whereas cell lines with PTEN alterations were relatively resistant to its effects. Pretreatment with GDC-0032 radiosensitized PIK3CA-mutant HNSCC cells, enhanced radiation-induced apoptosis, impaired DNA damage repair, and prolonged G2–M arrest following irradiation. Furthermore, combined GDC-0032 and radiation was more effective than either treatment alone in vivo in subcutaneous xenograft models. Conclusions GDC-0032 has increased potency in HNSCC cell lines harboring PIK3CA-activating aberrations. Further, combined GDC-0032 and radiotherapy was more efficacious than either treatment alone in PIK3CA-altered HNSCC in vitro and in vivo. This strategy warrants further clinical investigation PMID:26589432

  14. 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.

  15. Breast Cancer Heterogeneity Examined by High-Sensitivity Quantification of PIK3CA, KRAS, HRAS, and BRAF Mutations in Normal Breast and Ductal Carcinomas.

    PubMed

    Myers, Meagan B; Banda, Malathi; McKim, Karen L; Wang, Yiying; Powell, Michael J; Parsons, Barbara L

    2016-04-01

    Mutant cancer subpopulations have the potential to derail durable patient responses to molecularly targeted cancer therapeutics, yet the prevalence and size of such subpopulations are largely unexplored. We employed the sensitive and quantitative Allele-specific Competitive Blocker PCR approach to characterize mutant cancer subpopulations in ductal carcinomas (DCs), examining five specific hotspot point mutations (PIK3CA H1047R, KRAS G12D, KRAS G12V, HRAS G12D, and BRAF V600E). As an approach to aid interpretation of the DC results, the mutations were also quantified in normal breast tissue. Overall, the mutations were prevalent in normal breast and DCs, with 9/9 DCs having measureable levels of at least three of the five mutations. HRAS G12D was significantly increased in DCs as compared to normal breast. The most frequent point mutation reported in DC by DNA sequencing, PIK3CA H1047R, was detected in all normal breast tissue and DC samples and was present at remarkably high levels (mutant fractions of 1.1 × 10(-3) to 4.6 × 10(-2)) in 4/10 normal breast samples. In normal breast tissue samples, PIK3CA mutation levels were positively correlated with age. However, the PIK3CA H1047R mutant fraction distributions for normal breast tissues and DCs were similar. The results suggest PIK3CA H1047R mutant cells have a selective advantage in breast, contribute to breast cancer susceptibility, and drive tumor progression during breast carcinogenesis, even when present as only a subpopulation of tumor cells. PMID:27108388

  16. Mutations in PI3K/AKT pathway genes and amplifications of PIK3CA are associated with patterns of recurrence in gastric cancers

    PubMed Central

    Fang, Wen-Liang; Huang, Kuo-Hung; Lan, Yuan-Tzu; Lin, Chien-Hsing; Chen, Ming-Huang; Chao, Yee; Lin, Wen-Chang; Lo, Su-Shun; Li, Anna Fen-Yau; Wu, Chew-Wun; Chiou, Shih-Hwa

    2016-01-01

    Mutations in genes involved in the PI3K/AKT pathway and amplifications of the PIK3CA gene in gastric cancer and their associations with clinicopathological characteristics and EBV infection were analyzed in this study. A total of 431 patients with gastric adenocarcinomas were enrolled, and 39 mutation hotspots were evaluated in these patients using MALDI-TOF mass spectrometry were analyzed. PIK3CA amplifications were analyzed using real-time quantitative PCR. Regarding patients with intestinal-type gastric cancer, those with mutations in PI3K/AKT pathway genes were also more likely to have tumors located in the lower-third of the stomach than were those without mutations. Regarding patients with diffuse-type gastric cancer, those with PI3K/AKT pathway mutations were more likely to have tumors located in the upper-third of the stomach and to have more hematogenous metastases, particularly in the liver and lungs, than were patients without such mutations (22.2% vs. 4.5%). No significant survival difference was observed between patients with vs. without PI3K/AKT pathway mutations. Mutations in PI3K/AKT pathway genes were associated with hematogenous metastasis in patients with diffuse-type gastric cancer. Only when the tumors were located in the middle-third of stomach, tumor with mutations of the PIK3CA gene or mutations of the PI3K/AKT pathway genes were associated with more EBV infection than those without mutations. Patients with PIK3CA amplifications were more likely to have diffuse-type and poorly differentiated gastric cancers and were more likely to experience peritoneal recurrence compared with those without PIK3CA amplifications. Even upon subgroup analysis, PI3KCA amplifications were found to not affect the patients’ outcomes. PMID:26701847

  17. Breast Cancer Heterogeneity Examined by High-Sensitivity Quantification of PIK3CA, KRAS, HRAS, and BRAF Mutations in Normal Breast and Ductal Carcinomas12

    PubMed Central

    Myers, Meagan B.; Banda, Malathi; McKim, Karen L.; Wang, Yiying; Powell, Michael J.; Parsons, Barbara L.

    2016-01-01

    Mutant cancer subpopulations have the potential to derail durable patient responses to molecularly targeted cancer therapeutics, yet the prevalence and size of such subpopulations are largely unexplored. We employed the sensitive and quantitative Allele-specific Competitive Blocker PCR approach to characterize mutant cancer subpopulations in ductal carcinomas (DCs), examining five specific hotspot point mutations (PIK3CA H1047R, KRAS G12D, KRAS G12V, HRAS G12D, and BRAF V600E). As an approach to aid interpretation of the DC results, the mutations were also quantified in normal breast tissue. Overall, the mutations were prevalent in normal breast and DCs, with 9/9 DCs having measureable levels of at least three of the five mutations. HRAS G12D was significantly increased in DCs as compared to normal breast. The most frequent point mutation reported in DC by DNA sequencing, PIK3CA H1047R, was detected in all normal breast tissue and DC samples and was present at remarkably high levels (mutant fractions of 1.1 × 10− 3 to 4.6 × 10− 2) in 4/10 normal breast samples. In normal breast tissue samples, PIK3CA mutation levels were positively correlated with age. However, the PIK3CA H1047R mutant fraction distributions for normal breast tissues and DCs were similar. The results suggest PIK3CA H1047R mutant cells have a selective advantage in breast, contribute to breast cancer susceptibility, and drive tumor progression during breast carcinogenesis, even when present as only a subpopulation of tumor cells. PMID:27108388

  18. Somatic Mutations in the Notch, NF-KB, PIK3CA, and Hedgehog Pathways in Human Breast Cancers

    PubMed Central

    Jiao, Xiang; Wood, Laura; Lindman, Monica; Jones, Sian; Buckhaults, Phillip; Polyak, Kornelia; Sukumar, Saraswati; Carter, Hannah; Kim, Dewey; Karchin, Rachel; Sjöblom, Tobias

    2012-01-01

    Exome sequencing of human breast cancers has revealed a substantial number of candidate cancer genes with recurring but infrequent somatic mutations. To determine more accurately their mutation prevalence, we performed a mutation analysis of 36 novel candidate cancer genes in 96 human breast cancers. Somatic mutations with potential impact on protein function were observed in the genes ADAM12, CENTB1, CENTG1, DIP2C, GLI1, GRIN2D, HDLBP, IKBKB, KPNA5, NFKB1, NOTCH1, and OTOF. These findings strengthen the evidence for involvement of the Notch, Hedgehog, NF-KB, and PIK3CA pathways in breast cancer development, and point to novel processes that likely are involved. PMID:22302350

  19. 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.

  20. Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature.

    PubMed

    Petrovski, Slavé; Parrott, Roberta E; Roberts, Joseph L; Huang, Hongxiang; Yang, Jialong; Gorentla, Balachandra; Mousallem, Talal; Wang, Endi; Armstrong, Martin; McHale, Duncan; MacIver, Nancie J; Goldstein, David B; Zhong, Xiao-Ping; Buckley, Rebecca H

    2016-07-01

    The purpose of this research was to use next generation sequencing to identify mutations in patients with primary immunodeficiency diseases whose pathogenic gene mutations had not been identified. Remarkably, four unrelated patients were found by next generation sequencing to have the same heterozygous mutation in an essential donor splice site of PIK3R1 (NM_181523.2:c.1425 + 1G > A) found in three prior reports. All four had the Hyper IgM syndrome, lymphadenopathy and short stature, and one also had SHORT syndrome. They were investigated with in vitro immune studies, RT-PCR, and immunoblotting studies of the mutation's effect on mTOR pathway signaling. All patients had very low percentages of memory B cells and class-switched memory B cells and reduced numbers of naïve CD4+ and CD8+ T cells. RT-PCR confirmed the presence of both an abnormal 273 base-pair (bp) size and a normal 399 bp size band in the patient and only the normal band was present in the parents. Following anti-CD40 stimulation, patient's EBV-B cells displayed higher levels of S6 phosphorylation (mTOR complex 1 dependent event), Akt phosphorylation at serine 473 (mTOR complex 2 dependent event), and Akt phosphorylation at threonine 308 (PI3K/PDK1 dependent event) than controls, suggesting elevated mTOR signaling downstream of CD40. These observations suggest that amino acids 435-474 in PIK3R1 are important for its stability and also its ability to restrain PI3K activity. Deletion of Exon 11 leads to constitutive activation of PI3K signaling. This is the first report of this mutation and immunologic abnormalities in SHORT syndrome. PMID:27076228

  1. mTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer.

    PubMed

    Chen, Yaqing; Qian, Jianchang; He, Qun; Zhao, Hui; Toral-Barza, Lourdes; Shi, Celine; Zhang, Xuesai; Wu, Jiang; Yu, Ker

    2016-05-01

    The mechanistic target of rapamycin (mTOR) is a major regulator of cell growth and is frequently dysregulated in cancer. While mTOR complex-1 (mTORC1) is a validated cancer target, the role of mTOR complex-2 (mTORC2) remains less defined. Here, we reveal mTORC2 as a critical regulator of breast cancer metabolism. We showed that hyperphosphorylation in ATP citrate lyase (ACL) occurs frequently in human breast tumors and correlates well with HER2+ and/or PIK3CA-mutant (HER2+/PIK3CAmut) status in breast tumor cell lines. In HER2+/PIK3CAmut cells, mTORC2 controls Ser-455 phosphorylation of ACL thereby promoting acetyl-CoA production, de novo lipogenesis and mitochondrial physiology, all of which were inhibited by an mTORC1/mTORC2 kinase inhibitor (mTOR-KI) or cellular depletion of mTORC2 or ACL. mTOR-KI but not rapamycin blocked the IGF-1-induced ACL phosphorylation and glucose to lipid conversion. Depletion of mTORC2 but not mTORC1 specifically inhibited the ACL-dependent acetyl-CoA production. In the HER2+/PIK3CAmut MDA361, MDA453, BT-474 and T47D cells, depletion of mTORC2 or ACL led to growth inhibition and mitochondrial hyperpolarization, which were partially rescued by an alternate source of acetyl-CoA. These same changes were not apparent in mTORC2- or ACL-depleted HER2-/PIK3CAwt MDA231 and HCC1806 cells, highlighting a differential dependence of mTORC2-ACL for survival in these two cell types. Moreover, ACL Ser-455 mutants S455E (phosphomimetic) and S455A (non-phosphorylatable) each increased or decreased, respectively, the acetyl-CoA production, mitochondrial homeostasis and survival in ACL-depleted MDA453 cells. These studies define a new and rapamycin-resistant mechanism of mTORC2-ACL in lipogenesis and acetyl-CoA biology and provide a rationale for targeting of mTORC1 and mTORC2 in HER2+/PIK3CAmut breast cancer. PMID:27015560

  2. Diagnostic Accuracy of PIK3CA Mutation Detection by Circulating Free DNA in Breast Cancer: A Meta-Analysis of Diagnostic Test Accuracy

    PubMed Central

    Zhu, Hanjiang; Lin, Yan; Pan, Bo; Zhang, Xiaohui; Huang, Xin; Xu, Qianqian; Xu, Yali; Sun, Qiang

    2016-01-01

    Mutation of p110 alpha-catalytic subunit of phosphatidylinositol 3-kinase (PIK3CA) has high predictive and prognostic values for breast cancer. Hence, there has been a marked interest in detecting and monitoring PIK3CA genotype with non-invasive technique, such as circulating free DNA (cfDNA). However, the diagnostic accuracy of PIK3CA genotyping by cfDNA is still a problem of controversy. Here, we conducted the first meta-analysis to evaluate overall diagnostic performance of cfDNA for PIK3CA mutation detection. Literature search was performed in Pubmed, Embase and Cochrane Central Register of Controlled Trials databases. Seven cohorts from five studies with 247 patients were included. The pooled sensitivity, specificity, positive and negative likelihood ratio, diagnostic odds ratio and area under summary receiver operating characteristic curve were calculated for accuracy evaluation. The pooled sensitivity and specificity were 0.86 (95% confidence interval [CI] 0.32–0.99) and 0.98 (95% CI 0.86–1.00), respectively; the pooled positive and negative likelihood ratio were 42.8 (95% CI 5.1–356.9) and 0.14 (95% CI 0.02–1.34), respectively; diagnostic odds ratio for evaluating the overall diagnostic performance was 300 (95% CI 8–11867); area under summary receiver operating characteristic curve reached 0.99 (95% CI 0.97–0.99). Subgroup analysis with metastatic breast cancer revealed remarkable improvement in diagnostic performance (sensitivity: 0.86–0.91; specificity: 0.98; diagnostic odds ratio: 300–428). This meta-analysis proved that detecting PIK3CA gene mutation by cfDNA has high diagnostic accuracy in breast cancer, especially for metastatic breast cancer. It may serve as a reliable non-invasive assay for detecting and monitoring PIK3CA mutation status in order to deliver personalized and precise treatment. PMID:27336598

  3. 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

  4. 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. PMID:25201224

  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. 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. PMID:26502660

  7. Production of the neutron-rich hypernucleus 10LambdaLi in the (pi-,K+) double charge-exchange reaction.

    PubMed

    Saha, P K; Fukuda, T; Imoto, W; Ahn, J K; Ajimura, S; Aoki, K; Bhang, H C; Fujioka, H; Hotchi, H; Hwang, J I; Itabashi, T; Kang, B H; Kim, H D; Kim, M J; Kishimoto, T; Krutenkova, A; Maruta, T; Miura, Y; Miwa, K; Nagae, T; Noumi, H; Outa, H; Ohtaki, T; Sakaguchi, A; Sato, Y; Sekimoto, M; Shimizu, Y; Tamura, H; Tanida, K; Toyoda, A; Ukai, M; Yim, H J

    2005-02-11

    In order to produce a neutron-rich Lambda hypernucleus for the first time, we carried out an experiment by utilizing the (pi-,K+) double charge-exchange reaction on a 10B target. We observed the production of a 10LambdaLi hypernucleus. The cross section for the Lambda bound region was found to be 11.3+/-1.9 nb/sr with the 1.2 GeV/c incident momentum, which is compared with the 10LambdaB hypernucleus production cross section, 7.8+/-0.3 microb/sr, in the (pi+,K+) reaction with a 1.05 GeV/c incident momentum beam. PMID:15783631

  8. 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

  9. High-resolution mapping, cloning and molecular characterization of the Pi-k ( h ) gene of rice, which confers resistance to Magnaporthe grisea.

    PubMed

    Sharma, T R; Madhav, M S; Singh, B K; Shanker, P; Jana, T K; Dalal, V; Pandit, A; Singh, A; Gaikwad, K; Upreti, H C; Singh, N K

    2005-12-01

    In order to understand the molecular mechanisms involved in the gene-for-gene type of pathogen resistance, high-resolution genetic and physical mapping of resistance loci is required to facilitate map-based cloning of resistance genes. Here, we report the molecular mapping and cloning of a dominant gene (Pi-k ( h )) present in the rice line Tetep, which is associated with resistance to rice blast disease caused by Magnaporthe grisea. This gene is effective against M. grisea populations prevalent in the Northwestern Himalayan region of India. Using 178 sequence tagged microsatellite, sequence-tagged site, expressed sequence tag and simple sequence repeat (SSR) markers to genotype a population of 208 F(2) individuals, we mapped the Pi-k ( h ) gene between two SSR markers (TRS26 and TRS33) which are 0.7 and 0.5 cM away, respectively, and can be used in marker-assisted-selection for blast-resistant rice cultivars. We used the markers to identify the homologous region in the genomic sequence of Oryza sativa cv. Nipponbare, and a physical map consisting of two overlapping bacterial artificial chromosome and P1 artificial chromosome clones was assembled, spanning a region of 143,537 bp on the long arm of chromosome 11. Using bioinformatic analyses, we then identified a candidate blast-resistance gene in the region, and cloned the homologous sequence from Tetep. The putative Pi-k ( h ) gene cloned from Tetep is 1.5 kbp long with a single ORF, and belongs to the nucleotide binding site-leucine rich repeat class of disease resistance genes. Structural and expression analysis of the Pi-k ( h ) gene revealed that its expression is pathogen inducible. PMID:16228246

  10. 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

  11. 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

  12. BRAF, PIK3CA, and HER2 Oncogenic Alterations According to KRAS Mutation Status in Advanced Colorectal Cancers with Distant Metastasis

    PubMed Central

    Koh, Jiwon; Kwak, Yoonjin; Seo, An Na; Park, Kyoung Un; Kim, Duck-Woo; Kang, Sung-Bum; Kim, Woo Ho; Lee, Hye Seung

    2016-01-01

    Background Anti-EGFR antibody–based treatment is an important therapeutic strategy for advanced colorectal cancer (CRC); despite this, several mutations—including KRAS, BRAF, and PIK3CA mutations, and HER2 amplification—are associated with the mechanisms underlying the development of resistance to anti-EGFR therapy. The aim of our study was to investigate the frequencies and clinical implications of these genetic alterations in advanced CRC. Methods KRAS, BRAF, and PIK3CA mutations were determined by Cobas real-time polymerase chain reaction (PCR) in 191 advanced CRC patients with distant metastasis. Microsatellite instability (MSI) status was determined by a fragmentation assay and HER2 amplification was assessed by silver in situ hybridization. In addition, KRAS mutations were investigated by the Sanger sequencing method in 97 of 191 CRC cases. Results Mutations in KRAS, BRAF, and PIK3CA were found in 104 (54.5%), 6 (3.1%), and 25 (13.1%) cases of advanced CRC, respectively. MSI-high status and HER2 amplification were observed in 3 (1.6%) and 16 (8.4%) cases, respectively. PIK3CA mutations were more frequently found in KRAS mutant type (18.3%) than KRAS wild type (6.9%) (P = 0.020). In contrast, HER2 amplifications and BRAF mutations were associated with KRAS wild type with borderline significance (P = 0.052 and 0.094, respectively). In combined analyses with KRAS, BRAF and HER2 status, BRAF mutations or HER2 amplifications were associated with the worst prognosis in the wild type KRAS group (P = 0.004). When comparing the efficacy of detection methods, the results of real time PCR analysis revealed 56 of 97 (57.7%) CRC cases with KRAS mutations, whereas Sanger sequencing revealed 49 cases (50.5%). Conclusions KRAS mutations were found in 54.5% of advanced CRC patients. Our results support that subgrouping using PIK3CA and BRAF mutation or HER2 amplification status, in addition to KRAS mutation status, is helpful for managing advanced CRC patients. PMID

  13. PIK3CA and TP53 Gene Mutations in Human Breast Cancer Tumors Frequently Detected by Ion Torrent DNA Sequencing

    PubMed Central

    Ye, Hua; Nandakumar, Vijayalakshmi; Wang, Zhuo; Chen, Lihong; Tang, Chuanning; Li, Jianhui; Li, Huijin; Zhang, Wei; Han, Wei; Lou, Feng; Zhang, Dandan; Sun, Hong; Dong, Haichao; Zhang, Guangchun; Liu, Zhiyuan; Dong, Zhishou; Guo, Baishuai; Yan, He; Yan, Chaowei; Wang, Lu; Su, Ziyi; Li, Yangyang; Jones, Lindsey; Huang, Xue F.; Chen, Si-Yi; Gao, Jinglong

    2014-01-01

    Breast cancer is the most common malignancy and the leading cause of cancer deaths in women worldwide. While specific genetic mutations have been linked to 5–10% of breast cancer cases, other environmental and epigenetic factors influence the development and progression of the cancer. Since unique mutations patterns have been observed in individual cancer samples, identification and characterization of the distinctive breast cancer molecular profile is needed to develop more effective target therapies. Until recently, identifying genetic cancer mutations via personalized DNA sequencing was impractical and expensive. The recent technological advancements in next-generation DNA sequencing, such as the semiconductor-based Ion Torrent sequencing platform, has made DNA sequencing cost and time effective with more reliable results. Using the Ion Torrent Ampliseq Cancer Panel, we sequenced 737 loci from 45 cancer-related genes to identify genetic mutations in 105 human breast cancer samples. The sequencing analysis revealed missense mutations in PIK3CA, and TP53 genes in the breast cancer samples of various histologic types. Thus, this study demonstrates the necessity of sequencing individual human cancers in order to develop personalized drugs or combination therapies to effectively target individual, breast cancer-specific mutations. PMID:24918944

  14. A novel PI3K inhibitor PIK-C98 displays potent preclinical activity against multiple myeloma

    PubMed Central

    Yu, Yang; Qi, Huixin; Han, Kunkun; Tang, Juan; Zhang, Zubin; Zeng, Yuanying; Cao, Biyin; Qiao, Chunhua; Zhang, Hongjian; Hou, Tingjun; Mao, Xinliang

    2015-01-01

    Recent clinical trials have demonstrated targeting PI3K pathway is a promising strategy for the treatment of blood cancers. To identify novel PI3K inhibitors, we performed a high throughput virtual screen and identified several novel small molecule compounds, including PIK-C98 (C98). The cell-free enzymatic studies showed that C98 inhibited all class I PI3Ks at nano- or low micromolar concentrations but had no effects on AKT or mTOR activity. Molecular docking analysis revealed that C98 interfered with the ATP-binding pockets of PI3Ks by forming H-bonds and arene-H interactions with specific amino acid residues. The cellular assays demonstrated that C98 specifically inhibited PI3K/AKT/mTOR signaling pathway, but had no effects on other kinases and proteins including IGF-1R, ERK, p38, c-Src, PTEN, and STAT3. Inhibition of PI3K by C98 led to myeloma cell apoptosis. Furthermore, oral administration of C98 delayed tumor growth in two independent human myeloma xenograft models in nude mice but did not show overt toxicity. Pharmacokinetic analyses showed that C98 was well penetrated into myeloma tumors. Therefore, through a high throughput virtual screen we identified a novel PI3K inhibitor that is orally active against multiple myeloma with great potential for further development. PMID:25474140

  15. MARCH2 regulates autophagy by promoting CFTR ubiquitination and degradation and PIK3CA-AKT-MTOR signaling.

    PubMed

    Xia, Dan; Qu, Liujing; Li, Ge; Hongdu, Beiqi; Xu, Chentong; Lin, Xin; Lou, Yaxin; He, Qihua; Ma, Dalong; Chen, Yingyu

    2016-09-01

    MARCH2 (membrane-associated RING-CH protein 2), an E3 ubiquitin ligase, is mainly associated with the vesicle trafficking. In the present study, for the first time, we demonstrated that MARCH2 negatively regulates autophagy. Our data indicated that overexpression of MARCH2 impaired autophagy, as evidenced by attenuated levels of LC3B-II and impaired degradation of endogenous and exogenous autophagic substrates. By contrast, loss of MARCH2 expression had the opposite effects. In vivo experiments demonstrate that MARCH2 knockout mediated autophagy results in an inhibition of tumorigenicity. Further investigation revealed that the induction of autophagy by MARCH2 deficiency was mediated through the PIK3CA-AKT-MTOR signaling pathway. Additionally, we found that MARCH2 interacts with CFTR (cystic fibrosis transmembrane conductance regulator), promotes the ubiquitination and degradation of CFTR, and inhibits CFTR-mediated autophagy in tumor cells. The functional PDZ domain of MARCH2 is required for the association with CFTR. Thus, our study identified a novel negative regulator of autophagy and suggested that the physical and functional connection between the MARCH2 and CFTR in different conditions will be elucidated in the further experiments. PMID:27308891

  16. 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. PMID:27363420

  17. 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

  18. 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. PMID:24960874

  19. 33 CFR 207.440 - St. Marys Falls Canal and Locks, Mich.; use, administration, and navigation.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 33 Navigation and Navigable Waters 3 2013-07-01 2013-07-01 false St. Marys Falls Canal and Locks, Mich.; use, administration, and navigation. 207.440 Section 207.440 Navigation and Navigable Waters CORPS OF ENGINEERS, DEPARTMENT OF THE ARMY, DEPARTMENT OF DEFENSE NAVIGATION REGULATIONS § 207.440 St. Marys Falls Canal and Locks, Mich.;...

  20. 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...

  1. 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. PMID:25092060

  2. 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....

  3. Potential Hosts for Lambertella corni-maris and Phacidium lacerum within the Family Rosaceae

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  4. "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.…

  5. 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 1970-7 American…

  6. "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…

  7. 78 FR 38001 - Special Local Regulations; Marine Events, Breton Bay; St. Mary's County, Leonardtown, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-25

    ...; St. Mary's County, Leonardtown, MD'' in the Federal Register (78 FR 21864). The rulemaking concerned... Breton Bay, in St. Mary's County, MD, effective from 8 a.m. on July 13, 2013 to 5 p.m. on July 14, 2013... SECURITY Coast Guard 33 CFR Part 100 RIN 1625-AA08 Special Local Regulations; Marine Events, Breton Bay;...

  8. 33 CFR 207.441 - St. Marys Falls Canal and Locks, Mich.; security.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... material. Cleaning and gas freeing of tanks on all hazardous material cargo vessels (as defined in 49 CFR... 33 Navigation and Navigable Waters 3 2013-07-01 2013-07-01 false St. Marys Falls Canal and Locks... OF THE ARMY, DEPARTMENT OF DEFENSE NAVIGATION REGULATIONS § 207.441 St. Marys Falls Canal and...

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

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... material. Cleaning and gas freeing of tanks on all hazardous material cargo vessels (as defined in 49 CFR... 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...

  10. 33 CFR 117.261 - Atlantic Intracoastal Waterway from St. Marys River to Key Largo.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...) Editorial Note: For Federal Register citations affecting § 117.261, see the List of CFR Sections Affected... from St. Marys River to Key Largo. 117.261 Section 117.261 Navigation and Navigable Waters COAST GUARD....261 Atlantic Intracoastal Waterway from St. Marys River to Key Largo. (a) General. Public vessels...

  11. 33 CFR 117.261 - Atlantic Intracoastal Waterway from St. Marys River to Key Largo.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... List of CFR Sections Affected, which appears in the Finding Aids section of the printed volume and at... from St. Marys River to Key Largo. 117.261 Section 117.261 Navigation and Navigable Waters COAST GUARD....261 Atlantic Intracoastal Waterway from St. Marys River to Key Largo. (a) General. Public vessels...

  12. 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... Friday, except Federal holidays the draw need open only at 7 a.m., 8 a.m. and 5:30 p.m. (c)...

  13. 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... Friday, except Federal holidays the draw need open only at 7 a.m., 8 a.m. and 5:30 p.m. (c)...

  14. 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... pyrotechnic flare exercises launched from a U.S. Navy helicopter located near St. Inigoes, Maryland....

  15. 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.

  16. A space radiation shielding model of the Martian radiationenvironment experiment (MARIE)

    SciTech Connect

    Atwell, William; Saganti, Premkumar; Cucinotta, Francis A.; Zeitlin, Cary J.

    2004-12-01

    The 2001 Mars Odyssey spacecraft was launched towards Mars on April 7, 2001. On board 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.

  17. 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. PMID:15791735

  18. 76 FR 21677 - Safety Zones; Annual Events Requiring Safety Zones in the Captain of the Port Sault Sainte Marie...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-18

    ..., 2008, issue of the Federal Register (73 FR 3316). Public Meeting We do not now plan to hold a public... Sainte Marie, MI: (i) Location. All U.S. navigable waters of the St. Marys River within a 750-foot radius... St. Marys River within a 1200-foot radius from the fireworks launch site, centered approximately...

  19. Draft Genome Sequence of Dietzia maris DSM 43672, a Gram-Positive Bacterium of the Mycolata Group

    PubMed Central

    Ganguly, Sonalli; Jimenez-Galisteo, Guadalupe; Pletzer, Daniel; Winterhalter, Mathias; Benz, Roland

    2016-01-01

    Here, we report the draft genome sequence of Dietzia maris, known previously as Rhodococcus maris. It is 3,505,372 bp in size with a G+C content of 73%. The draft genome sequence will improve our understanding of Dietzia maris related to other mycolata species and constitutes a basic tool for exploring the cell wall proteins. PMID:27284155

  20. Draft Genome Sequence of Dietzia maris DSM 43672, a Gram-Positive Bacterium of the Mycolata Group.

    PubMed

    Ganguly, Sonalli; Jimenez-Galisteo, Guadalupe; Pletzer, Daniel; Winterhalter, Mathias; Benz, Roland; Viñas, Miguel

    2016-01-01

    Here, we report the draft genome sequence of Dietzia maris, known previously as Rhodococcus maris It is 3,505,372 bp in size with a G+C content of 73%. The draft genome sequence will improve our understanding of Dietzia maris related to other mycolata species and constitutes a basic tool for exploring the cell wall proteins. PMID:27284155

  1. 46 CFR 401.410 - Basic rates and charges on Lakes Huron, Michigan and Superior and the St. Mary's River.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... CFR Sections Affected, which appears in the Finding Aids section of the printed volume and on GPO... Steel Corporation Wharf at Sault Ste. Marie Ontario 2,559 $964 N/A Any point in Sault Ste. Marie, Ontario, except the Algoma Steel Corporation Wharf 2,145 964 N/A Sault Ste. Marie, MI 2,145 964 N/A...

  2. "What an Affliction": Mary Todd Lincoln's Fatal Pernicious Anemia.

    PubMed

    Sotos, John G

    2015-01-01

    To date, no single diagnosis has unified the psychiatric illness and the numerous poorly defined physical complaints that Mary Lincoln (née Todd, 1818-1882) suffered in adulthood. Here, I show that her physical ailments spanned 30 years and included sore mouth, pallor, paresthesias, the Lhermitte symptom, fever, headaches, fatigue, resting tachycardia, edema, episodic weight loss, progressive weakness, ataxia, and visual impairment. Long thought hypochondriacal, these findings, plus their time course and her psychopathology (irritability, delusions, hallucinations, with preserved clarity), are all consistent with vitamin B12 deficiency. Pernicious anemia most probably caused this deficiency: she lacked risk factors for other causes, and her consanguineous parents both derived from a region of Scotland having a high incidence of pernicious anemia. A diagnosis of chronic multisystem pernicious anemia would clarify the conduct of Mary Lincoln as First Lady and widow, and illuminate challenges faced by her husband, President Abraham Lincoln. Her case highlights many forgotten features of the natural history of untreated pernicious anemia and is unique in the medical literature in demonstrating such a course extending over a lifetime. PMID:27397049

  3. MiR-126 regulates proliferation and invasion in the bladder cancer BLS cell line by targeting the PIK3R2-mediated PI3K/Akt signaling pathway

    PubMed Central

    Xiao, Jun; Lin, Huan-Yi; Zhu, Yuan-Yuan; Zhu, Yu-Ping; Chen, Ling-Wu

    2016-01-01

    Objective To assess whether microRNA-126 (miR-126) targets phosphatidylinositol 3-kinase regulatory subunit beta (PIK3R2) and to determine the potential roles of miR-126 in regulating proliferation and invasion via the PIK3R2-mediated phosphatidylinositol 3 kinase (PI3K)-protein kinase B (Akt) signaling pathway in the human bladder BLS cell line. Materials and methods A recombinant lentivirus (Lv) vector expressing miR-216 (Lv-miR-126) was successfully constructed, and Lv-miR-126 and Lv vector were transfected into the BLS cell line. A direct regulatory relationship between miR-126 and the PIK3R2 gene was demonstrated by luciferase reporter assays. To determine whether PIK3R2 directly participates in the miR-126-induced effects in BLS cells, anti-miR-126 and a PIK3R2 small interfering RNA (siRNA) were transfected into the BLS cells. Quantitative real-time polymerase chain reaction was used to measure miR-126 and PIK3R2 expressions. 5-Ethynyl-2′-deoxyuridine and colony formation assays to assess cell proliferation, flow cytometry for cell apoptosis and cell cycle analysis, Transwell assays for cell migration and invasion, and Western blots for PIK3R2, PI3K, phosphorylated PI3K (p-PI3K), Akt, and phosphorylated Akt (p-Akt) protein expressions were performed. Results Lv-miR-126 significantly enhanced the relative expression of miR-126 in the BLS cells after infection (P<0.0001). MiR-126 overexpression inhibited the proliferation, cloning, migration, and invasion of BLS cells, promoted cell apoptosis, and induced S phase arrest (all P<0.05). PIK3R2, p-PI3K, and p-Akt protein expressions were significantly decreased in the BLS cells infected with Lv-miR-126. Luciferase assays showed that miR-126 significantly inhibited the PIK3R2 3′ untranslated region (3′UTR) luciferase reporter activity (P<0.05). The anti-miR-126 + PIK3R2 siRNA group had significantly decreased PIK3R2, p-PI3K, and p-Akt expressions compared with those of anti-miR-126 alone, as well as

  4. Epithelial PIK3R1 (p85) and TP53 Regulate Survivin Expression during Adaptation to Ileocecal Resection.

    PubMed

    Cohran, Valeria; Managlia, Elizabeth; Bradford, Emily M; Goretsky, Tatiana; Li, Ting; Katzman, Rebecca B; Cheresh, Paul; Brown, Jeffrey B; Hawkins, Jennifer; Liu, Shirley X L; De Plaen, Isabelle G; Weitkamp, Jörn-Hendrik; Helmrath, Michael; Zhang, Zheng; Barrett, Terrence A

    2016-07-01

    Intestinal adaptation to small-bowel resection (SBR) after necrotizing enterocolitis expands absorptive surface areas and promotes enteral autonomy. Survivin increases proliferation and blunts apoptosis. The current study examines survivin in intestinal epithelial cells after ileocecal resection. Wild-type and epithelial Pik3r1 (p85α)-deficient mice underwent sham surgery or 30% resection. RNA and protein were isolated from small bowel to determine levels of β-catenin target gene expression, activated caspase-3, survivin, p85α, and Trp53. Healthy and post-resection human infant small-bowel sections were analyzed for survivin, Ki-67, and TP53 by immunohistochemistry. Five days after ileocecal resection, epithelial levels of survivin increased relative to sham-operated on mice, which correlated with reduced cleaved caspase-3, p85α, and Trp53. At baseline, p85α-deficient intestinal epithelial cells had less Trp53 and more survivin, and relative responses to resection were blunted compared with wild-type. In infant small bowel, survivin in transit amplifying cells increased 71% after SBR. Resection increased proliferation and decreased numbers of TP53-positive epithelial cells. Data suggest that ileocecal resection reduces p85α, which lowers TP53 activation and releases survivin promoter repression. The subsequent increase in survivin among transit amplifying cells promotes epithelial cell proliferation and lengthens crypts. These findings suggest that SBR reduces p85α and TP53, which increases survivin and intestinal epithelial cell expansion during therapeutic adaptation in patients with short bowel syndrome. PMID:27157990

  5. 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

  6. 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. PMID:25681087

  7. mTORC1 Inhibition Is Required for Sensitivity to PI3K p110α Inhibitors in PIK3CA-Mutant Breast Cancer

    PubMed Central

    Elkabets, Moshe; Vora, Sadhna; Juric, Dejan; Morse, Natasha; Mino-Kenudson, Mari; Muranen, Taru; Tao, Jessica; Campos, Ana Bosch; Rodon, Jordi; Ibrahim, Yasir H.; Serra, Violeta; Rodrik-Outmezguine, Vanessa; Hazra, Saswati; Singh, Sharat; Kim, Phillip; Quadt, Cornelia; Liu, Manway; Huang, Alan; Rosen, Neal; Engelman, Jeffrey A.

    2014-01-01

    Activating mutations of the PIK3CA gene occur frequently in breast cancer, and inhibitors that are specific for phosphatidylinositol 3-kinase (PI3K) p110α, such as BYL719, are being investigated in clinical trials. In a search for correlates of sensitivity to p110α inhibition among PIK3CA-mutant breast cancer cell lines, we observed that sensitivity to BYL719 (as assessed by cell proliferation) was associated with full inhibition of signaling through the TORC1 pathway. Conversely, cancer cells that were resistant to BYL719 had persistently active mTORC1 signaling, although Akt phosphorylation was inhibited. Similarly, in patients, pS6 (residues 240/4) expression (a marker of mTORC1 signaling) was associated with tumor response to BYL719, and mTORC1 was found to be reactivated in tumors from patients whose disease progressed after treatment. In PIK3CA-mutant cancer cell lines with persistent mTORC1 signaling despite PI3K p110α blockade (that is, resistance), the addition of the allosteric mTORC1 inhibitor RAD001 to the cells along with BYL719 resulted in reversal of resistance in vitro and in vivo. Finally, we found that growth factors such as insulin-like growth factor 1 and neuregulin 1 can activate mammalian target of rapamycin (mTOR) and mediate resistance to BYL719. Our findings suggest that simultaneous administration of mTORC1 inhibitors may enhance the clinical activity of p110α-targeted drugs and delay the appearance of resistance. PMID:23903756

  8. 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.

  9. Mary Riddoch (1901-1966), an extraordinary tale of survival.

    PubMed

    Riddoch, G; Silver, J R; Weiner, M-F

    2016-12-01

    In 1934 Mary Riddoch sustained a traumatic spinal injury as a result of a road traffic accident. Although a few surviving servicemen from the First World War have been recorded, this is the first account of a female paraplegic patient surviving a traumatic spinal injury. Her personal circumstances greatly contributed to her long survival: she was a qualified doctor, she was the sister of George Riddoch the neurologist who treated soldiers who had sustained spinal cord injuries during the First World War, and she was fortunate to have benefited from the dedicated care of nurse Dorothy Fiddes. Her great-nephew, Graeme Riddoch, is one of the authors of this paper and his recollections provide a unique perspective to this case report. PMID:27092370

  10. 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.

  11. Mary Seacole: self taught nurse and heroine of the Crimean War.

    PubMed

    Harold, Ellis

    2009-09-01

    Mary Jane Seacole was born Mary Grant in Kingston Jamaica in 1805. Her father was a Scottish army officer and her mother a free Jamaican black, (slavery was not fully abolished in Jamaica until 1838). Her mother ran a hotel, Blundell Hall, in Kingston and was a traditional healer. Her skill as a nurse was much appreciated, as many of her residents were disabled British soldiers and sailors. It was from her mother that Mary learned the art of patient care, and she also assisted at the local British army hospital. PMID:19842522

  12. 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. PMID:12774712

  13. PIK3CA mutations, phosphatase and tensin homolog, human epidermal growth factor receptor 2, and insulin-like growth factor 1 receptor and adjuvant tamoxifen resistance in postmenopausal breast cancer patients

    PubMed Central

    2014-01-01

    Introduction Inhibitors of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway can overcome endocrine resistance in estrogen receptor (ER) α-positive breast cancer, but companion diagnostics indicating PI3K/AKT/mTOR activation and consequently endocrine resistance are lacking. PIK3CA mutations frequently occur in ERα-positive breast cancer and result in PI3K/AKT/mTOR activation in vitro. Nevertheless, the prognostic and treatment-predictive value of these mutations in ERα-positive breast cancer is contradictive. We tested the clinical validity of PIK3CA mutations and other canonic pathway drivers to predict intrinsic resistance to adjuvant tamoxifen. In addition, we tested the association between these drivers and downstream activated proteins. Methods Primary tumors from 563 ERα-positive postmenopausal patients, randomized between adjuvant tamoxifen (1 to 3 years) versus observation were recollected. PIK3CA hotspot mutations in exon 9 and exon 20 were assessed with Sequenom Mass Spectometry. Immunohistochemistry was performed for human epidermal growth factor receptor 2 (HER2), phosphatase and tensin homolog (PTEN), and insulin-like growth factor 1 receptor (IGF-1R). We tested the association between these molecular alterations and downstream activated proteins (like phospho-protein kinase B (p-AKT), phospho-mammalian target of rapamycin (p-mTOR), p-ERK1/2, and p-p70S6K). Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of canonic pathway drivers, by using Cox proportional hazard models, including a test for interaction. Results PIK3CA mutations (both exon 9 and exon 20) were associated with low tumor grade. An enrichment of PIK3CA exon 20 mutations was observed in progesterone receptor- positive tumors. PIK3CA exon 20 mutations were not associated with downstream-activated proteins. No significant interaction between PIK3CA mutations or any

  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. 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

  16. 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. PMID:26909613

  17. 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

  18. 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. PMID:27009151

  19. A Poem Is a House for Words: NCTE Profiles Mary Ann Hoberman

    ERIC Educational Resources Information Center

    McClure, Amy A.; Ernst, Shirley B.

    2004-01-01

    A profile of Mary Ann Hoberman, the 13th winner of the NCTE Award for Excellence in Poetry for Children is given. She uses poetic techniques in innovative ways, yet her poems are very accessible to young children.

  20. Patient Identification of the Symptomatic Impact of Charcot Marie Tooth Disease Type 1A

    PubMed Central

    Johnson, Nicholas E; Heatwole, Chad R.; Ferguson, Michele; Sowden, Janet E.; Jeanat, Shanie; Herrmann, David N.

    2013-01-01

    Objective The burden of Charcot Marie Tooth type 1A, the most common inherited peripheral neuropathy, including impact on patient quality of life is not well understood. This study aims to qualitatively describe the range of symptoms associated with Charcot Marie Tooth type 1A and impact on quality of life. Methods We performed qualitative interviews with 16 adult Charcot Marie Tooth type 1A patients. Each interview was analyzed using a qualitative framework technique to identify and index symptoms by theme. Results Sixteen patients provided 656 quotes. One hundred and forty-five symptoms of importance were identified representing 20 symptomatic themes. Symptoms associated with difficulty with mobility and ambulation, specific activity impairment, and emotional distress were the most frequently mentioned. Conclusions Multiple symptoms contribute to Charcot Marie Tooth type 1A disease burden, some previously under-recognized. Improved recognition of under-recognized symptoms will optimize patient care and quality of life. PMID:23965405

  1. Clinicopathologic Significance of HNF-1β, AIRD1A, and PIK3CA Expression in Ovarian Clear Cell Carcinoma: A Tissue Microarray Study of 130 Cases.

    PubMed

    Ye, Shuang; Yang, Jiaxin; You, Yan; Cao, Dongyan; Huang, Huifang; Wu, Ming; Chen, Jie; Lang, Jinghe; Shen, Keng

    2016-03-01

    Ovarian clear cell carcinoma (CCC) is a distinct histologic subtype with relatively poor survival. No prognostic or predictive molecular marker is currently available. Recent studies have shown that AT-rich interactive domain 1A (ARID1A) and phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutations are common genetic changes in ovarian CCC. Hepatocyte nuclear factor-1β (HNF-1β) expression has been proven to be highly sensitive and specific for clear cell histology. However, the correlations between these biomarkers and clinicopathologic variables and survival outcomes are controversial. The immunohistochemical analysis for HNF-1β, ARID1A, and PIK3CA was performed on a tissue microarray (TMA) consisting of 130 cases of ovarian CCC (237 tissue blocks) linked with clinical information. The immunostaining results were interpreted in a manner consistent with previous publications. The associations between biomarker expression and clinical and prognostic features were examined. All statistical analyses were conducted using 2-sided tests, and a value of P < 0.05 was considered significant. HNF-1β was expressed in 92.8% of all primary ovarian tumors, while the loss of ARID1A and PIK3CA was noted in 56.2% and 45.0%, respectively. Early-stage tumors tended to have high levels of HNF-1β immunoreactivity and expression of ARID1A (P = 0.02 and P = 0.03). Most patients (76.9%, 20/26) with concurrent endometriosis stained negative for ARID1A (P = 0.02). No relation was found between PIK3CA expression and clinical features. Low-level HNF-1β expression and loss of ARID1A were more commonly observed in patients with tumor recurrence (P = 0.02 and P < 0.001). Antibody expression was not associated with platinum-based chemotherapy response. Patients with negative ARID1A expression had worse survival outcome in terms of both overall survival (OS) and progression-free survival (PFS) (P = 0.03 and P = 0.01, respectively). On the

  2. Constitutive activation of the fucAO operon and silencing of the divergently transcribed fucPIK operon by an IS5 element in Escherichia coli mutants selected for growth on L-1,2-propanediol.

    PubMed Central

    Chen, Y M; Lu, Z; Lin, E C

    1989-01-01

    L-1,2-Propanediol is an irretrievable end product of L-fucose fermentation by Escherichia coli. Selection for increased aerobic growth rate on propanediol results in the escalation of basal synthesis of the NAD+-linked oxidoreductase encoded by fucO, a member of the fuc regulon for the utilization of L-fucose. In general, when fucO becomes constitutively expressed, two other simultaneous changes occur: the fucA gene encoding fuculose-1-phosphate aldolase becomes constitutively expressed and the fucPIK operon encoding fucose permease, fucose isomerase, and fuculose kinase becomes noninducible. In the present study, we show that fucO and fucA form an operon which is divergently transcribed from the adjacent fucPIK operon. In propanediol-positive and fucose-negative mutants the cis-controlling region shared by the operons fucAO and fucPIK is lengthened by 1.2 kilobases. DNA hybridization identified the insertion element to be IS5. This element, always oriented in the same direction with the left end (the BglII end) proximal to fucA, apparently causes constitutive expression of fucAO and noninducibility of fucPIK. The DNA of the fucAO operon and a part of the adjacent fucP was sequenced. Images PMID:2553671

  3. 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 Central

    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

    2016-01-01

    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

  4. "Typhoid Mary" and "HIV Jane": responsibility, agency and disease prevention.

    PubMed

    Chan, Kit Yee; Reidpath, Daniel D

    2003-11-01

    The construction of disease risks as knowable, calculable and preventable in dominant social science and public health discourses has fostered a certain kind of logic about individual risk and the responsibility for infection. Disease control measures that have developed out of this logic typically fail to recognise the socio-structural roots of many high-risk behaviours that are linked to the spread of infection. Instead, they hold the disease carrier responsible for managing his/her own risk of infection of others, and rely on constraining the agency of the carrier (e.g. by constraining movement, contact or occupation). In occupations associated with a high risk of infection, the idea of responsibility of the actor implicitly raises issues of "professional responsibility". Using the case of "Typhoid Mary" and a hypothetical case of "HIV Jane", this paper explores some of the problems with making sex workers responsible for the prevention of HIV transmission. It argues that for the notion of "responsibility" to make any sense, the HIV-positive person must be in a position to exercise responsibility, and for this they must have agency. PMID:14708397

  5. 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. PMID:27601958

  6. 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

  7. 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. PMID:25417019

  8. 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. PMID:26010435

  9. Dominant Charcot-Marie-Tooth syndrome and cognate disorders.

    PubMed

    Pareyson, Davide; Marchesi, Chiara; Salsano, Ettore

    2013-01-01

    Charcot-Marie-Tooth neuropathy (CMT) is a group of genetically heterogeneous disorders sharing a similar phenotype, characterized by wasting and weakness mainly involving the distal muscles of lower and upper limbs, variably associated with distal sensory loss and skeletal deformities. This chapter deals with dominantly transmitted CMT and related disorders, namely hereditary neuropathy with liability to pressure palsies (HNPP) and hereditary neuralgic amyotrophy (HNA). During the last 20 years, several genes have been uncovered associated with CMT and our understanding of the underlying molecular mechanisms has greatly improved. Consequently, a precise genetic diagnosis is now possible in the majority of cases, thus allowing proper genetic counseling. Although, unfortunately, treatment is still unavailable for all types of CMT, several cellular and animal models have been developed and some compounds have proved effective in these models. The first trials with ascorbic acid in CMT type 1A have been completed and, although negative, are providing relevant information on disease course and on how to prepare for future trials. PMID:23931817

  10. 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. PMID:1744021

  11. 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 CFR 165.7(a). The primary method of notification, however, will be through Broadcast Notice to... safety zones: (1) All U.S. navigable waters downstream of the Sabin and Davis Locks, Sault Sainte Marie... Lock downstream gate, to approximately 1,750 feet due east of the center of the Davis Lock...

  12. 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…

  13. 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

  14. 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. PMID:26991344

  15. Charcot-Marie-Tooth disease and related inherited neuropathies.

    PubMed

    Murakami, T; Garcia, C A; Reiter, L T; Lupski, J R

    1996-09-01

    Charcot-Marie-Tooth disease (CMT) was initially described more than 100 years ago by Charcot, Marie, and Tooth. It was only recently, however, that molecular genetic studies of CMT have uncovered the underlying causes of most forms of the diseases. Most cases of CMT1 are associated with a 1.5-Mb tandem duplication in 17p11.2-p12 that encompasses the PMP22 gene. Although many genes may exist in this large duplicated region, PMP22 appears to be the major dosage-sensitive gene. CMT1A is the first autosomal dominant disease associated with a gene dosage effect due to an inherited DNA rearrangement. There is no mutant gene, but instead the disease phenotype results from having 3 copies of a normal gene. Furthermore, these findings suggest that therapeutic intervention in CMT1A duplication patients may be possible by normalizing the amount of PMP22 mRNA levels. Alternatively, CMT1A can be caused by mutations in the PMP22 gene. Other forms of CMT are associated with mutations in the MPZ (CMT1B) and Cx32 (CMTX) genes. Thus, mutations in different genes can cause similar CMT phenotypes. The related but more severe neuropathy, Dejerine-Sottas syndrome (DSS), can also be caused by mutations in the PMP22 and MPZ genes. All 3 genes thus far identified by CMT researchers appear to play an important role in the myelin formation or maintenance of peripheral nerves. CMT1A, CMT1B, CMTX, hereditary neuropathy with liability to pressure palsies (HNPP), and DSS have been called myelin disorders or "myelino-pathies." Other demyelinating forms, CMT1C and CMT-AR, may be caused by mutations of not yet identified myelin genes expressed in Schwann cells. The clinically distinct disease HNPP is caused by a 1.5-Mb deletion in 17p11.2-p12, which spans the same region duplicated in most CMT1A patients. Underexpression of the PMP22 gene causes HNPP just as overexpression of PMP22 causes CMT1A. Thus, 2 different phenotypes can be caused by dosage variations of the same gene. It is apparent that

  16. St. Mary's has a "Sailabration". An Indiana hospital sets aside a day for spiritual renewal.

    PubMed

    Sister Betty Anne Darch; Newsmaster, Pamela

    2005-01-01

    Ascension Health has asked all of its health care ministries to promote spirituality in the workplace. St. Mary's Health System, Evansville, IN, responded to this request with several initiatives, including the development, facilitation, and implementation of a new model for what St. Mary's calls its "Employee Renewal Day." Revamped from a voluntary unpaid day to a paid day on which participation is strongly encouraged, Employee Renewal Day 2004 focused on fellowship, relaxation, and the history and heritage of St. Mary's and its sponsor. Based on an employee's suggestion, the mission team adopted a nautical theme, "Sailabration Cruise: A Day of Renewal," and took employees on "a voyage" complete with mission-themed ports, passenger photos, a ship's log, purser's desk, and an activities director. More than 1,200 St. Mary's employees-or 23 percent of the total workforce-participated. All of St. Mary's 135 leaders were in attendance. The new Employee Renewal Day model will be tried over a three-year period, so as to measure the progress of furthering the integration of spirituality within the organizational culture. PMID:15926423

  17. 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.

  18. 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.

  19. 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

  20. SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease

    PubMed Central

    Ghezzi, Daniele; Chassagne, Maïté; Mayençon, Martine; Padet, Sylvie; Melchionda, Laura; Rouvet, Isabelle; Lannes, Béatrice; Bozon, Dominique; Latour, Philippe; Zeviani, Massimo; Mousson de Camaret, Bénédicte

    2013-01-01

    Objective: To investigate whether mutations in the SURF1 gene are a cause of Charcot-Marie-Tooth (CMT) disease. Methods: We describe 2 patients from a consanguineous family with demyelinating autosomal recessive CMT disease (CMT4) associated with the homozygous splice site mutation c.107-2A>G in the SURF1 gene, encoding an assembly factor of the mitochondrial respiratory chain complex IV. This observation led us to hypothesize that mutations in SURF1 might be an unrecognized cause of CMT4, and we investigated SURF1 in a total of 40 unrelated patients with CMT4 after exclusion of mutations in known CMT4 genes. The functional impact of c.107-2A>G on splicing, amount of SURF1 protein, and on complex IV activity and assembly was analyzed. Results: Another patient with CMT4 was found to harbor 2 additional SURF1 mutations. All 3 patients with SURF1-associated CMT4 presented with severe childhood-onset neuropathy, motor nerve conduction velocities <25 m/s, and lactic acidosis. Two patients had brain MRI abnormalities, including putaminal and periaqueductal lesions, and developed cerebellar ataxia years after polyneuropathy. The c.107-2A>G mutation produced no normally spliced transcript, leading to SURF1 absence. However, complex IV remained partially functional in muscle and fibroblasts. Conclusions: We found SURF1 mutations in 5% of families (2/41) presenting with CMT4. SURF1 should be systematically screened in patients with childhood-onset severe demyelinating neuropathy and additional features such as lactic acidosis, brain MRI abnormalities, and cerebellar ataxia developing years after polyneuropathy. PMID:24027061

  1. Biomarkers research in neuromuscular disease Charcot-Marie-Tooth.

    PubMed

    Seco-Cervera, Marta; Ibañez-Cabellos, Jose Santiago; Garcia-Gimenez, Jose Luis; Espinos, Carmen; Palau, Francesc; Pallardo, Federico V

    2014-10-01

    Charcot-Marie-Tooth disease (CMT) (ORPHA166) is the most frequent hereditary neuropathy. CMT is a heterogeneous group of disorders which, despite some variability in their clinical features, share the same general phenotype, usually characterized by wasting and weakness of distal limb muscles, decreased to absent deep tendon reflexes, distal sensory loss, and frequent skeletal deformities. Despite the clinical and molecular description of this disease in the last 20 years, there is no effective drug or advanced therapy available. Here we have pretend the identification of metabolic and oxidative stress biomarkers in plasmas from patients with duplication at PMP22 gene, the most frequent mutation causing CMT, and clinically characterized as CMT1A. The samples were collected in the neuropathy units from "La Fe" Hospital of Valencia, "Bellvitge" Hospital of Barcelona, "La Paz" Hospital of Madrid, and "Virgen del Rocío" Hospital of Sevilla. The metabolic biomarkers research was performed using 2D-DIGE analysis (Typhoon TRIO, GE) and DeCyder software (GE). Protein identification was made by mass spectrometry by MALDI-TOF-TOF (ABSciex) and liquid Chromatography analysis (ABSciex). The oxidative stress biomarkers research consisted in carbonylated proteins analysis by reaction with DNPH and Dot-blot. Total antioxidant capacity and GSSG/GSH ratio were analyzed with Antioxidant Assay kit (Cayman) and Glutathione Fluorescent detection Kit (Arbor Assays), respectively. Finally now we are performing the MDA levels by HPLC-UV. We found 8, 13 and 36 proteins with differential expression in mild, moderate and severely affected patients, respectively compared with their own matched controls. Also we found differences on oxidative stress parameters between de different groups analyzed. Our results suggest differences in the oxidative stress profile between the studied phenotypes in CMT1A patients. PMID:26461392

  2. Charcot-Marie-Tooth disease and related peripheral neuropathies.

    PubMed

    De Jonghe, P; Timmerman, V; Nelis, E; Martin, J J; Van Broeckhoven, C

    1997-01-01

    Soon after the description of Charcot-Marie-Tooth disease (CMT) in 1886, it became apparent that this syndrome is clinically and genetically heterogeneous. Neuropathological and electrophysiological studies have further dissected this syndrome into distinct categories that are now classified in a complex nosology of the inherited peripheral neuropathies. The recent advent of molecular genetics has dramatically increased our understanding of the underlying disease mechanisms. Genetic linkage studies have identified at least 17 genetic loci for different types of inherited neuropathies although most genes involved still remain to be found. The application of molecular genetics has already had an important impact on clinical practice and genetic counselling. Three genes responsible for hereditary motor and sensory neuropathy type I (HMSNI) or CMT1 have been identified: peripheral myelin protein 22 (PMP22) and myelin protein zero (MPZ) for the autosomal dominant form and connexin 32 (Cx32) for the X-linked dominant variant. The PMP22 gene is also involved in the majority of families with hereditary neuropathy with liability to pressure palsies (HNPP). The observation of a 1.5 Mb tandem duplication in chromosome 17p11.2, containing the PMP22 gene, in CMT1 and the reciprocal deletion in the same region in HNPP has provided a novel disease paradigm for autosomal dominant disorders, i.e. the gene dosage mechanism. The study of phenotype-genotype correlations in transgenic animal models for PMP22, MPZ and Cx32 mutations will help elucidate the underlying disease mechanisms and will provide a basis for gene therapy and/or other therapeutic approaches such as treatment with neurotrophic growth factors. PMID:10975746

  3. 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.

  4. 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

    ... zone, in the Federal Register (76 FR 21677). We received 0 public submissions commenting on this rule... in the Captain of the Port Sault Sainte Marie zone, in the Federal Register (76 FR 21677). The Coast... in the Captain of the Port Sault Sainte Marie zone, in the Federal Register (76 FR 21677). The...

  5. 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

    ... SECURITY Coast Guard 33 CFR Part 165 RIN 1625-AA00 Safety Zone; International Bridge 50th Anniversary..., 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...

  6. 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)

  7. Electron self-exchange kinetics determined by MARY spectroscopy: theory and experiment.

    PubMed

    Justinek, M; Grampp, G; Landgraf, S; Hore, P J; Lukzen, N N

    2004-05-01

    The electron self-exchange between a neutral molecule and its charged radical, which is part of a spin-correlated radical ion pair, gives rise to line width effects in the fluorescence-detected MARY (magnetic field effect on reaction yield) spectrum similar to those observed in EPR spectroscopy. An increasing self-exchange rate (i.e., a higher concentration of the neutral molecule) leads to broadening and subsequent narrowing of the spectrum. Along with a series of MARY spectra recorded for several systems (the fluorophores pyrene, pyrene-d(10) and N-methylcarbazole in combination with 1,2- and 1,4-dicyanobenzene) in various solvents, a theoretical model is developed that describes the spin evolution and the diffusive recombination of the radical pair under the influence of the external magnetic field and electron self-exchange, thereby allowing the simulation of MARY spectra of the systems investigated experimentally. The spin evolution of the radicals in the pair is calculated separately using spin correlation tensors, thereby allowing rigorous quantum mechanical calculations for real spin systems. It is shown that the combination of these simulations with high resolution, low noise experimental spectra makes the MARY technique a novel, quantitative method for the determination of self-exchange rate constants. In comparison to a simple analytical formula which estimates the self-exchange rate constant from the slope of the linear part of a line width vs concentration plot, the simulation method yields more reliable and accurate results. The correctness of the results obtained by the MARY method is proved by a comparison with corresponding data from the well-established EPR line broadening technique. With its less stringent restrictions on radical lifetime and stability, the MARY technique provides an alternative to the classical EPR method, in particular for systems involving short-lived and unstable radicals. PMID:15113235

  8. Mary Mallon (1869-1938) and the history of typhoid fever.

    PubMed

    Marineli, Filio; Tsoucalas, Gregory; Karamanou, Marianna; Androutsos, George

    2013-01-01

    Mary Mallon was born in 1869 in Ireland and emigrated to the US in 1884. She had worked in a variety of domestic positions for wealthy families prior to settling into her career as a cook. As a healthy carrier of Salmonella typhi her nickname of "Typhoid Mary" had become synonymous with the spread of disease, as many were infected due to her denial of being ill. She was forced into quarantine on two separate occasions on North Brother Island for a total of 26 years and died alone without friends, having evidently found consolation in her religion to which she gave her faith and loyalty. PMID:24714738

  9. 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.

  10. Predictive value of K-ras and PIK3CA in non-small cell lung cancer patients treated with EGFR-TKIs: a systemic review and meta-analysis

    PubMed Central

    Chen, Jie-Ying; Cheng, Ya-Nan; Han, Lei; Wei, Feng; Yu, Wen-Wen; Zhang, Xin-Wei; Cao, Shui; Yu, Jin-Pu

    2015-01-01

    Objective A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways on the clinical efficiency of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment of non-small cell lung cancer (NSCLC) patients. Methods Network databases were explored in April, 2015. Papers that investigated the clinical outcomes of NSCLC patients treated with EGFR-TKIs according to the status of K-ras and/or PIK3CA gene mutation were included. A quantitative meta-analysis was conducted using standard statistical methods. Odds ratios (ORs) for objective response rate (ORR) and hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were calculated. Results Mutation in K-ras significantly predicted poor ORR [OR =0.22; 95% confidence interval (CI), 0.13-0.35], shorter PFS (HR =1.56; 95% CI, 1.27-1.92), and shorter OS (HR =1.59; 95% CI, 1.33-1.91) in NSCLC patients treated with EGFR-TKIs. Mutant PIK3CA significantly predicted shorter OS (HR =1.83; 95% CI, 1.05-3.20), showed poor ORR (OR =0.70; 95% CI, 0.22-2.18), and shorter PFS (HR =1.79; 95% CI, 0.91-3.53) in NSCLC patients treated with EGFR-TKIs. Conclusion K-ras mutation adversely affected the clinical response and survival of NSCLC patients treated with EGFR-TKIs. PIK3CA mutation showed similar trends. In addition to EGFR, adding K-ras and PIK3CA as routine gene biomarkers in clinical genetic analysis is valuable to optimize the effectiveness of EGFR-TKI regimens and identify optimal patients who will benefit from EGFR-TKI treatment. PMID:26175928

  11. Allied-Signal's Mary Good Analyzes New Threats to Chemical Profession.

    ERIC Educational Resources Information Center

    Chemical and Engineering News, 1986

    1986-01-01

    Recounts an interview with chemist, educator, and executive Mary Good. Opinions are expressed about the status of basic research in chemistry, the relationship of chemical research to several federal agencies, the value of education in chemistry, and the perceptions of the public regarding the chemical community, particularly the health risks. (TW)

  12. Telling Ideas by the Company They Keep: A Response to the Critique by Mary Juzwik

    ERIC Educational Resources Information Center

    Sfard, Anna

    2006-01-01

    In a number of personal communications and now in her article in "Educational Researcher", Mary Juzwik repeatedly observes that some elaborations may be needed for fuller understanding of the notion of "identity-as-narrative", introduced in the article this author co-wrote with Anna Prusak "Telling Identities: In Search of an Analytic Tool for…

  13. A DIY Campus Preservation Plan: Lessons Learned at the University of Mary Washington

    ERIC Educational Resources Information Center

    Smith, Andrea Livi; Spencer, Michael

    2012-01-01

    The University of Mary Washington (UMW) in Fredericksburg, Virginia, was founded in 1908. This article describes the process that led to the UMW preservation plan. Unlike most preservation plans, the UMW plan was developed in-house with limited funds. Furthermore, the catalyst for the plan was a grassroots effort on the part of students and alumni…

  14. The design and research of anti-color-noise chaos M-ary communication system

    NASA Astrophysics Data System (ADS)

    Fu, Yongqing; Li, Xingyuan; Li, Yanan; Zhang, Lin

    2016-03-01

    Previously a novel chaos M-ary digital communication method based on spatiotemporal chaos Hamilton oscillator has been proposed. Without chaos synchronization circumstance, it has performance improvement in bandwidth efficiency, transmission efficiency and anti-white-noise performance compared with traditional communication method. In this paper, the channel noise influence on chaotic modulation signals and the construction problem of anti-color-noise chaotic M-ary communication system are studied. The formula of zone partition demodulator's boundary in additive white Gaussian noise is derived, besides, the problem about how to determine the boundary of zone partition demodulator in additive color noise is deeply studied; Then an approach on constructing anti-color-noise chaos M-ary communication system is proposed, in which a pre-distortion filter is added after the chaos baseband modulator in the transmitter and whitening filter is added before zone partition demodulator in the receiver. Finally, the chaos M-ary communication system based on Hamilton oscillator is constructed and simulated in different channel noise. The result shows that the proposed method in this paper can improve the anti-color-noise performance of the whole communication system compared with the former system, and it has better anti-fading and resisting disturbance performance than Quadrature Phase Shift Keying system.

  15. Seven Lessons Learned from General Education Reform at Saint Mary's College

    ERIC Educational Resources Information Center

    Incandela, Joseph M.

    2011-01-01

    Saint Mary's College, a single-gender Catholic institution in northern Indiana with approximately 1,600 students, has just revised a general education curriculum that had been in place for nearly forty years. The board of trustees unanimously approved the new curriculum in April 2010. In this article, the author discusses seven key lessons learned…

  16. Women's Emancipation through Education: The Radical Agenda of Mary Wollstonecraft (1759-1797).

    ERIC Educational Resources Information Center

    Roberts, Leonard H.; Pollman, Mary Jo

    Two hundred years ago, Mary Wollstonecraft, the English women's rights pioneer, published her immortal work: "A Vindication of the Rights of Woman." In it she placed much of the blame for women's inferior political, intellectual, and social status on "faulty education." In "Vindication," she offered a number of recommendations aimed at enhancing…

  17. A Boolean Anthology. Selected Writings of Mary Boole - on Mathematical Education.

    ERIC Educational Resources Information Center

    Tahta, D. G., Comp.

    This volume is intended to provide a brief introduction to Mary Boole's writings. Short selections from her writings are organized under four areas: on teaching and learning, some mathematical lessons, the nature of mathematics, and the work of George Boole. A brief biography is also included. (DT)

  18. 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.

  19. 33 CFR 117.353 - Atlantic Intracoastal Waterway, Savannah River to 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 Atlantic Intracoastal Waterway, Savannah River to St. Marys River. 117.353 Section 117.353 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Georgia §...

  20. 33 CFR 117.353 - Atlantic Intracoastal Waterway, Savannah River to St. Marys River.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Atlantic Intracoastal Waterway, Savannah River to St. Marys River. 117.353 Section 117.353 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Georgia §...

  1. 33 CFR 117.353 - Atlantic Intracoastal Waterway, Savannah River to St. Marys River.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 1 2012-07-01 2012-07-01 false Atlantic Intracoastal Waterway, Savannah River to St. Marys River. 117.353 Section 117.353 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Georgia §...

  2. Re-Birthing the Monstrous: James Whale's (Mis)Reading of Mary Shelley's "Frankenstein."

    ERIC Educational Resources Information Center

    Picart, Caroline Joan S.

    1998-01-01

    Contributes to scholarship on film and feminism by showing how James Whale's film attempts to excise or severely delimit the disturbing critique of the Romantic politics of gender in Mary Shelley's novel "Frankenstein." Discusses parthenogenesis, showing how the novel critiques the Romantic rhetorical reconstructions of masculine divinity and…

  3. Life as the Middle Child: A Conversation With Mary Margaret Kerr

    ERIC Educational Resources Information Center

    Teagarden, James M.; Zabel, Robert H.; Kaff, Marilyn S.

    2015-01-01

    As part of an ongoing oral history project, a conversation was held with Dr. Mary Margaret Kerr on the past, present, and possible future of the field of providing services to children with emotional-behavioral disorders. Dr. Wood stresses the increasing importance of providing an interdisciplinary approach to meet the needs for children or, as…

  4. Rediscovering the Art of Developmental Therapy: An Interview with Mary M. Wood

    ERIC Educational Resources Information Center

    Teagarden, James M.; Kaff, Marilyn S.; Zabel, Robert H.

    2013-01-01

    Dr. Mary Margaret Wood is best known for developing psychoeducational programs that integrate mental health and special education interventions for children with emotional and behavioral disorders (EBD). Developmental Therapy (DT) includes comprehensive assessment of student behavior, communication, social, and cognitive development,…

  5. Reclaiming a Lost Leader: Mary Perkins Ryan, Visionary in Modern Catholic Education

    ERIC Educational Resources Information Center

    Heekin, Ann Morrow

    2008-01-01

    Mary Perkins Ryan remains one of the least recognized of the twentieth-century figures in the modern renewal of Catholic education in the United States. The reasons are many but none satisfactory. Ryan was an intellectual without a scholarly credential. She was an educator without an affiliation to an academic institution. She was a leading voice…

  6. Mary Lee Settle and the Mountain Kingdom: A World Where Nobody Forgets Anything.

    ERIC Educational Resources Information Center

    Woodside, Jane Harris

    1992-01-01

    Novelist Mary Lee Settle reminiscences about growing up in an Appalachian coal mining town and how she uses her life experiences as a back drop for developing stories and characters for her novels. She discusses family history, coal mine violence, and the proud heritage and culture of Appalachians. (LP)

  7. [PREGNANCY AND DELIVERY IN A PATIENT WITH CHARCOT-MARIE-TOOTH DISEASE].

    PubMed

    Pehlivanov, B; Matev, M

    2016-01-01

    We report a case of a 34 years old primigravida with Charcot-Marie-Tooth disease (CMTD). The course of pregnancy was uneventful with no deterioration of symptoms due to the disease. Performed amniocentesis showed healthy fetus. Planned cesarean section with spinal anesthesia was performed because of the restricted pelvis. The possible issues of combination pregnancy and CMTD are discussed. PMID:27514143

  8. Mary Cassatt: Celebrating Everyday Life. Teacher's Guide. School Arts: Looking/Learning.

    ERIC Educational Resources Information Center

    Denker, Eric

    Mary Cassatt's paintings and graphics depict the world of 19th-century women, mothers, and children. Her exploration of intimate domestic life is informed by an unsurpassed ability to capture the natural, sometimes awkward poses of her figures and her refusal to "prettify" her subjects. This teaching guide gives an overview of Cassatt's life, art…

  9. 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…

  10. 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…

  11. Bathymetric Survey and Storage Capacity of Upper Lake Mary near Flagstaff, Arizona

    USGS Publications Warehouse

    Hornewer, Nancy J.; Flynn, Marilyn E.

    2008-01-01

    Upper Lake Mary is a preferred drinking-water source for the City of Flagstaff, Arizona. Therefore, storage capacity and sedimentation issues in Upper Lake Mary are of interest to the City. The U.S. Geological Survey, in cooperation with the City of Flagstaff, collected bathymetric and land-survey data in Upper Lake Mary during late August through October 2006. Water-depth data were collected using a single-beam, high-definition fathometer. Position data were collected using real-time differential global position system receivers. Data were processed using commercial software and imported into geographic information system software to produce contour maps of lakebed elevations and for the computation of area and storage-capacity information. At full pool (spillway elevation of 6,828.5 feet above mean sea level), Upper Lake Mary has a storage capacity of 16,300 acre-feet, a surface area of 939 acres, a mean depth of 17.4 feet, and a depth near the dam of 39 feet. It is 5.6 miles long and varies in width from 308 feet near the central, narrow portion of the lake to 2,630 feet in the upper portion. Comparisons between this survey and a previous survey conducted in the 1950s indicate no apparent decrease in reservoir area or storage capacity between the two surveys.

  12. Mary Munford Model School and Virginia Commonwealth University: Unexpected Benefits in a Working Partnership.

    ERIC Educational Resources Information Center

    Fox, Jill Englebright; Branch, Stacey B.

    1999-01-01

    Describes the 5-year-old Professional Development School (PDS) relationship between the Mary Munford Model School near Richmond, Virginia, and Virginia Commonwealth University. The PDS focuses on goals of the Holmes Partnership. This paper looks at the stories of a classroom teacher and a university educator involved in the PDS. (SM)

  13. Dr. Mary McLeod Bethune: A Life Devoted to Service

    ERIC Educational Resources Information Center

    Long, Kim Cliett

    2011-01-01

    The purpose of this paper is to explore and analyze the leadership traits of Dr. Mary McLeod Bethune, an African-American woman of history, using the servant leadership theory developed by Robert K. Greenberg and the ten characteristics of servant leadership as conceived by Larry C. Spears. This exploration seeks to identify the significant…

  14. 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,…

  15. 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,…

  16. 75 FR 31835 - Environmental Impact Statement: Calvert and St. Mary's Counties, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-04

    ... Counties, Maryland (Federal Register Vol. 72, No. 203; FR Doc. 07-5190) is being withdrawn and an... Federal Highway Administration Environmental Impact Statement: Calvert and St. Mary's Counties, MD AGENCY... this notice to advise the public that a prior Notice of Intent to prepare an Environmental...

  17. Water Quality Protection of the Grand Lake St. Marys in Ohio

    EPA Science Inventory

    Grand Lake St. Marys (GLSM) in northwestern Ohio is experiencing toxic levels of algal blooms resulting from nutrients, especially phosphorus (P) input from agricultural runoff. Originally constructed as a feeder reservoir for the Miami and Erie Canal, recreation activities on t...

  18. Walt Disney Meets Mary Daly: Invention, Imagination, and the Construction of Community.

    ERIC Educational Resources Information Center

    Covino, William A.

    2000-01-01

    Posits Walt Disney as an influential sorcerer in the process of integrating the real world into Disney's synthetic universe, and Mary Daly's work "Wickedary" as a work that constructs an alternative "magic kingdom" through an insistence on an anti-patriarchal lexicon. (NH)

  19. Mary Ritter Beard and Marion Thompson Wright: Shaping Inclusive Social Education.

    ERIC Educational Resources Information Center

    Crocco, Margaret Smith

    1997-01-01

    Examines contributions by Mary Ritter Beard and Marion Thompson Wright to inclusive social education curricula. Beard established the field of women's history; Wright promoted the application of black history. Both saw social betterment as the goal of knowledge and sought inclusive understanding of the nature of legitimate knowledge in schools.…

  20. Women in History: Mary Parker Follett--A Leadership Theorist Ahead of Her Time

    ERIC Educational Resources Information Center

    Gaspar, Sandy

    2004-01-01

    This article profiles Mary Parker Follet, a management and leadership voice in the 1920s and 30s who was far ahead of her time. Throughout her lifetime, Follet refused to accept the dualities and dichotomies that threatened to divide individuals and organizations. In her book, "The New State," Follet argued that group organization and local…

  1. Mary Lincoln's Madness: Understanding the Factors that Influence the Diagnosis and Treatment of Bipolar Disorder

    ERIC Educational Resources Information Center

    Dick, Carina; Renes, Susan L.; Strange, Anthony T.

    2010-01-01

    Mary Lincoln, wife of President Abraham Lincoln, lived a tragic life. Beginning with the death of her mother when she was a little girl, Mrs. Lincoln experienced a number of family deaths, including three brothers, three sons, and the murder of her beloved husband while she sat by his side. In addition to tragedy, Mrs. Lincoln suffered from poor…

  2. 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…

  3. Marie Zimmermann Farm, U.S. Route 209, 5 Miles Southwest of ...

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

    Marie Zimmermann Farm, U.S. Route 209, 5 Miles Southwest of Milford. The property is defined at its northern boundary by Zimmermann Road and at the west by Long Meadow Road. The east boundary of the parcel is the edge of the Delaware River. The south edge of the parcel is irregularly oriented east-to-west. , Milford, Pike County, PA

  4. Sister Mary Emil Penet, I.H.M.: Founder of the Sister Formation Conference

    ERIC Educational Resources Information Center

    Glisky, Joan

    2006-01-01

    Mary Emil Penet, I.H.M., (1916-2001) used her talents and charisma to shape the first national organization of American women religious, the Sister Formation Conference (SFC; 1954-1964), facilitating the integrated intellectual, spiritual, psychological, and professional development of vowed women religious. In the decade preceding Vatican II, her…

  5. Mary S. Peake and Charlotte F. Forten: Black Teachers during the Civil War and Reconstruction

    ERIC Educational Resources Information Center

    Taylor, Kay Ann

    2005-01-01

    The teaching lives of Mary S. Peake and Charlotte L. Forten during the Civil War and Reconstruction through a limited life history approach are examined. It is a contribution to the roles of African American women in the history of American education.

  6. 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…

  7. Unheralded Historian: Mary Sheldon Barnes and Primary Source Material in History Books

    ERIC Educational Resources Information Center

    Chisholm, James A., Jr.

    2013-01-01

    In the latter part of the nineteenth century, Mary Sheldon Barnes emerged as a leading historical methods professor and history textbook author. Although men dominated the field, she wrote several articles and books alone or with her husband Earl Barnes about primary source materials and teaching. She lived during an era in United States history…

  8. Mary Hayes and Deborah Sampson: The Rhetoric of Neglect, Praise, and Expectation.

    ERIC Educational Resources Information Center

    Hassencahl, Fran

    This study focuses on the rhetoric about, rather than the rhetoric of, two Revolutionary War heroines, Mary Hayes and Deborah Sampson Gannet. The rhetoric about these women is divided into three areas: the rhetoric of neglect, as practiced by conventional historians; the rhetoric of praise, as given by patriotic societies such as the Daughters of…

  9. Principal Succession: A View through the Lens of Mary Douglas' Grid and Group

    ERIC Educational Resources Information Center

    Mills, Angela

    2012-01-01

    Scope and Method of Study: This Naturalistic Inquiry Case Study examines principal succession at two small, rural high schools through naturalistic inquiry presented through the lens of Mary Douglas' grid and group cultural typology. A grid and group cultural analysis survey was sent to all school employees then in-depth, follow-up interviews…

  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 "static brochure" into…

  11. The Gendering of Albert Einstein and Marie Curie in Children's Biographies: Some Tensions

    ERIC Educational Resources Information Center

    Wilson, Rachel E.; Jarrard, Amber R.; Tippins, Deborah J.

    2009-01-01

    Few twentieth century scientists have generated as much interest as Albert Einstein and Marie Currie. Their lives are centrally depicted in numerous children's biographies of famous scientists. Yet their stories reflect interesting paradoxes and tacit sets of unexplored sociocultural assumptions about gender in science education and the larger…

  12. Science and Special Needs at Mary Hare School for the Deaf.

    ERIC Educational Resources Information Center

    Wright, Kevin

    2002-01-01

    Introduces the Mary Hare School which caters to academically able but very deaf children and explains the philosophy of a school that uses an oral approach to enable all students to have access to the normal curriculum and maximize their potential. (Author/YDS)

  13. Strangers and Orphans: Knowledge and Mutuality in Mary Shelley's "Frankenstein"

    ERIC Educational Resources Information Center

    Gomez, Claudia Rozas

    2013-01-01

    Paulo Freire consistently upheld humanization and mutuality as educational ideals. This article argues that conceptualizations of knowledge and how knowledge is sought and produced play a role in fostering humanization and mutuality in educational contexts. Drawing on Mary Shelley's novel "Frankenstein," this article focuses on the…

  14. From Cradleboard to Motherboard: Buffy Sainte-Marie's Interactive Multimedia Curriculum Transforms Native American Studies.

    ERIC Educational Resources Information Center

    King, Claire

    2000-01-01

    Describes "Science: Through Native American Eyes," an interactive multimedia CD-ROM for middle school that is part of the Cradleboard Teaching Project developed by musician and teacher Buffy Sainte-Marie. The Cradleboard joins Native American tradition and high-tech innovation to explore the core curriculum of the National Content Standards. (SLD)

  15. Assessing a Couple's Relationship and Compatibility Using the MARI[R] Card Test and Mandala Drawings

    ERIC Educational Resources Information Center

    Frame, Phyllis G.

    2006-01-01

    This paper illustrates the use of the MARI[R] Card Test, a transpersonal assessment tool which includes archetypal designs and color choices, as well as the drawing of a white and black mandala, or circle picture, for assessing the compatibility of two people in a committed relationship. In an informal pilot research study, 22 couples were given…

  16. 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, "Women and…

  17. Open Concept School for Indian Education. Sault Sainte Marie, Michigan, 1973.

    ERIC Educational Resources Information Center

    Sault Sainte Marie Public Schools, MI.

    The product of an Elementary Secondary Education Act Title III project produced by the staff and administration of the Finlayson Elementary School in Sault Ste. Marie, Michigan for American Indian students, this handbook is designed as a guide to educators engaging in open concept education. Constituting a model, this handbook incorporates the…

  18. Living Proof: What Helen Keller, Marilyn Monroe, and Marie Curie Have in Common.

    ERIC Educational Resources Information Center

    Saul, E. Wendy

    1986-01-01

    Examines biographies of Marie Curie written for children and discusses two types of distortions: simple misrepresentations of fact and selective retelling of the past. It is concluded that biographies of minority or female success should deal specifically with strategies used by the hero or heroine to combat prejudice. (EM)

  19. 75 FR 22436 - Michael Williams-Control Exemption-St. Maries River Railroad, Inc.

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-28

    ... Surface Transportation Board Michael Williams-Control Exemption-St. Maries River Railroad, Inc. Michael Williams (applicant),\\1\\ a noncarrier, has filed a verified notice of exemption to acquire control of St.... Petitions for stay must be filed no later than May 5, 2010 (at least 7 days before the exemption...

  20. Saint Mary's College Small Library Planning Program. Report of a Self Study, September 1979-October 1980.

    ERIC Educational Resources Information Center

    Saint Mary's Coll., Notre Dame, IN.

    A nine month self-study aimed at improving public and technical services, internal operations, and overall management was conducted during 1979-80 by the library staff at Saint Mary's College. A part of the Small Library Planning Program, the study was funded by the Lilly Foundation through the Office of Management Studies, Association of Research…

  1. Mary Pickersgill: The Woman Who Sewed the Star-Spangled Banner

    ERIC Educational Resources Information Center

    Smith, Megan; Wei, Jenny

    2013-01-01

    Just imagine: you live in a time before electricity. There are no sewing machines, no light bulbs, and certainly no television shows to keep you entertained. You spend six days a week working 12-hours each day inside your small home with four teenage girls and your elderly mother. This was the life of Mary Pickersgill, the woman who sewed the…

  2. Magic Women on the Margins: Ec-Centric Models in Mary Poppins and Ms Wiz

    ERIC Educational Resources Information Center

    Valverde, Cristina Perez

    2009-01-01

    This paper offers a comparative analysis of two characters belonging to the tradition of empowered "spinster" in children's fiction, namely Mary Poppins and Ms Wiz, from the perspective of gender politics and child/adult interactions. A distinction is made between the figure portrayed in P. L. Travers' texts and the Disney film starring Julie…

  3. Public archaeological interpretation on the campus of St. Mary's College of Maryland

    NASA Astrophysics Data System (ADS)

    Horrom, Alexander Michael

    2011-12-01

    Communicating archaeological findings to non-archaeologists is one of the most important and challenging aspects of the discipline. Archaeologists must serve multiple publics, bring communities into the archaeological process, and effectively disseminate information in order for their work to achieve relevance in the modern world. Communication with the public can take many forms, and brings together aspects of historic preservation, dialogic interpretation, applied critical archaeology, heritage, and landscape studies. This dissertation analyzes public interpretation at St. Mary's City, Maryland, a multi-component historic landscape containing historic and prehistoric sites from various time periods and proposes measures to be taken there to better engage the public. This site presents a unique context for public interpretation: the Historic St. Mary's City archaeological museum occupies a portion of the landscape, while neighboring St. Mary's College of Maryland is a public collegiate campus that contains an imposing number of uninterpreted sites. Exploration of the histories and relationships between these institutions provide insight into the many factors which impact public interpretation. Examination of this case includes identifying audiences, gauging attitudes towards archaeology, assessing current interpretive measures, and identifying areas where public engagement can be improved. The example of St. Mary's outlines how an individual's relationship to archaeology is interwoven into their experience of the landscape. The past and present coexist on historic landscapes, and public communication can use this juxtaposition to engage audiences in meaningful ways. I conclude by developing an archaeological walking tour of the St. Mary's landscape aimed at creating discussion and making people aware of the sites around them.

  4. Spatially detailed quantification of metal loading for decision making: Metal mass loading to American fork and Mary Ellen Gulch, Utah

    USGS Publications Warehouse

    Kimball, B.A.; Runkel, R.L.

    2009-01-01

    Effective remediation requires an understanding of the relative contributions of metals from all sources in a catchment, and that understanding must be based on a spatially detailed quantification of metal loading. A traditional approach to quantifying metal loading has been to measure discharge and chemistry at a catchment outlet. This approach can quantify annual loading and the temporal changes in load, but does not provide the needed spatial detail to evaluate specific sources, which is needed to support remediation decisions. A catchment or massloading approach provides spatial detail by combining tracer-injection and synoptic-sampling methods to quantify loading. Examples of studies in American Fork, Utah, and its tributary Mary Ellen Gulch illustrate this different approach. The mass-loading study in American Fork treated Mary Ellen Gulch as a single inflow. From that point of view, Mary Ellen Gulch was one of the greatest sources of Fe, Mn, Zn, and colloidal Pb loads to American Fork. But when Mary Ellen Gulch was evaluated in a separate catchment study, the detailed locations of metal loading were identified, and the extent of metal attenuation upstream from the mouth of Mary Ellen Gulch was quantified. The net, instantaneous load measured at the mouth of Mary Ellen Gulch for remediation planning would greatly underestimate the contributions of principal sources within the catchment. Extending the detailed sampling downstream from Mary Ellen Gulch indicated the possibility of diffuse groundwater inflow from Mary Ellen Gulch to American Fork. Comparing loads for Mary Ellen Gulch in the two studies indicates that metal loads could be substantially underestimated for planning purposes without the detailed catchment approach for the low-flow conditions in these studies. A mass-loading approach provides both the needed quantification of metal loading and the spatial detail to guide remediation decisions that would be the most effective in the catchments

  5. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.

    PubMed

    Montecchiani, Celeste; Pedace, Lucia; Lo Giudice, Temistocle; Casella, Antonella; Mearini, Marzia; Gaudiello, Fabrizio; Pedroso, José L; Terracciano, Chiara; Caltagirone, Carlo; Massa, Roberto; St George-Hyslop, Peter H; Barsottini, Orlando G P; Kawarai, Toshitaka; Orlacchio, Antonio

    2016-01-01

    Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼ 40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot-Marie

  6. 77 FR 43644 - Culturally Significant Objects Imported for Exhibition Determinations: “Byzantine Art in the Mary...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-25

    ... Michael Jaharis Galleries of Greek, Roman and Byzantine Art'' SUMMARY: Notice is hereby given of the... exhibition ``Byzantine Art in the Mary and Michael Jaharis Galleries of Greek, Roman and Byzantine...

  7. [Marie Curie, née Maria Sklodowska (1867-1934)--contribution to the development of radiology].

    PubMed

    Babić, Rade R; Babić, Gordana Stanković

    2011-01-01

    Marie Curie, née Maria Sklodowska, was born on November 7, 1867 in Warsaw (Poland). She suffered from leukaemia and died on June 4, 1934. She was buried with full honours at Pantheon. Marie Curie and her husband Pierre Curie discovered the radioactive elements Polonium (84Po210), Thorium (90Th232) and Radium (88Ra226). Marie Curie introduced the term radioactivity into science. She was the first woman who got Ph.D. in France, the first woman professor at Sorbonne, Paris and Medical Academy. Of all the women who have ever won the Nobel Prize, Marie Curie was the only who received it twice. During World War I Marie Curie designed a mobile x-ray room "radiologic car". Marie Curie had an x-ray machine installed into a car and demonstrated how to use its dynamo for electric power production necessary for the x-ray machine to work. She had 20 cars with moving radiological lab made and trained 150 people to work on them. She brought something radically new into military medicine--mobile x-ray diagnostics. With the discovery of radioactive elements a new medical branch, radiotherapy, was developed. PMID:21905607

  8. The ties that bind: Soil surveyor William Edgar Tharp and oceanographic cartographer Marie Tharp

    NASA Astrophysics Data System (ADS)

    Landa, Edward R.

    The link between soil science and geology is personified in the American father and daughter: soil surveyor William Edgar Tharp (1870-1959) and oceanographic cartographer Marie Tharp (1920-2006). From 1904 to 1935, W.E. Tharp mapped soils in 14 states for the US Department of Agriculture, and campaigned during the late 1920s-early 1930s to raise awareness of the high rates of soil erosion from croplands. The lifestyle of the federal soil surveyor in the United States during the early 20th century involved frequent household moves, and it played a formative role in Marie Tharp’s childhood. Her path to a career in geology was molded by this family experience, by mentors encountered in the classroom, and by social barriers that faced women scientists of that era.

  9. Genome sequence of the marine bacterium Corynebacterium maris type strain Coryn-1(T) (= DSM 45190(T)).

    PubMed

    Schaffert, Lena; Albersmeier, Andreas; Bednarz, Hanna; Niehaus, Karsten; Kalinowski, Jörn; Rückert, Christian

    2013-07-30

    Corynebacterium maris Coryn-1(T) Ben-Dov et al. 2009 is a member of the genus Corynebacterium which contains Gram-positive, non-spore forming bacteria with a high G+C content. C. maris was isolated from the mucus of the Scleractinian coral Fungia granulosa and belongs to the aerobic and non-haemolytic corynebacteria. It displays tolerance to salts (up to 10%) and is related to the soil bacterium Corynebacterium halotolerans. As this is a type strain in a subgroup of Corynebacterium without complete genome sequences, this project, describing the 2.78 Mbp long chromosome and the 45.97 kbp plasmid pCmaris1, with their 2,584 protein-coding and 67 RNA genes, will aid the G enomic E ncyclopedia of Bacteria and Archaea project. PMID:24501635

  10. Mining Cultures and Mary Cults: Where the Sacred and Profane Meet.

    PubMed

    Munday, Pat

    2016-01-01

    Our Lady of the Rockies (OLR) is a ninety-foot-tall statue of the Virgin Mary overlooking Butte, Montana, from its perch high atop the Continental Divide. In the popularized account, OLR is a uniquely local undertaking reflecting the community's character and pride. Yet OLR is far more than this, for it taps into a rich vein of cultural and spiritual tradition. As Mircea Eliade pointed out, the notion of the earth as female pervaded early Western civilizations. Mines were like the vagina of the earth, leading to the womb where metallic ores waxed like embryos. Accordingly, miners purified themselves through various rites to amend their violation. OLR began as a plan for a small, private altar. With the collapse of Butte's copper mining economy, unemployed miners rallied around the idea of building a major shrine to the Virgin Mary that would help restore the city's culture and economy. PMID:26971726

  11. De Novo duplication in Charcot-Marie-Tooth Type 1A

    SciTech Connect

    Mandich, P.; Bellone, E.; Ajmar, F.

    1996-09-01

    We read with interest the paper on {open_quotes}Prevalence and Origin of De Novo Duplications in Charcot-Marie-Tooth Disease Type 1A: First Report of a De Novo Duplication with a Maternal Origin,{close_quotes}. They reported their experience with 10 sporadic cases of Charcot-Marie-Tooth type 1A (CMT1A) in which it was demonstrated that the disease had arisen as the result of a de novo duplication. They analyzed the de novo-duplication families by using microsatellite markers and identified the parental origin of the duplication in eight cases. In one family the duplication was of maternal origin, whereas in the remaining seven cases it was of paternal origin. The authors concluded that their report was the first evidence of a de novo duplication of maternal origin, suggesting that this is not a phenomenon associated solely with male meiosis. 7 refs.

  12. GPS evidence for a coherent Antarctic plate and for postglacial rebound in Marie Byrd Land

    NASA Astrophysics Data System (ADS)

    Donnellan, Andrea; Luyendyk, Bruce P.

    2004-07-01

    GPS measurements collected between 1999 and 2002 in Marie Byrd Land, West Antarctica indicate no significant present motion between East and West Antarctica greater than 1-2 mm/year. Low strain rates imply that the Ross Sea rift is either inactive or active at a very low rate. This result indicates that the two subcontinents are likely joined as a single coherent lithospheric plate. They could have been joined since the end of Adare Trough spreading in Oligocene time. The volcanic activity in the Ross Sea sector at present such as at Mount Erebus is most likely related to mantle upwelling and not associated with continental rifting. GPS measurements of vertical rates indicate postglacial rebound of up to 12±4 mm/year in western Marie Byrd Land (wMBL). Errors are scaled 1 σ. The rock uplift rates are consistent with postglacial rebound models of significant ice thinning in the eastern Ross Ice Shelf in the late Holocene.

  13. 250 Years of Physics at the College of William and Mary: 1760-2010

    NASA Astrophysics Data System (ADS)

    von Baeyer, Hans

    2010-02-01

    The recorded history of physics at William and Mary begins when Thomas Jefferson, the College's most distinguished alumnus, meets his mentor, Dr. William Small of Scotland, who opens his eyes to the wonders of natural philosophy. After the vicissitudes of the Revolution and the Civil War, physics enjoys a revival in the twentieth century, culminating in the creation of a Ph.D. program in the 1960s and the building of the William Small Physical Laboratory in Williamsburg. In the 1980s the modern era is launched by the establishment of the US Department of Energy's Jefferson Lab for nuclear physics in nearby Newport News. Today both Small Hall and Jefferson Lab are in the process of renovation. The legacies of Small and Jefferson for physics at William and Mary are secure! )

  14. I Want to Believe: A Short Psychobiography of Mary Baker Eddy.

    PubMed

    Dean, Taylor Wilson

    2016-01-01

    The 18th and 19th centuries were beset with new religious movements in the United States: Shakers, Latter Day Saints, Millerites, and Seventh Day Adventists to name a few. One group, Christian Science, held radically different views than their counterparts and their origins lay in the most unlikely of places, a perpetually ill and poor woman from New Hampshire. Much has been said about Mary Baker Eddy: some say that she was a prophet, others that she was a fraud. Herein no such judgments are made. This study seeks to look into the life of Mary Baker Eddy from a psychological lens in the hopes that insight can be gained into the founding of the First Church of Jesus Christ Scientist and perhaps to allay the binary of Mrs. Eddy as either prophet or fanatic. PMID:27480014

  15. Concept And Its Implementation During The Reconstruction Of The Church Of Blessed Virgin Mary In Chojna

    NASA Astrophysics Data System (ADS)

    Płotkowiak, Maciej

    2015-12-01

    St. Mary's parish church in Chojna was erected at the turn of XIV and XVc. in a shape of three aisles, hall church without transept, completed from the west with a single tower and from the east with polygonal presbytery with an ambulatory attached. The convergence of characteristic structural and decorative features with employed ones in medieval churches being attributed to Hinrich Brunsberg's fabric resulted in such a way, that also authorship of St. Mary in Chojna was assigned to this legendary architect and master builder of late Middle Ages period. The church was destroyed by fire during WWII in February 1945 and since then had remained as an open ruin. In 1997 reconstruction procedure of the church was begun under the leadership of the author and it still continues. This text consists of the sum of experiences connected with confronting design ideas and solutions with their executions on the site during construction works.

  16. Overlapping molecular pathological themes link Charcot-Marie-Tooth neuropathies and hereditary spastic paraplegias.

    PubMed

    Timmerman, Vincent; Clowes, Virginia E; Reid, Evan

    2013-08-01

    In this review we focus on Charcot-Marie-Tooth (CMT) neuropathies and hereditary spastic paraplegias (HSPs). Although these diseases differ in whether they primarily affect the peripheral or central nervous system, both are genetically determined, progressive, long axonopathies that affect motor and sensory pathways. This commonality suggests that there might be similarities in the molecular pathology underlying these conditions, and here we compare the molecular genetics and cellular pathology of the two groups. PMID:22285450

  17. 1935 Period Plan Marie Zimmermann Farm, U.S. Route 209, ...

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

    1935 Period Plan - Marie Zimmermann Farm, U.S. Route 209, 5 Miles Southwest of Milford. The property is defined at its northern boundary by Zimmermann Road and at the west by Long Meadow Road. The east boundary of the parcel is the edge of the Delaware River. The south edge of the parcel is irregularly oriented east-to-west. , Milford, Pike County, PA

  18. 1972 Period Plan Marie Zimmermann Farm, U.S. Route 209, ...

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

    1972 Period Plan - Marie Zimmermann Farm, U.S. Route 209, 5 Miles Southwest of Milford. The property is defined at its northern boundary by Zimmermann Road and at the west by Long Meadow Road. The east boundary of the parcel is the edge of the Delaware River. The south edge of the parcel is irregularly oriented east-to-west. , Milford, Pike County, PA

  19. Carbon Cycle 2.0: Mary Ann Piette: Impact of efficient buildings

    SciTech Connect

    Mary Ann Piette

    2010-02-09

    Mary Ann Piette speaks at the Carbon Cycle 2.0 kick-off symposium Feb. 2, 2010. We emit more carbon into the atmosphere than natural processes are able to remove - an imbalance with negative consequences. Carbon Cycle 2.0 is a Berkeley Lab initiative to provide the science needed to restore this balance by integrating the Labs diverse research activities and delivering creative solutions toward a carbon-neutral energy future. http://carboncycle2.lbl.gov/

  20. Exploring variation-aware contig graphs for (comparative) metagenomics using MaryGold

    PubMed Central

    Nijkamp, Jurgen F.; Pop, Mihai; Reinders, Marcel J. T.; de Ridder, Dick

    2013-01-01

    Motivation: Although many tools are available to study variation and its impact in single genomes, there is a lack of algorithms for finding such variation in metagenomes. This hampers the interpretation of metagenomics sequencing datasets, which are increasingly acquired in research on the (human) microbiome, in environmental studies and in the study of processes in the production of foods and beverages. Existing algorithms often depend on the use of reference genomes, which pose a problem when a metagenome of a priori unknown strain composition is studied. In this article, we develop a method to perform reference-free detection and visual exploration of genomic variation, both within a single metagenome and between metagenomes. Results: We present the MaryGold algorithm and its implementation, which efficiently detects bubble structures in contig graphs using graph decomposition. These bubbles represent variable genomic regions in closely related strains in metagenomic samples. The variation found is presented in a condensed Circos-based visualization, which allows for easy exploration and interpretation of the found variation. We validated the algorithm on two simulated datasets containing three respectively seven Escherichia coli genomes and showed that finding allelic variation in these genomes improves assemblies. Additionally, we applied MaryGold to publicly available real metagenomic datasets, enabling us to find within-sample genomic variation in the metagenomes of a kimchi fermentation process, the microbiome of a premature infant and in microbial communities living on acid mine drainage. Moreover, we used MaryGold for between-sample variation detection and exploration by comparing sequencing data sampled at different time points for both of these datasets. Availability: MaryGold has been written in C++ and Python and can be downloaded from http://bioinformatics.tudelft.nl/software Contact: d.deridder@tudelft.nl PMID:24058058

  1. Laparoscopic appendectomy in a pediatric patient with type 1 Charcot-Marie-Tooth disease.

    PubMed

    Heller, Joshua A; Marn, Richard Y

    2015-12-01

    A pediatric patient with type 1 Charcot-Marie-Tooth disease-a disorder associated with a demyelinating polyneuropathy-presented for laparoscopic appendectomy in the setting of acute appendicitis. Induction and maintenance of anesthesia were successfully managed without the use of any depolarizing or nondepolarizing neuromuscular blocking agents. The patient was successfully extubated at the completion of the procedure without any respiratory or neuromuscular sequelae, with excellent pain control and no postoperative nausea or vomiting. PMID:26403061

  2. 2012 Existing Landscape Plan Marie Zimmermann Farm, U.S. Route ...

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

    2012 Existing Landscape Plan - Marie Zimmermann Farm, U.S. Route 209, 5 Miles Southwest of Milford. The property is defined at its northern boundary by Zimmermann Road and at the west by Long Meadow Road. The east boundary of the parcel is the edge of the Delaware River. The south edge of the parcel is irregularly oriented east-to-west. , Milford, Pike County, PA

  3. 2012 Existing Vegetation Plan Marie Zimmermann Farm, U.S. Route ...

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

    2012 Existing Vegetation Plan - Marie Zimmermann Farm, U.S. Route 209, 5 Miles Southwest of Milford. The property is defined at its northern boundary by Zimmermann Road and at the west by Long Meadow Road. The east boundary of the parcel is the edge of the Delaware River. The south edge of the parcel is irregularly oriented east-to-west. , Milford, Pike County, PA

  4. Refined genetic mapping of X-linked Charcot-Marie-Tooth neuropathy

    SciTech Connect

    Fain, P.R.; Barker, D.F.; Chance, P.F. )

    1994-02-01

    Genetic linkage studies were conducted in four multigenerational families with X-linked Charcot-Marie-Tooth disease (CMTX), using 12 highly polymorphic short-tandem-repeat markers for the pericentromeric region of the X Chromosome. Pairwise linkage analysis with individual markers confirmed tight linkage of CMTX to the pericentromeric region in each family. Multipoint analyses strongly support the order DXS337-CMTX-DXS441-(DXS56, PGK1). 38 refs., 2 figs., 1 tab.

  5. Carbon Cycle 2.0: Mary Ann Piette: Impact of efficient buildings

    ScienceCinema

    Mary Ann Piette

    2010-09-01

    Mary Ann Piette speaks at the Carbon Cycle 2.0 kick-off symposium Feb. 2, 2010. We emit more carbon into the atmosphere than natural processes are able to remove - an imbalance with negative consequences. Carbon Cycle 2.0 is a Berkeley Lab initiative to provide the science needed to restore this balance by integrating the Labs diverse research activities and delivering creative solutions toward a carbon-neutral energy future. http://carboncycle2.lbl.gov/

  6. Mary Shelley's Frankenstein: exploring neuroscience, nature, and nurture in the novel and the films.

    PubMed

    Ginn, Sheryl R

    2013-01-01

    The story of Victor Frankenstein's quest to conquer death produced a legacy that has endured for almost 200 years. Powerful in its condemnation of the scientist's quest to achieve knowledge at any cost, Mary Shelley's Frankenstein is one of the most enduring novels of all time. It has never been out of print and has been translated to both stage and screen many times since its "birth." Numerous novels, short stories, and scripts have drawn upon Shelley's primary theme: the creation of a living organism from the dead, dying, and decaying body parts of human beings. Although Mary does not provide details of the animation process, particularly in her first edition, the process has been explored with a great deal of imagination and originality in the various cinematic portrayals of the story. Equally important as the theme of the scientist's quest for knowledge is the role that a creator plays in the life of its creation. Mary Shelley's novel pondered on how rejection would affect the offspring of such "unnatural" origins. In keeping with the "scientific" basis of the Creature's birth, cinematic portrayals attempted to provide a scientific rationale for the Creature's descent into madness and its evil behavior. From Robert Florey's initial script for the 1931 film directed by James Whale to the more recent films and television series, an abnormal brain is considered to be the cause of the madness and malignity of the Creature. PMID:24041324

  7. XAS studies of the effectiveness of iron chelating treatments of Mary Rose timbers

    NASA Astrophysics Data System (ADS)

    Berko, A.; Smith, A. D.; Jones, A. M.; Schofield, E. J.; Mosselmans, J. F. W.; Chadwick, A. V.

    2009-11-01

    The oxidation of sulfur in marine archaeological timbers under museum storage conditions is a recently identified problem, particularly for major artefacts such as historic ships excavated from the seabed. Recent work on the Vasa has stressed the role of iron in catalysing the oxidative degradation of the wood cellulose and the polyethylene glycols used to restore mechanical integrity to the timbers. In developing new treatment protocols for the long term preservation of Henry VIII of England's flagship, the Mary Rose, we are investigating the potential of chelating agents to neutralise and remove the iron products from the ships timbers. We have explored the use of aqueous solutions of chelating agents of calcium phytate, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA) and ammonium citrate to extract the iron compounds. All of these solutions exhibit some level of iron removal; however the key is to find the most effective concentration at pH of around 7 of the reagent solution, to minimise the treatment time and find the most cost-effective treatment for the whole of the Mary Rose hull. Fe K-edge XAFS data from samples of Mary Rose timbers, before and after treatment by the chelating agents mentioned has been collected. The data collected provide valuable insights into the effectiveness of the treatment solutions.

  8. Long-term trends in the St. Marys River open water fish community

    USGS Publications Warehouse

    Schaeffer, Jeffrey S.; Fielder, David G.; Godby, Neal; Bowen, Anjanette; O'Connor, Lisa; Parrish, Josh; Greenwood, Susan; Chong, Stephen; Wright, Greg

    2011-01-01

    We examined trends in species composition and abundance of the St. Marys River fish community. Abundance data were available approximately once every six years from 1975 through 2006, and size and age data were available from 1995 through 2006. We also compared survey data in 2006 with results of a concurrent creel survey that year, as well as data from prior surveys spanning a 69 year time frame. The St. Marys River fish community was best characterized as a coolwater fish community with apparent little variation in species composition, and only slight variation in overall fish abundance since 1975. However, we did find recent trends in abundance among target species sought by anglers: centrarchids increased, percids appeared stable, and both northern pike Esox lucius and cisco Coregonus artedii declined. Survey results suggested that walleye (Sander vitreus) and yellow perch (Perca flavescens) experienced moderate exploitation but benefited from recent strong recruitment and faster growth. Mechanisms underlying declines of northern pike and cisco were not clear; reduced abundance could have resulted from high exploitation, variation in recruitment, or a combination of both factors. Despite these challenges, the St. Marys River fish community appears remarkably stable. We suggest that managers insure that creel surveys occur simultaneously with assessments, but periodic gill net surveys may no longer provide adequate data in support of recent, more complex management objectives. While additional surveys would add costs, more frequent data might ensure sustainability of a unique fish community that supports a large proportion of angler effort on Lake Huron.

  9. Solar Particle Events at Mars Seen by MARIE, 2002-2003

    NASA Technical Reports Server (NTRS)

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

    2004-01-01

    The MARIE detector aboard the 200 1 Mars Odyssey operated continuously between March 13, 2002, and October 28, 2003. During these twenty months, approximately 12 periods of enhanced solar particle activity were observed. The last of these, on October 26-28, 2003, caused the instrument to lose communication with the spacecraft. In addition to that very large event, several other major Solar Particle Events (SPEs) were observed. Those prior to March 2003 have been discussed elsewhere [I] and will be reviewed here. Many of the solar events seen at Mars correspond well to observations by GOES and ACE satellites near Earth. Some SPEs were observed by MARIE when Mars was on, or near, the opposite side of the sun as seen from Earth; and while a few of them - most notably the large full-halo Coronal Mass Ejections of July 2002 - coincided with events seen by the near-Earth satellites, others were not seen at Earth. Conversely, in this same time period, some SPEs were seen at Earth but not at Mars. Subsequent to February 2003, three SPEs were observed by MARIE, on March 18- 20, May 28 - June 3, and Oct. 26-28. Observations of solar energetic particles at Mars can be combined with data from other points in the heliosphere from, e.g., the Solar Heliospheric Observatory, ACE/CRIS, and GOES satellites near Earth, and Ulysses. Having several different observation points is useful for testing models of CME initiation and propagation.

  10. What Mary Toft Felt: Women’s Voices, Pain, Power and the Body

    PubMed Central

    2015-01-01

    In autumn 1726, Mary Toft began to deliver rabbits in Godalming, Surrey. The case became a sensation and was reported widely in newspapers, popular pamphlets, poems and caricatures. Toft was attended by at least six different doctors, some members of the Royal College of Physicians or attached to the Royal Court, but no doctor declared the affair a hoax until Toft herself confessed on 7 December 1726. This article focuses on Toft’s three surviving confessions in order to explore not the doctors or even wider representations of the affair but instead the person of Mary Toft herself. These rare sources give rare insight into one woman’s experiences of reproduction in the early eighteenth century. The essay engages with recent work on recovering women’s voices in the past, reconstructing Mary Toft’s words and her embodied and affective experience of the affair. These documents suggest a revision to our understanding of the hoax of 1726, one that situates the affair not in the context of the scientific revolution and Enlightenment or the assumption of men’s control over midwifery, but instead in the context of power dynamics amongst women in the practices of early-modern reproduction and birth. PMID:27019607

  11. An Overview of the MaRIE X-FEL and Electron Radiography LINAC RF Systems

    SciTech Connect

    Bradley, Joseph Thomas III; Rees, Daniel Earl; Scheinker, Alexander; Sheffield, Richard L.

    2015-05-04

    The purpose of the Matter-Radiation Interactions in Extremes (MaRIE) facility at Los Alamos National Laboratory is to investigate the performance limits of materials in extreme environments. The MaRIE facility will utilize a 12 GeV linac to drive an X-ray Free-Electron Laser (FEL). Most of the same linac will also be used to perform electron radiography. The main linac is driven by two shorter linacs; one short linac optimized for X-FEL pulses and one for electron radiography. The RF systems have historically been the one of the largest single component costs of a linac. We will describe the details of the different types of RF systems required by each part of the linacs. Starting with the High Power RF system, we will present our methodology for the choice of RF system peak power and pulselength with respect to klystron parameters, modulator parameters, performance requirements and relative costs. We will also present an overview of the Low Level RF systems that are proposed for MaRIE and briefly describe their use with some proposed control schemes.

  12. Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.

    PubMed

    Sevilla, Teresa; Lupo, Vincenzo; Martínez-Rubio, Dolores; Sancho, Paula; Sivera, Rafael; Chumillas, María J; García-Romero, Mar; Pascual-Pascual, Samuel I; Muelas, Nuria; Dopazo, Joaquín; Vílchez, Juan J; Palau, Francesc; Espinós, Carmen

    2016-01-01

    Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a

  13. Single cell mutational analysis of PIK3CA in circulating tumor cells and metastases in breast cancer reveals heterogeneity, discordance, and mutation persistence in cultured disseminated tumor cells from bone marrow

    PubMed Central

    2014-01-01

    Background Therapeutic decisions in cancer are generally guided by molecular biomarkers or, for some newer therapeutics, primary tumor genotype. However, because biomarkers or genotypes may change as new metastases emerge, circulating tumor cells (CTCs) from blood are being investigated for a role in guiding real-time drug selection during disease progression, expecting that CTCs will comprehensively represent the full spectrum of genomic changes in metastases. However, information is limited regarding mutational heterogeneity among CTCs and metastases in breast cancer as discerned by single cell analysis. The presence of disseminated tumor cells (DTCs) in bone marrow also carry prognostic significance in breast cancer, but with variability between CTC and DTC detection. Here we analyze a series of single tumor cells, CTCs, and DTCs for PIK3CA mutations and report CTC and corresponding metastatic genotypes. Methods We used the MagSweeper, an immunomagnetic separation device, to capture live single tumor cells from breast cancer patients’ primary and metastatic tissues, blood, and bone marrow. Single cells were screened for mutations in exons 9 and 20 of the PIK3CA gene. Captured DTCs grown in cell culture were also sequenced for PIK3CA mutations. Results Among 242 individual tumor cells isolated from 17 patients and tested for mutations, 48 mutated tumor cells were identified in three patients. Single cell analyses revealed mutational heterogeneity among CTCs and tumor cells in tissues. In a patient followed serially, there was mutational discordance between CTCs, DTCs, and metastases, and among CTCs isolated at different time points. DTCs from this patient propagated in vitro contained a PIK3CA mutation, which was maintained despite morphological changes during 21 days of cell culture. Conclusions Single cell analysis of CTCs can demonstrate genotypic heterogeneity, changes over time, and discordance from DTCs and distant metastases. We present a cautionary

  14. Temperature history of Coregonus artedi in the St. Marys River, Laurentian Great Lakes, inferred from oxygen isotopes in otoliths

    USGS Publications Warehouse

    Joukhadar, Zeina; Patterson, W.P.; Todd, T.N.; Smith, G.R.

    2002-01-01

    The population of Coregonus artedi in the St. Marys River, between lakes Superior and Huron, was sampled and otoliths were analyzed for oxygen isotopic composition to determine whether the fish are residents in the St. Marys River and its warm bays or migrants to and from cold Lake Huron. Otoliths were extracted, sectioned, and growth ring-specific samples of calcium carbonate were milled to obtain samples for determination of oxygen isotope ratios (18O values). The 18O values of calcium carbonate (CaCO3) in accretionary structures such as otoliths allow calculation of growth temperatures of the fish, because of differential fractionation of oxygen isotopes at different temperatures. Growth temperatures of 10 St. Marys River lake herring were compared with lake and catch data as well as growth temperatures of lake herring collected from Lake Huron and other ciscoes from the Great Lakes. Results of this analysis indicate that these fish remained in the bays of the St. Marys River for their entire life history. After their second year they grew at average temperatures between 11 C and 13 C, consistent with temperature in the warmer bays of the St. Marys River and 6 C higher than expected for growth of this species in Lake Huron.

  15. Analytical performance of the automated multianalyte point-of-care mariPOC® for the detection of respiratory viruses.

    PubMed

    Sanbonmatsu-Gámez, Sara; Pérez-Ruiz, Mercedes; Lara-Oya, Ana; Pedrosa-Corral, Irene; Riazzo-Damas, Cristina; Navarro-Marí, José María

    2015-11-01

    The analytical performance of mariPOC® respi test (ArcDia® Laboratories, Turku, Finland) was evaluated using nucleic acid amplification techniques (NAATs) as the gold standard. The mariPOC assay allows automated detection of antigens from 8 respiratory viruses: influenza A and B viruses, respiratory syncytial virus, adenovirus, human metapneumovirus, and parainfluenza viruses 1-3. Positive results from samples with high viral load are available in 20min. Nasopharyngeal aspirates (n=192) from patients with acute respiratory infection and from previously positive samples were analyzed by mariPOC and NAATs (Simplexa(TM) FluA/FluB & RSV kit [n=118] and Luminex® Respiratory virus panel xTAG® RVP FAST [n=74]). Sensitivity, specificity, positive predictive value, and negative predictive value of mariPOC were 85.4%, 99.2%, 95.9%, and 97%, respectively, and 84.6% of positive results were reported in 20min. The good analytical performance and extended portfolio of mariPOC show this rapid assay as a good alternative for the etiological diagnosis of acute respiratory infection in laboratories that are not equipped with molecular assays. PMID:26283523

  16. Lack of Association between ABO, PPAP2B, ADAMST7, PIK3CG, and EDNRA and Carotid Intima-Media Thickness, Carotid Plaques, and Cardiovascular Disease in Patients with Rheumatoid Arthritis

    PubMed Central

    López-Mejías, Raquel; Genre, Fernanda; García-Bermúdez, Mercedes; Ubilla, Begoña; Castañeda, Santos; Llorca, Javier; González-Juanatey, Carlos; Corrales, Alfonso; Miranda-Filloy, José A.; Pina, Trinitario; Gómez-Vaquero, Carmen; Rodríguez-Rodríguez, Luis; Fernández-Gutiérrez, Benjamín; Balsa, Alejandro; Pascual-Salcedo, Dora; López-Longo, Francisco J.; Carreira, Patricia; Blanco, Ricardo; Martín, Javier; González-Gay, Miguel A.

    2014-01-01

    Introduction. Rheumatoid arthritis (RA) is a polygenic disease associated with accelerated atherosclerosis and increased cardiovascular (CV) mortality. Recent studies have identified the ABO rs579459, PPAP2B rs17114036, and ADAMTS7 rs3825807 polymorphisms as genetic variants associated with coronary artery disease and the PIK3CG rs17398575 and EDNRA rs1878406 polymorphisms as the most significant signals related to the presence of carotid plaque in nonrheumatic Caucasian individuals. Accordingly, we evaluated the potential relationship between these 5 polymorphisms and subclinical atherosclerosis (assessed by carotid intima-media thickness (cIMT) and presence/absence of carotid plaques) and CV disease in RA. Material and Methods. 2140 Spanish RA patients were genotyped for the 5 polymorphisms by TaqMan assays. Subclinical atherosclerosis was evaluated in 620 of these patients by carotid ultrasonography technology. Results. No statistically significant differences were found when each polymorphism was assessed according to cIMT values and presence/absence of carotid plaques in RA, after adjusting the results for potential confounders. Moreover, no significant differences were obtained when RA patients were stratified according to the presence/absence of CV disease after adjusting for potential confounders. Conclusion. Our results do not confirm association between ABO rs579459, PPAP2B rs17114036, ADAMTS7 rs3825807, PIK3CG rs17398575, and EDNRA rs1878406 and subclinical atherosclerosis and CV disease in RA. PMID:24795506

  17. Land degradation monitoring in the Ocnele Mari salt mining area using satellite imagery

    NASA Astrophysics Data System (ADS)

    Poenaru, Violeta D.; Badea, Alexandru; Savin, Elena; Teleaga, Delia; Poncos, Valentin

    2011-11-01

    Mining is an important activity contributing to the economic development with long lasting environmental impacts. A major disaster took place in 2001 in Ocnele Mari salt mining area located in the central-south part of Romania when the artificial lake brine was poured in rural areas, devastating homes and polluting the Olt River. Towards a sustainable and harmonious development of the Ocnele Mari area, the Romanian Authorities decided to ecology and rehabilitate it. This ongoing project is focused on land degradation monitoring from 2001 disasters until now. High Resolution Spotlight TerraSar-X synthetic aperture radar data acquired within TerraSAR-X proposal LAN0778 are used to analyze terrain deformation by interferometric techniques knowing the mine subsidence is not constant; periods of relative stability are followed by quick deformation. The rocks forming in the region situated above the salt cushion have very low mechanical resistance and high intergranular fissured permeability so the hill's slopes are affected by landslides which are reactivated periodically. Additionally, analysis of the vegetation coverage (leaf area index and normalized difference vegetation index) from the optical data gathered by different sensors such as LANDSAT and MODIS combined with the meteorological data (temperature, wind speed, humidity and solar radiation) provide indicators for the land degradation. The results will be validating on ancillary data. Satellite derived information in conjunction with in-situ measurements can provide valuable information for existing conservation development models for defining the essential elements of a planning process designed to maximize the values provided by salt ponds from Ocnele Mari.

  18. A novel transgenic mouse model of Chinese Charcot-Marie-Tooth disease type 2L

    PubMed Central

    Zhang, Ruxu; Zhang, Fufeng; Li, Xiaobo; Huang, Shunxiang; Zi, Xiaohong; Liu, Ting; Liu, Sanmei; Li, Xuning; Xia, Kun; Pan, Qian; Tang, Beisha

    2014-01-01

    We previously found that the K141N mutation in heat shock protein B8 (HSPB8) was responsible for Charcot-Marie-Tooth disease type 2L in a large Chinese family. The objective of the present study was to generate a transgenic mouse model bearing the K141N mutation in the human HSPB8 gene, and to determine whether this K141NHSPB8 transgenic mouse model would manifest the clinical phenotype of Charcot-Marie-Tooth disease type 2L, and consequently be suitable for use in studies of disease pathogenesis. Transgenic mice overexpressing K141NHSPB8 were generated using K141N mutant HSPB8 cDNA cloned into a pCAGGS plasmid driven by a human cytomegalovirus expression system. PCR and western blot analysis confirmed integration of the K141NHSPB8 gene and widespread expression in tissues of the transgenic mice. The K141NHSPB8 transgenic mice exhibited decreased muscle strength in the hind limbs and impaired motor coordination, but no obvious sensory disturbance at 6 months of age by behavioral assessment. Electrophysiological analysis showed that the compound motor action potential amplitude in the sciatic nerve was significantly decreased, but motor nerve conduction velocity remained normal at 6 months of age. Pathological analysis of the sciatic nerve showed reduced myelinated fiber density, notable axonal edema and vacuolar degeneration in K141NHSPB8 transgenic mice, suggesting axonal involvement in the peripheral nerve damage in these animals. These findings indicate that the K141NHSPB8 transgenic mouse successfully models Charcot-Marie-Tooth disease type 2L and can be used to study the pathogenesis of the disease. PMID:25206829

  19. Geochronology and geochemistry of pre-Jurassic superterranes in Marie Byrd Land, Antarctica

    NASA Astrophysics Data System (ADS)

    Pankhurst, R. J.; Weaver, S. D.; Bradshaw, J. D.; Storey, B. C.; Ireland, T. R.

    1998-02-01

    Marie Byrd Land, Antarctica, is a major part of the proto-Pacific supercontinental margin. On the basis of new geochronological and geochemical data relating to its pre-Jurassic evolution, Marie Byrd Land is subdivided into western or interior ("Ross") and eastern or exterior ("Amundsen") provinces, equivalent to two superterranes in New Zealand. The Ross province is characterized by Cambrian? metagraywackes and I-type orthogneiss dated at 505±5 Ma by U-Pb SHRIMP (Sensitive High Resolution Ion Microprobe). Its magmatic record consists of Devonian-Carboniferous (375±5 Ma and circa 339±6 Ma), predominantly I-type granitoids, and further minor granitic magmatism in Permo-Triassic times. This Paleozoic history is comparable to that of the Gondwana margin in northern Victoria Land, western New Zealand, and SE Australia. The Amundsen province has no observed Paleozoic graywacke succession; evidence from Rb-Sr and U-Pb SHRIMP dating supports calc-alkaline granitoid events in Ordovician/Silurian (450-420 Ma) and Permian (276±2 Ma) times. The latter may be the previously unknown source of Permian volcanic detritus in the Ellsworth and Transantarctic mountains. The Amundsen province is considered to be the equivalent of the Median Tectonic Zone of New Zealand, and arc magmatism of comparable ages is found in the Antarctic Peninsula and Thurston Island. The underlying lithosphere of the two provinces may be distinguished by Nd isotope data; granitoids and metasedimentary rocks of the Ross province have Meso-Proterozoic Nd model ages, generally 1300-1500 Ma, compared to 1000-1300 Ma for the Amundsen province. On the basis of published palaeomagnetic data, the two provinces amalgamated to form Marie Byrd Land in mid-Cretaceous times, only shortly before rifting of the New Zealand continental block away from Antarctica.

  20. Marys Lake 69/115-kV transmission line upgrade and substation expansion projects

    SciTech Connect

    1996-05-01

    Western Area Power Administration (Western) and the Platte River Power Authority (Platte River) propose to upgrade portions of the existing electric transmission and substation system that serves the Town of Estes Park, Colorado. The existing transmission lines between the Estes Power Plant Switchyard and the Marys Lake Substation include a 115,000 volt (115-kV) line and 69,000 volt (69-kV) line. Approximately one mile is a double-circuit 115/69-kV line on steel lattice structures, and approximately two miles consists of separate single-circuit 115-kV and a 69-kV lines, constructed on wood H-Frame structures. Both lines were constructed in 1951 by the US Bureau of Reclamation. The existing transmission lines are on rights-of-way (ROW) that vary from 75 feet to 120 feet and are owned by Western. There are 48 landowners adjacent to the existing ROW. All of the houses were built adjacent to the existing ROW after the transmission lines were constructed. Upgrading the existing 69-kV transmission line between the Marys Lake Substation and the Estes Power Plant Switchyard to 115-kV and expanding the Marys Lake Substation was identified as the most effective way in which to improve electric service to Estes Park. The primary purpose and need of the proposed project is to improve the reliability of electric service to the Town of Estes Park. Lack of reliability has been a historical concern, and reliability will always be less than desired until physical improvements are made to the electrical facilities serving Estes Park.

  1. Mary Adams and the producer's role in early BBC science broadcasts.

    PubMed

    Jones, Allan

    2012-11-01

    Mary Adams was a science producer at the BBC from 1930-6. She is shown to have played a crucial role in shaping science broadcasts, in particular devising formats and styles of presentation. However, her approach is shown to have been primarily motivated by broadcasting considerations rather than by the popularisation of science. Through her interaction with scientists she helped to construct a new professional domain, that of the science-broadcasting professional, at a time when other producers were creating analogous roles in other areas of broadcasting. This paper is based largely on unpublished archival documents. PMID:23832748

  2. The gendering of Albert Einstein and Marie Curie in children's biographies: some tensions

    NASA Astrophysics Data System (ADS)

    Wilson, Rachel E.; Jarrard, Amber R.; Tippins, Deborah J.

    2009-12-01

    Few twentieth century scientists have generated as much interest as Albert Einstein and Marie Currie. Their lives are centrally depicted in numerous children's biographies of famous scientists. Yet their stories reflect interesting paradoxes and tacit sets of unexplored sociocultural assumptions about gender in science education and the larger society. Trevor Owens' analysis of common Einstein and Currie biographies for children provides a context for us to consider a deeper reading of these scientists' stories in ways that can be both empowering and liberating. In the process, we consider some interesting tensions surrounding the gendered nature of their stories.

  3. Mary Mallon (1869-1938) and the history of typhoid fever

    PubMed Central

    Marineli, Filio; Tsoucalas, Gregory; Karamanou, Marianna; Androutsos, George

    2013-01-01

    Mary Mallon was born in 1869 in Ireland and emigrated to the US in 1884. She had worked in a variety of domestic positions for wealthy families prior to settling into her career as a cook. As a healthy carrier of Salmonella typhi her nickname of “Typhoid Mary” had become synonymous with the spread of disease, as many were infected due to her denial of being ill. She was forced into quarantine on two separate occasions on North Brother Island for a total of 26 years and died alone without friends, having evidently found consolation in her religion to which she gave her faith and loyalty. PMID:24714738

  4. MaRIE X-Ray Free-Electron Laser Pre-Conceptual Design

    SciTech Connect

    Carlsten, Bruce E.; Barnes, Cris W.; Bishofberger, Kip A.; Duffy, Leanne D.; Heath, Cynthia E.; Marksteiner, Quinn R.; Nguyen, Dinh Cong; Russell, Steven J.; Ryne, Robert D.; Sheffield, Richard L.; Simakov, Evgenya I.; Yampolsky, Nikolai A.

    2011-01-01

    The proposed Matter-Radiation Interactions in Extremes (MaRIE) facility at the Los Alamos National Laboratory will include a 50-keV X-Ray Free-Electron Laser (XFEL), a significant extension from planned and existing XFEL facilities. To prevent an unacceptably large energy spread arsing from energy diffusion, the electron beam energy should not exceed 20 GeV, which puts a significant constraint on the beam emittance. A 100-pC baseline design is presented along with advanced technology options to increase the photon flux and to decrease the spectral bandwidth through pre-bunching the electron beam.

  5. Geothermal heating project at St. Mary's Hospital, Pierre, South Dakota. Final report

    SciTech Connect

    Not Available

    1984-12-01

    St. Mary's Hospital, Pierre, South Dakota, with the assistance of the US Department of Energy, drilled a 2176 ft well into the Madison Aquifer ot secure 108/sup 0/F artesian flow water at 385 gpm (475 psig shut-in pressure). The objective was to provide heat for domestic hot water and to space heat 163,768 sq. ft. Cost savings for the first three years were significant and, with the exception of a shutdown to replace some corroded pipe, the system has operated reliably and continuously for the last four years.

  6. Recursive ideal observer detection of known M-ary signals in multiplicative and additive Gaussian noise.

    NASA Technical Reports Server (NTRS)

    Painter, J. H.; Gupta, S. C.

    1973-01-01

    This paper presents the derivation of the recursive algorithms necessary for real-time digital detection of M-ary known signals that are subject to independent multiplicative and additive Gaussian noises. The motivating application is minimum probability of error detection of digital data-link messages aboard civil aircraft in the earth reflection multipath environment. For each known signal, the detector contains one Kalman filter and one probability computer. The filters estimate the multipath disturbance. The estimates and the received signal drive the probability computers. Outputs of all the computers are compared in amplitude to give the signal decision. The practicality and usefulness of the detector are extensively discussed.

  7. Heavy Ion Flux Comparison of MARIE and ACE/CRIS Instruments

    NASA Technical Reports Server (NTRS)

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

    2003-01-01

    The charged particle spectrum for nuclei from protons to neon, (charge Z=10) has been observed during the cruise phase and in orbit around Mars by the MARIE charge particle spectrometer aboard the Odyssey spacecraft. The cruise data was taken between April 23, 2001 and August 11, 2001. The Mars orbit data was taken from March 5, 2002 through December 2002. Both the cruise data set and the orbital data set are compared with the simultaneous observations made by the CRIS instrument aboard the ACE space-craft, located at L1. Any detectable differences between the two spacecraft data sets could lead to the understanding of the radial dependence of solar modulation.

  8. Sport activity in Charcot-Marie-Tooth disease: A case study of a Paralympic swimmer.

    PubMed

    Vita, Giuseppe; La Foresta, Stefania; Russo, Massimo; Vita, Gian Luca; Messina, Sonia; Lunetta, Christian; Mazzeo, Anna

    2016-09-01

    This study reports the positive physical, emotional and psychosocial changes induced by sport activity in a Paralympic swimmer with Charcot-Marie-Tooth (CMT) type 4A. When we compared evaluations before initiating sport activity with those after five years of competitive activity, we found: i) increased proximal muscles strength of upper limbs; ii) augmented ability to propel wheelchair independently; iii) improved quality of life; iv) reduced trait anxiety and striking improvement of depression; v) enhanced self-esteem. Longitudinal studies in large cohorts to evaluate the positive effects of sport activity are needed to support provision of evidence-based advice to patients and families. PMID:27460291

  9. Replica Analysis of Multiuser Detection for Code Division Multiple Access with M-Ary Phase-Shift Keying

    NASA Astrophysics Data System (ADS)

    Kato, Hiroyuki; Okada, Masato; Miyoshi, Seiji

    2013-07-01

    We analyze the performance of the maximizer of the posterior marginals (MPM) detector for code division multiple access (CDMA) multiuser detection with M-ary phase shift keying (M-ary PSK) in the large system limit by the replica method. The obtained theory agrees with computer simulation reasonably well. We also derive the theory in the case of the large M limit and discuss the dependence of the properties of M-ary PSK CDMA communication on M. We show that the waterfall phenomenon occurs for both the finite and infinite values of M. We also show that a value of M for which the decoded phase information on the original user symbol becomes minimum exists. Furthermore, we discuss the relationship between the theory based on the replica method and that based on self-consistent signal-to-noise analysis (SCSNA).

  10. Decision-directed automatic gain control for MAPSK systems. [M-ary Amplitude and Phase Shift Keying

    NASA Technical Reports Server (NTRS)

    Weber, W. J., III

    1974-01-01

    An automatic gain control (AGC) loop is presented for use with M-ary amplitude and phase shift keying (MAPSK) systems. The gain control amplifier is regulated by an error signal formed by the difference between the estimated amplitude level and the received amplitude level. The AGC performance is thus independent of the short-term average received signal energy. AGC loop analysis and simulation is presented for M-ary amplitude shift keying and quadrature amplitude shift keying. The AGC is shown to have a negligible degradation on the symbol probability of error for most practical cases. A generalized AGC for an arbitrary MAPSK system is presented.

  11. Self-Consistent Signal-to-Noise Analysis of CDMA Multiuser Detection with M-Ary Phase-Shift Keying

    NASA Astrophysics Data System (ADS)

    Kato, Hiroyuki; Okada, Masato; Miyoshi, Seiji

    2013-02-01

    We present a theory of the performance of parallel interference cancellation (PIC) for code division multiple access (CDMA) multiuser detection with M-ary phase-shift keying (M-ary PSK) in the large-system limit. The behavior of PIC is essentially the same as that of the associative memory model. Therefore, we analyze the PIC for CDMA using self-consistent signal-to-noise analysis (SCSNA), which was developed to describe the behavior of the associative memory model. We obtain a quantitative description of the performance of PIC.

  12. Life cycle of a mayfly Hexagenia limbata in the St. Marys River between Lakes Superior and Huron

    USGS Publications Warehouse

    Schloesser, Donald W.; Hiltunen, Jarl K.

    1984-01-01

    Length-frequency distribution curves of Hexagenia limbata nymphs collected in May, August, and October 1974 and May 1975 in the St. Marys River between Lakes Superior and Huron were bimodal for each sampling period. These curves, combined with interpretation of nymphal emergence period and mean surface water temperatures, indicate that the population of Hexagenia nymphs in the St. Marys River is composed of two year classes or cohorts. One cohort emerges per season, 2 years after egg deposition.

  13. Oil degradation and biosurfactant production by the deep sea bacterium Dietzia maris As-13-3

    PubMed Central

    Wang, Wanpeng; Cai, Bobo; Shao, Zongze

    2014-01-01

    Recent investigations of extreme environments have revealed numerous bioactive natural products. However, biosurfactant-producing strains from deep sea extreme environment are largely unknown. Here, we show that Dietzia maris As-13-3 isolated from deep sea hydrothermal field could produce di-rhamnolipid as biosurfactant. The critical micelle concentration (CMC) of the purified di-rhamnolipid was determined to be 120 mgL−1, and it lowered the surface tension of water from 74 ± 0.2 to 38 ± 0.2 mN m−1. Further, the alkane metabolic pathway-related genes and di-rhamnolipid biosynthesis-related genes were also analyzed by the sequencing genome of D. maris As-13-3 and quantitative real-time PCR (Q-PCR), respectively. Q-PCR analysis showed that all these genes were induced by n-Tetradecane, n-Hexadecane, and pristane. To the best of our knowledge, this is first report about the complete pathway of the di-rhamnolipid synthesis process in the genus Dietzia. Thus, our study provided the insights into Dietzia in respects of oil degradation and biosurfactant production, and will help to evaluate the potential of Dietzia in marine oil removal. PMID:25566224

  14. Oral Health and Frailty in the Medieval English Cemetery of St. Mary Graces

    PubMed Central

    DeWitte, Sharon N.; Bekvalac, Jelena

    2011-01-01

    The analysis of oral pathologies is routinely a part of bioarchaeological and paleopathological investigations. Oral health, while certainly interesting by itself, is also potentially informative about general or systemic health. Numerous studies within modern populations have shown associations between oral pathologies and other diseases, such as cardiovascular disease, certain types of cancer, and pulmonary infections. This paper addresses the question of how oral health was associated with general health in past populations by examining the relationship between two oral pathologies (periodontal disease and dental caries) and the risk of mortality in a cemetery sample from medieval England. The effects of periodontitis and dental caries on risk of death were assessed using a sample of 190 individuals from the St. Mary Graces, London cemetery dating to approximately A.D. 1350–1538. The results suggest that the oral pathologies are associated with elevated risks of mortality in the St. Mary Graces cemetery, such that individuals with periodontitis and dental caries were more likely to die than their peers without such pathologies. The results shown here suggest that these oral pathologies can be used as informative indicators of general health in past populations. PMID:19927365

  15. THE DEAD-LIVING-MOTHER: MARIE BONAPARTE'S INTERPRETATION OF EDGAR ALLAN POE'S SHORT STORIES.

    PubMed

    Obaid, Francisco Pizarro

    2016-06-01

    Princess Marie Bonaparte is an important figure in the history of psychoanalysis, remembered for her crucial role in arranging Freud's escape to safety in London from Nazi Vienna, in 1938. This paper connects us to Bonaparte's work on Poe's short stories. Founded on concepts of Freudian theory and an exhaustive review of the biographical facts, Marie Bonaparte concluded that the works of Edgar Allan Poe drew their most powerful inspirational force from the psychological consequences of the early death of the poet's mother. In Bonaparte's approach, which was powerfully influenced by her recognition of the impact of the death of her own mother when she was born-an understanding she gained in her analysis with Freud-the thesis of the dead-living-mother achieved the status of a paradigmatic key to analyze and understand Poe's literary legacy. This paper explores the background and support of this hypothesis and reviews Bonaparte's interpretation of Poe's most notable short stories, in which extraordinary female figures feature in the narrative. PMID:27194275

  16. Oil degradation and biosurfactant production by the deep sea bacterium Dietzia maris As-13-3.

    PubMed

    Wang, Wanpeng; Cai, Bobo; Shao, Zongze

    2014-01-01

    Recent investigations of extreme environments have revealed numerous bioactive natural products. However, biosurfactant-producing strains from deep sea extreme environment are largely unknown. Here, we show that Dietzia maris As-13-3 isolated from deep sea hydrothermal field could produce di-rhamnolipid as biosurfactant. The critical micelle concentration (CMC) of the purified di-rhamnolipid was determined to be 120 mgL(-1), and it lowered the surface tension of water from 74 ± 0.2 to 38 ± 0.2 mN m(-1). Further, the alkane metabolic pathway-related genes and di-rhamnolipid biosynthesis-related genes were also analyzed by the sequencing genome of D. maris As-13-3 and quantitative real-time PCR (Q-PCR), respectively. Q-PCR analysis showed that all these genes were induced by n-Tetradecane, n-Hexadecane, and pristane. To the best of our knowledge, this is first report about the complete pathway of the di-rhamnolipid synthesis process in the genus Dietzia. Thus, our study provided the insights into Dietzia in respects of oil degradation and biosurfactant production, and will help to evaluate the potential of Dietzia in marine oil removal. PMID:25566224

  17. Assignment of a second Charcot-Marie-Tooth type II locus to chromosome 3q

    SciTech Connect

    Kwon, J.M.; Elliott, J.L.; Yee, W.C.

    1995-10-01

    Charcot-Marie-Tooth disease (CMT) is the most common inherited motor and sensory neuropathy. The neuronal form of this disorder is referred to as Charcot-Marie-Tooth type II disease (CMT2). CMT2 is usually inherited as an autosomal dominant trait with a variable age at onset of symptoms associated with progressive axonal neuropathy. In some families, the locus that predisposes to CMT2 has been demonstrated to map to the distal portion of the short arm of chromosome 1. Other families with CMT2 do not show linkage with 1p markers, suggesting genetic heterogeneity in CMT2. We investigated linkage in a single large kindred with autosomal dominant CMT2. The gene responsible for CMT2 in this kindred (CMT2B) was mapped to the interval between the microsatellite markers D3S1769 and D3S1744 in the 3q13-22 region. Study of additional CMT2 kindreds should serve to further refine the disease gene region and may ultimately lead to the identification of a gene defect that underlies the CMT2 phenotype. 21 refs., 3 figs., 1 tab.

  18. Polyphasic Characterization of Lysobacter maris sp. nov., a Bacterium Isolated from Seawater.

    PubMed

    Yoon, Jaewoo

    2016-03-01

    A strictly aerobic, Gram-negative, apricot-pigmented, non-motile, rod-shaped strain designated KMU-14(T) was isolated from seawater collected from the coastal zone of Yokji Island, Gyeongsangnam-do, Republic of Korea. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that the novel isolate was affiliated with the genus Lysobacter within the class Gammaproteobacteria and that it showed the highest sequence similarity (97.1 %) to Lysobacter concretionis Ko07(T). The hybridization value for DNA-DNA relatedness between the strains of KMU-14(T) and L. concretionis Ko07(T) was 34.8 %, which was lower than 70 %, the recommended delineation value for differentiation of species. The DNA G+C content of strain KMU-14(T) was 64.9 mol%. The major respiratory quinone was ubiquinone 8 (Q-8), and iso-C15:0, iso-C16:0, and 10-methyl C16:0 and/or iso-C17:1 ω9c were the major (>10 %) cellular fatty acids. A polar lipid profile was present consisting of diphosphatidylglycerol, phosphatidylethanolamine, an unidentified phosphoglycolipid, two unidentified aminophospholipids, and two unidentified phospholipids. From the distinct phylogenetic position and combination of genotypic and phenotypic characteristics, the strain is considered to represent a novel species for which the name Lysobacter maris sp. nov. is proposed. The type strain of L. maris sp. nov. is KMU-14(T) (=KCTC 42381(T) =NBRC 110750(T)). PMID:26616671

  19. Copy Number Variations in a Population-Based Study of Charcot-Marie-Tooth Disease

    PubMed Central

    Høyer, Helle; Braathen, Geir J.; Eek, Anette K.; Nordang, Gry B. N.; Skjelbred, Camilla F.; Russell, Michael B.

    2015-01-01

    Copy number variations (CNVs) are important in relation to diversity and evolution but can sometimes cause disease. The most common genetic cause of the inherited peripheral neuropathy Charcot-Marie-Tooth disease is the PMP22 duplication; otherwise, CNVs have been considered rare. We investigated CNVs in a population-based sample of Charcot-Marie-Tooth (CMT) families. The 81 CMT families had previously been screened for the PMP22 duplication and point mutations in 51 peripheral neuropathy genes, and a genetic cause was identified in 37 CMT families (46%). Index patients from the 44 CMT families with an unknown genetic diagnosis were analysed by whole-genome array comparative genomic hybridization to investigate the entire genome for larger CNVs and multiplex ligation-dependent probe amplification to detect smaller intragenomic CNVs in MFN2 and MPZ. One patient had the pathogenic PMP22 duplication not detected by previous methods. Three patients had potentially pathogenic CNVs in the CNTNAP2, LAMA2, or SEMA5A, that is, genes related to neuromuscular or neurodevelopmental disease. Genotype and phenotype correlation indicated likely pathogenicity for the LAMA2 CNV, whereas the CNTNAP2 and SEMA5A CNVs remained potentially pathogenic. Except the PMP22 duplication, disease causing CNVs are rare but may cause CMT in about 1% (95% CI 0–7%) of the Norwegian CMT families. PMID:25648254

  20. Unusual Rebuilding Method of Historic St Mary's Cathedral in the Capital of Western Australia

    NASA Astrophysics Data System (ADS)

    Wysokowski, Adam

    2016-06-01

    St Mary's Cathedral is the Archbishop church of the Archdiocese in Perth in Western Australia. The presented sacral building was built in neo-Gothic style during the years 1863-1865. Cathedral was officially dedicated and opened for the service on 29th January, 1865. In 1973 was proclaimed the Marian Sanctuary and now represents one of the largest religious facilities in Perth. In 2005, the city authorities, together with the Archdiocese took a collective decision on the necessity of a comprehensive renovation of this sacred object. The renovation was due to the technical condition and the lack of usability of the object. The author of the paper had the opportunity to experience these problems by visiting this place several times, first time in 1989 and next years. Thus, the renovation of the present Cathedral was in its assumption not only to perform maintenance of the building and its specific architectural elements but also to increase its functional features - usable for the faithful and tourists. Reconstruction of St Mary's Cathedral in Perth can be a good example increasing the wider functionality of such facilities while keeping their antique and historical qualities. In this paper the above-mentioned issues will be more widely developed by the author.

  1. Oral health and frailty in the medieval English cemetery of St Mary Graces.

    PubMed

    DeWitte, Sharon N; Bekvalac, Jelena

    2010-07-01

    The analysis of oral pathologies is routinely a part of bioarcheological and paleopathological investigations. Oral health, while certainly interesting by itself, is also potentially informative about general or systemic health. Numerous studies within modern populations have shown associations between oral pathologies and other diseases, such as cardiovascular disease, certain types of cancer, and pulmonary infections. This article addresses the question of how oral health was associated with general health in past populations by examining the relationship between two oral pathologies (periodontal disease and dental caries) and the risk of mortality in a cemetery sample from medieval England. The effects of periodontitis and dental caries on risk of death were assessed using a sample of 190 individuals from the St Mary Graces cemetery, London, dating to approximately AD 1350-1538. The results suggest that the oral pathologies are associated with elevated risks of mortality in the St Mary Graces cemetery such that individuals with periodontitis and dental caries were more likely to die than their peers without such pathologies. The results shown here suggest that these oral pathologies can be used as informative indicators of general health in past populations. PMID:19927365

  2. Detection of Group A Streptococcus from Pharyngeal Swab Samples by Bacterial Culture Is Challenged by a Novel mariPOC Point-of-Care Test

    PubMed Central

    Koskinen, Janne O.; Brandt, Annika; Muotiala, Anna; Liukko, Viivi; Soittu, Sari; Meriluoto, Siiri; Vesalainen, Marika; Huovinen, Pentti; Irjala, Kerttu

    2015-01-01

    mariPOC is a novel point-of-care test system for rapid detection of respiratory tract infections. We compared the performance of the mariPOC test to that of bacterial culture for detecting group A streptococcus (GAS) in 219 pharyngitis patients (ages 1–64 years) and 109 healthy asymptomatic controls (ages 19–69 years). In addition, 42 patient samples were analyzed by quantitative PCR (qPCR). Of the 219 pharyngeal patient samples, 32 were positive in a GAS bacterial culture (prevalence 15%) and 65 (30%) in the mariPOC test. The amount of GAS in samples reported positive by the mariPOC test and negative by culture was, on average, 10-fold less than that of those positive in both methods. This indicated that the negative results in bacterial cultures were due to lower sensitivity. The qPCR results were positive and in line with the mariPOC results in 43% of the discordant samples studied. Two GAS culture-positive samples were negative by the mariPOC test. The prevalences of GAS in the control subjects were 2% and 6% by culture and mariPOC results, respectively. We conclude that the mariPOC antigen detection test is more sensitive than the conventional bacterial culture for the detection of GAS among symptomatic pharyngitis patients. The higher prevalence of GAS by the mariPOC test among symptomatic patients was probably not due to carriership, since among the control patients, the difference in the prevalence of GAS by the mariPOC test and culture was not nearly as high, 15% versus 4%, respectively. Clinical trials are needed to show the clinical importance of our findings. PMID:25903570

  3. Une analyse phonologique d'une parler acadien de la Nouvelle-Ecosse, Canada. Region de la Baie Sainte-Marie (A Phonological Analysis of Acadian Speech in Nova Scotia, Canada. The Baie Sainte-Marie Region).

    ERIC Educational Resources Information Center

    Ryan, Robert W.

    This study identifies the phonological system in the idiolects of three native speakers of the Acadian dialect in southwest Nova Scotia, on the coast of Baie Sainte-Marie. The study also highlights the specificity of the phonological system by comparing it with the speech of Acadians in Moncton, New Brunswick and with standard French. The…

  4. Mary Braddon's "Good Lady Ducayne" in Context(s): Victorian Medicine, Literary Gothicism, and 21st Century Feminist Pedagogy

    ERIC Educational Resources Information Center

    Wooden, Shannon R.

    2007-01-01

    Mary Elizabeth Braddon's novels and stories exemplify some of the main issues surrounding women's texts and their place in literature: aesthetic value, intellectual challenge, universality, and contemporary popularity. Her work, it may be argued, betrays occasional aesthetic imperfections; however, she produced a tremendous amount of published…

  5. A Study of Selected Developing Colleges and Universities. Case Study II: St. Mary's Junior College, Minneapolis, Minnesota.

    ERIC Educational Resources Information Center

    St. John, Edward P.

    As part of a study of selected developing colleges and universities funded in the Advanced Institutional Development Program (AIDP), this report focuses on St. Mary's Junior College (SMJC), a Roman Catholic, two-year college specializing exclusively in health, health-related and human service fields. The report considers SMJC's state of…

  6. Pedagogy and Sex: Mary Dendy (1855-1933), Feeble-Minded Girls and the Sandlebridge Schools, 1902-33

    ERIC Educational Resources Information Center

    Goodman, Joyce

    2005-01-01

    Mary Dendy has received attention from historians because she was the first paid commissioner under the Board of Control (the administrative body that regulated the 1913 Mental Deficiency Act), was at the forefront in disseminating views regarding the sexual proclivities of feeble-minded women and because she advocated permanent segregated care…

  7. "No Philosophy Carries So Much Conviction as the Personal Life": Mary Wright Plummer as an Independent Woman.

    ERIC Educational Resources Information Center

    Maack, Mary Niles

    2000-01-01

    Provides an overview of the life of Mary Wright Plummer, a leader in American librarianship, and her effort to construct a personal identity as an independent woman. Highlights include her Quaker childhood; European travels; self-actualization and career strategies; and blending public and private spheres. (Contains 101 references.) (LRW)

  8. Teaching Eighteenth-Century Poetic Satire with a Competency-Based Approach: Jonathan Swift and Lady Mary Wortley Montagu

    ERIC Educational Resources Information Center

    Modia, María Jesús Lorenzo; Álvarez, Begoña Lasa

    2011-01-01

    The purpose of this essay is to analyse the teaching of literature with a competency-based approach. This is exemplified by means of a thorough study of a poetic duel between two relevant eighteenth-century writers, Jonathan Swift and Lady Mary Wortley Montagu, and more specifically, by means of the satires entitled respectively "The Lady's…

  9. Active Regions on the Farside of the Sun as Seen from Mars: 3D Visualization with Marie Data

    NASA Technical Reports Server (NTRS)

    Saganti, P. B.; Cueinotra, F. A.; Cleghorn, T. F.; Zeitlin, C. J.

    2004-01-01

    From March 2002, the MARIE (Martian Radiation Environment Experiment) instrument of NASA-JSC onboard the 2001 Mars Odyssey spacecraft has been providing radiation data from the Martian orbit. During the past two years, the orbit alignment of Mars-Sun-Earth provided a wealth of opportunity between 180 degrees (August 2002) and 0 degrees (October 2003). During this time, the MARIE data included the background GCR (Galactic Cosmic Rays) and several SPE (Solar Particle Events) enhanced radiation dose-rate measurements at Mars. The MARIE instrument provided a unique data set of radiation dose-rate at Mars from the active regions on the solar disk facing the Mars side. The SPE observations of October 2002 at Mars by the MARIE instrument are unique and there were no indications of these events towards the Earth at that time. Nearly 40 times increase in the quiet-time GCR dose-rate was noted from about 25 mradday to nearly 1000 mradday at Mars. Radiation dose-rate enhancement was not observed toward the Earth or in the Low Earth Orbit (LEO) during this time. Understanding the active regions on the Sun that are likely to result into SPE on the far side will also be of concern for future deep space explorations beyond LEO. We present the observations of these SPE enhanced dose rates due to the active regions from the far side of the Sun with the 3D visualization of solar disks facing Mars and Earth.

  10. "The Queen of the Lobby": Mary Hunt, Scientific Temperance, and the Dilemma of Democratic Education in America, 1879-1906.

    ERIC Educational Resources Information Center

    Zimmerman, Jonathan

    1992-01-01

    Describes the work of Mary Hunt and the Scientific Temperance movement to mandate teaching about the nature of alcohol and narcotics in the public schools. Examines the struggle over organization and planning within the public school system. Discusses organization in the Scientific Temperance movement's response to public school administration and…

  11. To Bring into Play: Miss Mary Richmond's Utilization of Kindred Networks in the Diffusion of Kindergarten Ideals into Practice

    ERIC Educational Resources Information Center

    Bethell, Kerry

    2006-01-01

    In the setting up of kindergarten systems in colonial New Zealand over the late nineteenth century, kindergarten founders such as Miss Mary Richmond in Wellington developed global links with kindergarten movements in a number of countries including England. This article examines the nature and significance of two key global interconnected networks…

  12. 33 CFR 165.731 - Safety/Security Zone: Cumberland Sound, Georgia and St. Marys River Entrance Channel.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., Florida. (3) The general regulations governing safety and security zones contained in 33 CFR 165.23 and... 33 Navigation and Navigable Waters 2 2013-07-01 2013-07-01 false Safety/Security Zone: Cumberland... Seventh Coast Guard District § 165.731 Safety/Security Zone: Cumberland Sound, Georgia and St. Marys...

  13. Flood-inundation maps for the St. Marys River at Fort Wayne, Indiana

    USGS Publications Warehouse

    Menke, Chad D.; Kim, Moon H.; Fowler, Kathleen K.

    2012-01-01

    Digital flood-inundation maps for a 9-mile reach of the St. Marys River that extends from South Anthony Boulevard to Main Street at Fort Wayne, Indiana, were created by the U.S. Geological Survey (USGS) in cooperation with the City of Fort Wayne. The inundation maps, which can be accessed through the USGS Flood Inundation Mapping Science Web site, depict estimates of the areal extent of flooding corresponding to selected water levels (stages) at the USGS streamgage 04182000 St. Marys River near Fort Wayne, Ind. Current conditions at the USGS streamgages in Indiana may be obtained from the National Water Information System: Web Interface. In addition, the information has been provided to the National Weather Service (NWS) for incorporation into their Advanced Hydrologic Prediction Service (AHPS) flood warning system. The NWS forecasts flood hydrographs at many places that are often collocated at USGS streamgages. That forecasted peak-stage information, also available on the Internet, may be used in conjunction with the maps developed in this study to show predicted areas of flood inundation. In this study, water-surface profiles were simulated for the stream reach by means of a hydraulic one-dimensional step-backwater model. The model was calibrated using the most current stage-discharge relation at the USGS streamgage 04182000 St. Marys River near Fort Wayne, Ind. The hydraulic model was then used to simulate 11 water-surface profiles for flood stages at 1-ft intervals referenced to the streamgage datum and ranging from bankfull to approximately the highest recorded water level at the streamgage. The simulated water-surface profiles were then combined with a geographic information system digital elevation model (derived from Light Detection and Ranging (LiDAR) data) in order to delineate the area flooded at each water level. A flood inundation map was generated for each water-surface profile stage (11 maps in all) so that for any given flood stage users will be

  14. Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kα and PI3Kδ, Demonstrates Treatment Strategies for PIK3CA-Dependent Breast Cancers.

    PubMed

    Hudson, Kevin; Hancox, Urs J; Trigwell, Cath; McEwen, Robert; Polanska, Urszula M; Nikolaou, Myria; Morentin Gutierrez, Pablo; Avivar-Valderas, Alvaro; Delpuech, Oona; Dudley, Phillippa; Hanson, Lyndsey; Ellston, Rebecca; Jones, Alys; Cumberbatch, Marie; Cosulich, Sabina C; Ward, Lara; Cruzalegui, Francisco; Green, Stephen

    2016-05-01

    The PIK3CA gene, encoding the p110α catalytic unit of PI3Kα, is one of the most frequently mutated oncogenes in human cancer. Hence, PI3Kα is a target subject to intensive efforts in identifying inhibitors and evaluating their therapeutic potential. Here, we report studies with a novel PI3K inhibitor, AZD8835, currently in phase I clinical evaluation. AZD8835 is a potent inhibitor of PI3Kα and PI3Kδ with selectivity versus PI3Kβ, PI3Kγ, and other kinases that preferentially inhibited growth in cells with mutant PIK3CA status, such as in estrogen receptor-positive (ER(+)) breast cancer cell lines BT474, MCF7, and T47D (sub-μmol/L GI50s). Consistent with this, AZD8835 demonstrated antitumor efficacy in corresponding breast cancer xenograft models when dosed continuously. In addition, an alternative approach of intermittent high-dose scheduling (IHDS) was explored given our observations that higher exposures achieved greater pathway inhibition and induced apoptosis. Indeed, using IHDS, monotherapy AZD8835 was able to induce tumor xenograft regression. Furthermore, AZD8835 IHDS in combination with other targeted therapeutic agents further enhanced antitumor activity (up to 92% regression). Combination partners were prioritized on the basis of our mechanistic insights demonstrating signaling pathway cross-talk, with a focus on targeting interdependent ER and/or CDK4/6 pathways or alternatively a node (mTOR) in the PI3K-pathway, approaches with demonstrated clinical benefit in ER(+) breast cancer patients. In summary, AZD8835 IHDS delivers strong antitumor efficacy in a range of combination settings and provides a promising alternative to continuous dosing to optimize the therapeutic index in patients. Such schedules merit clinical evaluation. Mol Cancer Ther; 15(5); 877-89. ©2016 AACR. PMID:26839307

  15. Standards of radium-226: from Marie Curie to the International Committee for Radionuclide Metrology.

    PubMed

    Coursey, B M; Collé, R; Coursey, J S

    2002-01-01

    In the early part of the 20th century, the pioneers of radioactivity research, led by Marie Curie, Ernest Rutherford and Stefan Meyer, formed a Commission internationale des étalons de radium. The Commission made arrangements for the preparation and intercomparisons of the international standards of radium, which were identified as the Paris standard and the Vienna standard. Otto Hönigschmid from Vienna prepared a first set of international secondary standards in 1912 and a second set in 1934. In both instances, these secondary standards were compared by gamma-ray measurements with the Paris and Vienna standards. The usage of these international standards of radium in the 20th century is described. PMID:11839059

  16. Charcot-Marie-Tooth 1A concurrent with schwannomas of the spinal cord and median nerve.

    PubMed

    Kwon, Joo Young; Chung, Ki Wha; Park, Eun Kyung; Park, Sun Wha; Choi, Byung-Ok

    2009-08-01

    We identified Charcot-Marie-Tooth disease type 1A (CMT1A) in a family with schwannomas in the spinal cord and median nerve. The CMT1A in this family showed an autosomal dominant pattern, like other CMT patients with PMP22 duplication, and the family also indicated a possible genetic predisposition to schwannomas by 'mother-to-son' transmission. CMT1A is mainly caused by duplication of chromosome 17p11.2-p12 (PMP22 gene duplication). A schwannoma is a benign encapsulated tumor originating from a Schwann cell. A case of hereditary neuropathy with liability to pressure palsies (HNPP) concurrent with schwannoma has been previously reported. Although it seems that the co-occurrence of CMT1A and schwannomas in a family would be the result of independent events, we could not completely ignore the possibility that the coincidence of two diseases might be due to a shared genetic background. PMID:19654968

  17. The use of TWT amplifiers in M-ary amplitude and phase shift keying systems

    NASA Technical Reports Server (NTRS)

    Weber, W. J., III

    1975-01-01

    A great deal of research is presently being conducted to study modulation schemes in order to reduce the bandwidth of digital communications. These M-ary amplitude and phase shift keying (MAPSK) modulation systems place new requirements on TWT amplifiers in space applications in that the various signal sets usually include two or more discrete output power levels as well as discrete phases at each power level. This paper presents a variety of predistortion schemes to circumvent the TWT problems of AM distortion and AM-to-PM conversion in order to produce MAPSK signal sets. A feedback scheme is presented to correct for long-term phase and amplitude drifts in the transmitter. A complete transmitter is proposed using predistortion to produce the desired MAPSK signal set at very high data rates including the possible use of a feedback stabilization scheme.

  18. [Acute vincristine neurotoxicity in a non-Hodgkin's lymphoma patient with Charcot-Marie-Tooth disease].

    PubMed

    Uno, S; Katayama, K; Dobashi, N; Hirano, A; Ogihara, A; Yamazaki, H; Usui, N; Kobayashi, T; Inoue, K; Kuraishi, Y

    1999-05-01

    A 44-year-old, previously healthy man with a diagnosis of non-Hodgkin's lymphoma (NHL, diffuse large B-cell type, stage IIA) was treated with combination chemotherapy including vincristine (VCR). After receiving a cumulative dose of VCR, he experienced rapid and marked weakening which progressed to quadriplegia and bulbar palsy. Prior to this therapy, the patient had no neurological problems, and his siblings were asymptomatic. Physical examination identified pes cavus (hollow foot), and electrodiagnostic studies showed markedly slower nerve conduction velocity of myelinated fibers, with abundant "onion bulb" formations. Chromosomal analysis detected 17p11.2-12 duplication, thus yielding a diagnosis of Charcot-Marie-Tooth (CMT) 1A. CMT disease is a familial neuromuscular disorder, and the incidence is approximately 1 in 2,500. We concluded that if CMT disease is diagnosed, vincristine should be avoided due to the potential severity of neurotoxicity to small doses. PMID:10390891

  19. Anesthetic Management of a Patient With Charcot-Marie-Tooth Disease.

    PubMed

    Ohshita, Naohiro; Oka, Saeko; Tsuji, Kaname; Yoshida, Hiroaki; Morita, Shosuke; Momota, Yoshihiro; Tsutsumi, Yasuo M

    2016-01-01

    Charcot-Marie-Tooth disease (CMTD) is a hereditary peripheral neuropathy and is characterized by progressive muscle atrophy and motor-sensory disorders in all 4 limbs. Most reports have indicated that major challenges with general anesthetic administration in CMTD patients are the appropriate use of nondepolarizing muscle relaxants and preparation for malignant hyperthermia in neuromuscular disease. Moderate sedation may be associated with the same complications as those of general anesthesia, as well as dysfunction of the autonomic nervous system, reduced perioperative respiratory function, difficulty in positioning, and sensitivity to intravenous anesthetic agents. We decided to use intravenous sedation in a CMTD patient and administered midazolam initially and propofol continuously, with total doses of 1.5 mg and 300 mg, respectively. Anesthesia was completed in 3 hours and 30 minutes without adverse events. We suggest that dental anesthetic treatment with propofol and midazolam may be effective for patients with CMTD. PMID:27269665

  20. [Therapy for Charcot-Marie-Tooth Disease: From the Standpoint of Neurologists].

    PubMed

    Nakagawa, Masanori

    2016-01-01

    To date, there is no approved pharmacologic treatment for any form of Charcot-Marie-Tooth disease (CMT). However, some clinical or preclinical trials for CMT1A have been undertaken, for example Neurotrophin-3, PXT3003, and neuregulin-1. Gene therapy for CMT1X, CMT2F and Giant axonal neuropathy using animal model or culture cells have been reported with some interesting results. Stem cell research for example iPS cells derived from patients with CMT2A or CMT2E, is being conducted to clarify the mechanism of CMT and find therapeutic clues. The development of new surrogate markers for clinical trials is also needed. Additionally, steps should be taken to improve the quality of life of patients with CMT, including pain control and life style enhancement. PMID:26764298

  1. Connexin mutations in X-linked Charcot-Marie-Tooth disease

    SciTech Connect

    Bergoffen, J. ); Scherer, S.S.; Wang, S.; Scott, M.; Bone, L.J.; Chen, K.; Lensch, M.W.; Fischbeck, K.H. ); Paul, D.L. ); Change, P.F. )

    1993-12-24

    X-linked Charcot-Marie-Tooth disease (CMTX) is a form of hereditary neuropathy with demyelination. Recently, this disorder was mapped to chromosome Xq13.1. The gene for the gap junction protein connexin32 is located in the same chromosomal segment, which led to its consideration as a candidate gene for CMTX. With the use of Northern (RNA) blot and immunohistochemistry techniques, it was found that connexin32 is normally expressed in myelinated peripheral nerve. Direct sequencing of the connexin32 gene showed seven different mutations in affected persons from eight CMTX families. These findings, a demonstration of inherited defects in a gap junction protein, suggest that connexin32 plays an important role in peripheral nerve.

  2. Squamous Cell Carcinoma Arising in a Testicular Teratoma and Presenting as Sister Mary Joseph Nodule

    PubMed Central

    Khan, Kalyan; Bagchi, Dibakar

    2011-01-01

    The most common somatic type malignancy arising in patients with testicular germ cell tumors (GCTs) is sarcoma. Development of carcinomas, especially squamous cell carcinoma is an extremely rare event. Most cases of metastatic umbilical nodules (Sister Mary Joseph nodule) develop from adenocarcinomas. Fifteen percent of such cases have unknown origin; but development from a testicular squamous cell carcinoma has not yet been reported in the literature. We report a rare case of somatic type squamous cell carcinoma arising in a testicular teratoma. It is also possibly the first reported case of its kind which presented with a metastatic umbilical nodule. This possibility should be kept in mind while evaluating metastatic umbilical nodules in young male patients. PMID:22413055

  3. Solar Particle Events Observed by the Odyssey MARIE Instrument at Mars: Dose and Model Calculations

    NASA Technical Reports Server (NTRS)

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

    2003-01-01

    One of the primary concerns prior to human exploration of Mars is the need to accurately characterize the charged particle radiation environment both for the surface stay, and for the transit period to and from the planet. The Odyssey spacecraft, currently in Mars orbit includes a charged particle radiation detector, MARIE, which can measure particle fluxes with energies above approx. 30 MeV and charges between 1 and 10. Two classes of particles are of particular interest: the Galactic Cosmic Rays, (GCR), and those charged particles associated with Solar Particle Events, (SPE). The GCR are present continuously throughout the solar activity cycle, and their numbers vary inversely with the level of solar activity. They are characteristically more energetic than those particles originating from solar activity, and hence less influences by the solar magnetic field.

  4. Temporal and Spatial Variation of Surface Water Stable Isotopes in the Marys River Basin, Oregon

    NASA Astrophysics Data System (ADS)

    Nickolas, L. B.; Segura, C.; Brooks, J. R.

    2015-12-01

    Understanding the temporal and spatial variability of water sources within a basin is vital to our ability to manage the impacts of climate variability and land cover change. Water stable isotopes can be used as a tool to determine geographic and seasonal sources of water at the basin scale. Previous studies in the Coastal Range of Oregon reported that the variation in the isotopic signatures of surface water does not conform to the commonly observed "rainout effect", which exhibits a trend of increasing isotopic depletion with rising elevation. The primary purpose of this research is to investigate the mechanisms governing seasonal and spatial variations in the isotopic signature of surface waters within the Marys River Basin, located in the Oregon Coastal Range. We hypothesize that catchment orientation, drainage area, geology, and topography act as controlling factors on groundwater flow, storage, and atmospheric moisture cycling, which explain variations in source water contribution. Surface water and precipitation samples were collected every 2-3 weeks for isotopic analysis of δ18O and δ2H for one year. Preliminary results indicate a significant difference (p<0.001) in isotopic signature between watersheds underlain by basalt and sandstone. The degree of separation is the most distinct during the summer when low flows likely reflect deeper groundwater sources, whereas isotopic signatures during the rainy season (fall & winter) show a greater degree of similarity between the two lithologies. These findings indicate that the more permeable sandstone formations may be hydrologically connected to enriched water sources on the windward side of the Coastal Range that sustain baseflow within catchments on the leeward side, while streams draining basalt catchments are fed by a more depleted source of water (e.g. precipitation originating within the Marys River Basin).

  5. Analysis of coastal change in Marie Byrd Land and Ellsworth Land, West Antarctica, using Landsat imagery

    USGS Publications Warehouse

    Ferrigno, J.G.; Williams, R.S., Jr.; Rosanova, C.E.; Lucchitta, B.K.; Swithinbank, C.

    1998-01-01

    The U.S. Geological Survey is using Landsat imagery from the early 1970s and mid- to late 1980s/early 1990s to analyze glaciological features, compile a glacier inventory, measure surface velocities of outlet glaciers, ice streams and ice shelves, determine coastline change and calculate the area and volume of iceberg calving in Antarctica. Ice-surface velocities in Marie Byrd and Ellsworth Lands, West Antarctica, range from the fast-moving Thwaites, Pine Island, Land and DeVicq Glaciers to the slower-moving ice shelves. The average ice-front velocity during the time interval of Landsat imagery, for the faster-moving outlet glaciers, was 2.9 km a-1 for Thwaites Glacier, 2.4 km a-1 for Pine Island Glacier, 2.0 km a-1 for Land Glacier and 1.4 km a-1 for DeVicq Glacier. Evaluation of coastal change from the early 1970s to the early 1990s shows advance of the floating ice front in some coastal areas and recession in others, with an overall small average advance in the entire coastal study area, but no major trend towards advance or retreat. Comparison of average ice-surface velocities with changes in the ice front has yielded estimates of iceberg calving. The total iceberg calving from the Marie Byrd Land and Ellsworth Land coasts during the study period was greater than 8500 km2 (estimated volume of about 2400 km3) or an average of about 550 km2 a-1 (more than 150 km3 a-1). Almost 70% of this discharge is contributed by Thwaites and Pine Island Glaciers.

  6. HUMAN RIGHTS ASSESSMENT IN PARC JEAN MARIE VINCENT, PORT-AU-PRINCE, HAITI

    PubMed Central

    Cullen, Kimberly A.; Ivers, Louise C.

    2014-01-01

    Months after a 7.0 magnitude earthquake hit Port-au-Prince, Haiti, over one million remain homeless and living in spontaneous internally displaced person (IDP) camps. Billions of dollars from aid organizations and government agencies have been pledged toward the relief effort, yet many basic human needs, including food, shelter, and sanitation, continue to be unmet. The Sphere Project, “Humanitarian Charter and Minimum Standards in Disaster Response,” identifies the minimum standards to be attained in disaster response. From a human rights perspective and utilizing key indicators from the Sphere Project as benchmarks, this article reports on an assessment of the living conditions approximately 12 weeks after the earthquake in Parc Jean Marie Vincent, a spontaneous IDP camp in Port-au-Prince. A stratified random sample of households in the camp, proportionate to the number of families living in each sector, was selected. Interview questions were designed to serve as “key indicators” for the Sphere Project minimum standards. A total of 486 interviews were completed, representing approximately 5% of households in each of the five sectors of the camp. Our assessment identified the relative achievements and shortcomings in the provision of relief services in Parc Jean Marie Vincent. At the time of this survey, the Sphere Project minimum standards for access to health care and quantity of water per person per day were being met. Food, shelter, sanitation, and security were below minimum accepted standard and of major concern. The formal assessment reported here was completed by September 2010, and is necessarily limited to conditions in Haiti before the cholera outbreak in October. PMID:21178190

  7. [MARY LYON (1925-2014) AND THE RANDOM INACTIVATION OF CHROMOSOME X].

    PubMed

    Sagie, Shira; Monovich, Einat

    2016-03-01

    Since the beginning of the last century, genetic research has been preoccupied with the dosage compensation question: What mechanism controls equal expression of chromosome X genes between females and males? In the 1950s, many discoveries occurred in the field of cytogenetics related to the sex chromatin of female mammals. Concomitantly, genetic information accumulated with regard to expression patterns of X-linked genes in female mice and the expression effect of translocations between chromosome X and autosomes. In addition, many case reports were published about families with sex-linked diseases. The lately deceased scientist Mary F. Lyon suggested a unifying theory of these findings. In her articles "Gene action in the X-chromosome of the mouse (Mus musculus L.T in 1961, and "Sex chromatin and gene action in the mammalian X-chromosome" in 1962, she suggested that: (1) the heteropyknotic chromosome X was genetically inactivated, (2) the inactivated chromosome X could be either paternal or maternal in origin in different cells of the same animal, and (3) the inactivation occurred early in embryonic development. This theory led to an immediate breakthrough in understanding the basic mechanisms responsible for X-linked diseases and solved many unexplained case studies. Moreover, the inquiry of the mechanism of the phenomenon promoted scientific understanding of a wide range of areas in molecular biology such as DNA methylation, the silencing mechanism by XIST, histone modifications, DNA replication timing and more. The current article deals with some biographical details about Mary F. Lyon, the background of her theory, her historical articles and the development of the field since. PMID:27305745

  8. A Silent Witness for Peace: The Case of Schoolteacher Mary Stone McDowell and America at War

    ERIC Educational Resources Information Center

    Howlett, Patricia; Howlett, Charles F.

    2008-01-01

    A 1964 television series, "Profiles in Courage," based on the late President John F. Kennedy's Pulitzer prize-winning book, featured the life of Mary Stone McDowell, a quiet, yet strong, teacher. Within peace circles, McDowell was a well-known figure. Yet what captured the interest of the show's producers was the stand she took during World War I.…

  9. Trellis Coding of Non-coherent Multiple Symbol Full Response M-ary CPFSK with Modulation Index 1/M

    NASA Technical Reports Server (NTRS)

    Lee, H.; Divsalar, D.; Weber, C.

    1994-01-01

    This paper introduces a trellis coded modulation (TCM) scheme for non-coherent multiple full response M-ary CPFSK with modulation index 1/M. A proper branch metric for the trellis decoder is obtained by employing a simple approximation of the modified Bessel function for large signal to noise ratio (SNR). Pairwise error probability of coded sequences is evaluated by applying a linear approximation to the Rician random variable.

  10. Respiratory dysfunction in Charcot-Marie-Tooth disease type 1A.

    PubMed

    de Carvalho Alcântara, Mônica; Nogueira-Barbosa, Marcello H; Fernandes, Regina Maria França; da Silva, Geruza Alves; Lourenço, Charles Marques; Sander, Heide H; Marques Junior, Wilson

    2015-05-01

    We aimed to investigate the relationship between neurological compromise, respiratory parameters in wakefulness and in sleep, physiology, and morphology of phrenic nerves in patients with Charcot-Marie-Tooth disease type 1A (CMT1A). Sixteen patients with CMT1A were evaluated by spirometry, maximal expiratory and maximal inspiratory pressures (MEP, MIP), polysomnography, phrenic nerve compound muscle action potential (CMAP), and ultrasonography (roots C3,C4,C5 and phrenic nerves). Clinical disability was measured with Charcot-Marie-Tooth neuropathy score (CMT-NS; range 0-36). Two control groups, comprising 30 individuals matched for age, sex, and body mass index, were used for comparison. Ten patients were female (62%), mean age was 37.88 years (range 24-76); and CMT-NS range was 7-34. MIP was reduced in five (31%) and MEP in 12 patients (75%), although only one had restrictive respiratory dysfunction in spirometry. Apnoea-hypopnea index (AHI) was significantly higher in patients (12.01 ± 11.57/h × 5.89 ± 8.36/h; p value = 0.05) and increased in REM sleep compared with NREM (9.94 ± 10.96/h × 19.13 ± 19.93/h; p value = 0.01). There were significant correlations between CMT-NS and AHI (Pearson = 0.69; p value = 0.03); CMT-NS and MIP (Pearson = -0.691, p value = 0.003); and CMT-NS and MEP (Pearson = -0.603, p value = 0.013). Also, AHI showed negative correlation with MIP (Pearson = -0.52, p value = 0.036) and MEP (Pearson = -0.55, p value = 0.026). Phrenic nerves were enlarged in ultrasonography in all patients and presented significant correlations with CMAPs (right: Pearson = -0.554, p value = 0.026; left: Pearson = -0.558, p value = 0.025). We suggest that axonal degeneration of nerves directed to muscles of respiration might explain the high prevalence of respiratory weakness in patients with CMT1A. Clinical manifestations are frequent during sleep, where the diaphragm alone can only partially surpass the overload in breathing apparatus. PMID:25761374

  11. [A study of development of medicine and science in the nineteenth century science fiction: biomedical experiments in Mary Shelley's Frankenstein].

    PubMed

    Choo, Jae-Uk

    2014-12-01

    As the sciences advanced rapidly in the modern European world, outstanding achievements have been made in medicine, chemistry, biology, physiology, physics and others, which have been co-influencing each of the scientific disciplines. Accordingly, such medical and scientific phenomena began to be reflected in novels. In particular, Mary Shelley's Frankenstein includes the diverse aspects of the change and development in the medicine and science. Associated with medical and scientific information reflected in Frankenstein and Frankenstein's experiments in the text, accordingly, this research will investigate the aspects of medical and scientific development taking place in the nineteenth century in three ways. First, the medical and scientific development of the nineteenth century has been reviewed by summerizing both the information of alchemy in which Frankenstein shows his interest and the new science in general that M. Waldman introduces in the text. Second, the actual features of medical and scientific development have been examined through some examples of the experimental methods that M. Waldman implicitly uttered to Frankenstein. Third, it has been checked how the medical and scientific development is related to the main issues of mechanism and vitalism which can be explained as principles of life. Even though this research deals with the developmental process of medicine & science and origin & principles of life implied in Mary Shelley's Frankenstein, its significance is that it is the interdisciplinary research focussing on how deeply medical and scientific discourse of Mary Shelley's period has been imbedded in the nineteenth century novel. PMID:25608508

  12. Sister Mary Joseph Nodule as a First Manifestation of a Metastatic Ovarian Cancer

    PubMed Central

    Ogino, Mai; Kinuta, Takatoshi; Hori, Masateru; Mori, Tatsuo

    2016-01-01

    A 76-year-old female presented to our hospital with a 2 cm firm, nontender, protuberant umbilical nodule. She received treatment with antibiotics for suspected granuloma, with no improvement after two months. High levels of CA125 as well as an ovarian cyst and intrathoracic and intra-abdominal lesions on imaging studies made us suspect an ovarian cancer with a Sister Mary Joseph nodule (SMJN) and other metastases. A bilateral salpingo-oophorectomy and umbilical and omentum tumor resections were performed and a metastatic ovarian serous adenocarcinoma was diagnosed by histopathology. After surgery, the patient received chemotherapy with paclitaxel, carboplatin, and bevacizumab; however paclitaxel allergy was observed. As a result, chemotherapy continued with carboplatin and bevacizumab every three weeks for a total of 6 courses. Currently, she is still undergoing treatment with bevacizumab and CA125 levels have been progressively decreasing. SMJN is a rare umbilical metastasis which needs to be considered as a differential diagnosis in the presence of an umbilical tumor for prompt treatment initiation.

  13. Coexistence of Charcot-Marie-Tooth disease type 1A and anti-MAG neuropathy.

    PubMed

    Piscosquito, Giuseppe; Salsano, Ettore; Ciano, Claudia; Palamara, Luisa; Morbin, Michela; Pareyson, Davide

    2013-06-01

    At age 35, a man with a genetic diagnosis of Charcot-Marie-Tooth disease type 1A (CMT1A) but no family history of neuropathy and no clinical symptoms developed rapidly progressive loss of balance, distal limb numbness, loss of manual dexterity, and hand tremor. Five years later, he walked with support and had mild pes cavus, marked sensory ataxia, severe leg and hand weakness, absent deep tendon reflexes (DTRs), severe sensory loss, and hand tremor. He had dramatically reduced motor nerve conduction velocity (MNCV), strikingly prolonged motor distal latencies, absent sensory action potentials and lower limb compound muscle action potentials. CMT1A duplication was reconfirmed but the dramatic change in his clinical course suggested a superimposed acquired neuropathy. An IgM-kappa monoclonal gammopathy of uncertain significance (MGUS) with high titer anti-myelin associated glycoprotein (anti-MAG) activity was found. Nerve biopsy showed severe loss of myelinated fibers with onion bulbs, no evidence of uncompacted myelin, and few IgM deposits. Rituximab was given and he improved. It is very likely that this is a chance association of two rare and slowly progressive neuropathies; rapidly worsening course may have been due to a "double hit". Interestingly, there are reports of possible superimposition of dysimmune neuropathies on hereditary ones, and the influence of the immune system on inherited neuropathies is matter for debate. PMID:23781967

  14. A brief review of recent Charcot-Marie-Tooth research and priorities

    PubMed Central

    Ekins, Sean; Litterman, Nadia K.; Arnold, Renée J.G.; Burgess, Robert W.; Freundlich, Joel S.; Gray, Steven J.; Higgins, Joseph J.; Langley, Brett; Willis, Dianna E.; Notterpek, Lucia; Pleasure, David; Sereda, Michael W.; Moore, Allison

    2015-01-01

    This brief review of current research progress on Charcot-Marie-Tooth (CMT) disease is a summary of discussions initiated at the Hereditary Neuropathy Foundation (HNF) scientific advisory board meeting on November 7, 2014. It covers recent published and unpublished in vitro and in vivo research. We discuss recent promising preclinical work for CMT1A, the development of new biomarkers, the characterization of different animal models, and the analysis of the frequency of gene mutations in patients with CMT. We also describe how progress in related fields may benefit CMT therapeutic development, including the potential of gene therapy and stem cell research. We also discuss the potential to assess and improve the quality of life of CMT patients. This summary of CMT research identifies some of the gaps which may have an impact on upcoming clinical trials. We provide some priorities for CMT research and areas which HNF can support. The goal of this review is to inform the scientific community about ongoing research and to avoid unnecessary overlap, while also highlighting areas ripe for further investigation. The general collaborative approach we have taken may be useful for other rare neurological diseases. PMID:25901280

  15. A saw-based demodulator for dehopped FDMA M-ary FSK satellite signals

    NASA Astrophysics Data System (ADS)

    Felstead, E. B.; Pearce, J. L.

    A demodulator has been built and tested, that is capable of performing the functions of an onboard-the-satellite processor for receiving M-ary noncoherent FSK signals with multiple users being separated by FDMA. It is based on spectral analysis of the received signal by a chirp transformer implemented with surface acoustic-wave devices. Demodulation of M = 4-, 8-, and 16-ary FSK signals of 25 microsec symbol duration was demonstrated with capability of handling up to 40/M users. The implementation loss was only 0.5 dB. Measurement of bit error rate performance in the presence of system noise, frequency errors, and partial-band-noise and multiple-tone jamming were made and found to agree well with theory. The effects were examined of three different time windows: rectangular, Kaiser Bessel alpha = 1.6, and one intermediate between these two. The intermediate window is promising because of low window loss combined with good adjacent channel interference tolerance.

  16. Charcot-Marie-Tooth (CMT) disease 1A with superimposed inflammatory polyneuropathy in children.

    PubMed

    Desurkar, A; Lin, J-P; Mills, K; Al-Sarraj, S; Jan, W; Jungbluth, H; Wraige, E

    2009-04-01

    Charcot-Marie-Tooth (CMT) disease is genetically heterogeneous and subdivided into demyelinating (CMT 1) and axonal (CMT 2) types based on neurophysiology findings. CMT1A, the commonest form associated with duplication of the PMP22 segment on chromosome 17p, often arises in childhood but is generally a slowly progressive disease. We report 2 children presenting with clinical features of an acute inflammatory demyelinating polyneuropathy (AIDP) who were subsequently diagnosed with underlying CMT1A. Both children had neurophysiology and histopathology features consistent with CMT1. Immunoglobulin treatment was initiated considering the evidence of superimposed inflammation and appeared to modify disease progression. Our findings indicate that CMT1A predisposes to a superimposed inflammatory neuropathy. Recognition of this association is difficult, particularly in children without clear family history, but of great importance as immunomodulatory treatment may improve outcome. In addition, we postulate that an underlying genetic polyneuropathy should be suspected if the recovery from AIDP is slower than expected, or incomplete. PMID:19809938

  17. Charcot-Marie-Tooth disease: frequency of genetic subtypes in a Southern Italy population.

    PubMed

    Manganelli, Fiore; Tozza, Stefano; Pisciotta, Chiara; Bellone, Emilia; Iodice, Rosa; Nolano, Maria; Geroldi, Alessandro; Capponi, Simona; Mandich, Paola; Santoro, Lucio

    2014-12-01

    The objective of this study is to assess the genetic distribution of Charcot-Marie-Tooth (CMT) disease in Campania, a region of Southern Italy. We analyzed a cohort of 197 index cases and reported the type and frequency of mutations for the whole CMT population and for each electrophysiological group (CMT1, CMT2, and hereditary neuropathy with susceptibility to pressure palsies [HNPP]) and for familial and isolated CMT cases. Genetic diagnosis was achieved in 148 patients (75.1%) with a higher success rate in HNPP and CMT1 than CMT2. Only four genes (PMP22, GJB1, MPZ, and GDAP1) accounted for 92% of all genetically confirmed CMT cases. In CMT1, PMP22 duplication was the most common mutation while the second gene in order of frequency was MPZ in familial and SH3TC2 in isolated cases. In CMT2, GJB1 was the most frequent mutated gene and GJB1 with GDAP1 accounted for almost 3/4 of genetically defined CMT2 patients. The first gene in order of frequency was GJB1 in familial and GDAP1 in isolated cases. In HNPP, the majority of patients harbored the PMP22 gene deletion. The novelty of our data is the relatively high frequency of SH3TC2 and GDAP1 mutations in demyelinating and axonal forms, respectively. These epidemiological data can help in panel design for our patients' population. PMID:25429913

  18. Genetic Diagnosis of Charcot-Marie-Tooth Disease in a Population by Next-Generation Sequencing

    PubMed Central

    Høyer, Helle; Braathen, Geir J.; Busk, Øyvind L.; Holla, Øystein L.; Svendsen, Marit; Hilmarsen, Hilde T.; Strand, Linda; Skjelbred, Camilla F.; Russell, Michael B.

    2014-01-01

    Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited neuropathy. Today more than 40 CMT genes have been identified. Diagnosing heterogeneous diseases by conventional Sanger sequencing is time consuming and expensive. Thus, more efficient and less costly methods are needed in clinical diagnostics. We included a population based sample of 81 CMT families. Gene mutations had previously been identified in 22 families; the remaining 59 families were analysed by next-generation sequencing. Thirty-two CMT genes and 19 genes causing other inherited neuropathies were included in a custom panel. Variants were classified into five pathogenicity classes by genotype-phenotype correlations and bioinformatics tools. Gene mutations, classified certainly or likely pathogenic, were identified in 37 (46%) of the 81 families. Point mutations in known CMT genes were identified in 21 families (26%), whereas four families (5%) had point mutations in other neuropathy genes, ARHGEF10, POLG, SETX, and SOD1. Eleven families (14%) carried the PMP22 duplication and one family carried a MPZ duplication (1%). Most mutations were identified not only in known CMT genes but also in other neuropathy genes, emphasising that genetic analysis should not be restricted to CMT genes only. Next-generation sequencing is a cost-effective tool in diagnosis of CMT improving diagnostic precision and time efficiency. PMID:25025039

  19. Perk Ablation Ameliorates Myelination in S63del-Charcot-Marie-Tooth 1B Neuropathy.

    PubMed

    Musner, Nicolò; Sidoli, Mariapaola; Zambroni, Desireè; Del Carro, Ubaldo; Ungaro, Daniela; D'Antonio, Maurizio; Feltri, Maria L; Wrabetz, Lawrence

    2016-04-01

    In peripheral nerves, P0 glycoprotein accounts for more than 20% of myelin protein content. P0 is synthesized by Schwann cells, processed in the endoplasmic reticulum (ER) and enters the secretory pathway. However, the mutant P0 with S63 deleted (P0S63del) accumulates in the ER lumen and induces a demyelinating neuropathy in Charcot-Marie-Tooth disease type 1B (CMT1B)-S63del mice. Accumulation of P0S63del in the ER triggers a persistent unfolded protein response. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) is an ER stress sensor that phosphorylates eukaryotic initiation factor 2 alpha (eIF2alpha) in order to attenuate protein synthesis. We have shown that increasing phosphophorylated-eIF2alpha (P-eIF2alpha) is a potent therapeutic strategy, improving myelination and motor function in S63del mice. Here, we explore the converse experiment:Perkhaploinsufficiency reduces P-eIF2alpha in S63del nerves as expected, but surprisingly, ameliorates, rather than worsens S63del neuropathy. Motor performance and myelin abnormalities improved in S63del//Perk+/- compared with S63del mice. These data suggest that mechanisms other than protein translation might be involved in CMT1B/S63del neuropathy. In addition,Perkdeficiency in other cells may contribute to demyelination in a non-Schwann-cell autonomous manner. PMID:27095827

  20. Myelin protein zero gene mutated in Charcot-Marie-Tooth type 1B patients

    SciTech Connect

    Su, Ying; Li, Lanying; Lepercq, J.; Lebo, R.V. ); Brooks, D.G.; Ravetch, J.V. ); Trofatter, J.A. )

    1993-11-15

    The autosomal dominant of Charcot-Marie-Tooth disease (CMT), whose gene is type 1B (CMT1B), has slow nerve conduction with demyelinated Schwann cells. In this study the abundant peripheral myelin protein zero (MPZ) gene, MPZ, was mapped 130 kb centromeric to the Fc receptor immunoglobulin gene cluster in band 1q22, and a major MPZ point mutation was found to cosegregate with CMT1B in one large CMT1B family. The MPZ point mutation in 18 of 18 related CMT1B pedigree 1 patients converts a positively charged lysine in codon 96 to a negatively charged glutamate. The same MPZ locus cosegregates with the CMT1B disease gene in a second CMT1B family [total multipoint logarithm of odds (lod) = 11.4 at [theta] = 0.00] with a splice junction mutation. Both mutations occur in MPZ protein regions otherwise conserved identically in human, rat, and cow since these species diverged 100 million years ago. MPZ protein, expressed exclusively in myelinated peripheral nerve Schwann cells, constitutes >50% of myelin protein. These mutations are anticipated to disrupt homophilic MPZ binding and result in CMT1B peripheral nerve demyelination.

  1. Oral Health, Temporomandibular Disorder, and Masticatory Performance in Patients with Charcot-Marie-Tooth Type 2

    PubMed Central

    Rezende, Rejane L. S.; Bonjardim, Leonardo R.; Neves, Eduardo L. A.; Santos, Lidiane C. L.; Nunes, Paula S.; Garcez, Catarina A.; Souza, Cynthia C.; Araújo, Adriano A. S.

    2013-01-01

    Background. The aim of this study was to evaluate the oral health status of temporomandibular disorders (TMD) and bruxism, as well as to measure masticatory performance of subjects with Charcot-Marie-Tooth type 2 (CMT2). Methods and Results. The average number of decayed, missing, and filled teeth (DMFT) for both groups, control (CG) and CMT2, was considered low (CG = 2.46; CMT2 = 1.85, P = 0.227). The OHIP-14 score was considered low (CG = 2.86, CMT2 = 5.83, P = 0.899). The prevalence of self-reported TMD was 33.3% and 38.9% (P = 0.718) in CG and CMT2 respectively and for self-reported bruxism was 4.8% (CG) and 22.2% (CMT2), without significant difference between groups (P = 0.162). The most common clinical sign of TMD was masseter (CG = 38.1%; CMT2 = 66.7%) and temporalis (CG = 19.0%; GCMT2 = 33.3%) muscle pain. The geometric mean diameter (GMD) was not significantly different between groups (CG = 4369; CMT2 = 4627, P = 0.157). Conclusion. We conclude that the CMT2 disease did not negatively have influence either on oral health status in the presence and severity of TMD and bruxism or on masticatory performance. PMID:24391462

  2. Determination of evaporation and seepage losses, Upper Lake Mary near Flagstaff, Arizona

    USGS Publications Warehouse

    Blee, J.W.

    1988-01-01

    Two mass-transfer equations were developed to compute evaporation as a part of the evaporation were seepage-loss study for the Upper Lake Mary Reservoir near Flagstaff, Arizona, which has a capacity of 15,620 acre-feet and a surface area of 876 acres. The mass-transfer equations do not require an independent measure of evaporation to define the mass-transfer coefficient. Data from other evaporation studies were used to define the mass-transfer coefficient as a function of wind shear and atmospheric stability. Long-term seepage losses were determined by use of a seepage-probability curve-derived from a stage-seepage relation and defined by several selected short-term water budgets-and a lake-stage probability curve. Seepage curves were derived for several different amounts of assumed reservoir sealing. The long-term water saving that would result from each increment of lake-bottom sealing were computed. The study revealed that the evaporation loss was 27 percent of 2 ,100 acre-feet per year of the total reservoir inflow during 1950-71; seepage loss was 45 percent or 3,500 acre-feet per year. (USGS)

  3. Severe phenotypes in a Charcot-Marie-Tooth 1A patient with PMP22 triplication.

    PubMed

    Kim, Sung Min; Lee, Jinho; Yoon, Bo Ram; Kim, Ye Jin; Choi, Byung-Ok; Chung, Ki Wha

    2015-02-01

    Charcot-Marie-Tooth disease (CMT) is a genetically and clinically heterogeneous hereditary motor and sensory neuropathy signified by a distal symmetric polyneuropathy. The most frequent subtype is type 1A (CMT1A) caused by duplication in chromosome 17p12 that includes PMP22. This study reports a woman with a family history of CMT1A due to PMP22 duplication. However, she presented with a more severe phenotype than her sibling or ancestors and was found to have a PMP22 triplication instead of the duplication. This was caused by de novo mutation on her affected mother's duplication chromosome. Her lower limb magnetic resonance imaging revealed severe diffused atrophy and fatty replacement. However, her affected sister with typical PMP22 duplication showed almost intact lower limb. Triplication patient's median motor nerve conduction velocity was far lower compared with her sister. Her onset age was faster (8 years) than her sister (42 years). CMT1A triplication might be generated by a female-specific chromosomal rearrangement mechanism that is different from the frequent paternal-originated CMT1A duplication. It also suggests that the wide phenotypic variation of CMT1A might be partly caused by unstable genomic rearrangement, including PMP22 triplication. PMID:25500726

  4. Cerebral involvement in axonal Charcot-Marie-Tooth neuropathy caused by mitofusin2 mutations.

    PubMed

    Brockmann, Knut; Dreha-Kulaczewski, Steffi; Dechent, Peter; Bönnemann, Carsten; Helms, Gunther; Kyllerman, Marten; Brück, Wolfgang; Frahm, Jens; Huehne, Kathrin; Gärtner, Jutta; Rautenstrauss, Bernd

    2008-07-01

    Mutations in the mitofusin 2 (MFN2) gene are a major cause of primary axonal Charcot- Marie-Tooth (CMT) neuropathy. This study aims at further characterization of cerebral white matter alterations observed in patients with MFN2 mutations. Molecular genetic, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) investigations were performed in four unrelated patients aged 7 to 38 years with early onset axonal CMT neuropathy. Three distinct and so far undescribed MFN2 mutations were detected. Two patients had secondary macrocephaly and mild diffuse predominantly periventricular white matter alterations on MRI. In addition, one boy had symmetrical T2-hyperintensities in both thalami. Two patients had optic atrophy, one of them with normal MRI. In three patients proton MRS revealed elevated concentrations of total N-acetyl compounds (neuronal marker), total creatine (found in all cells) and myo-inositol (astrocytic marker) in cerebral white and gray matter though with regional variation. These alterations were most pronounced in the two patients with abnormal MRI. DTI of these patients revealed mild reductions of fractional anisotropy and mild increase of mean diffusivity in white matter. The present findings indicate an enhanced cellular density in cerebral white matter of MFN2 neuropathy which is primarily due to a reactive gliosis without axonal damage and possibly accompanied by mild demyelination. PMID:18425620

  5. Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2.

    PubMed

    Cottenie, Ellen; Kochanski, Andrzej; Jordanova, Albena; Bansagi, Boglarka; Zimon, Magdalena; Horga, Alejandro; Jaunmuktane, Zane; Saveri, Paola; Rasic, Vedrana Milic; Baets, Jonathan; Bartsakoulia, Marina; Ploski, Rafal; Teterycz, Pawel; Nikolic, Milos; Quinlivan, Ros; Laura, Matilde; Sweeney, Mary G; Taroni, Franco; Lunn, Michael P; Moroni, Isabella; Gonzalez, Michael; Hanna, Michael G; Bettencourt, Conceicao; Chabrol, Elodie; Franke, Andre; von Au, Katja; Schilhabel, Markus; Kabzińska, Dagmara; Hausmanowa-Petrusewicz, Irena; Brandner, Sebastian; Lim, Siew Choo; Song, Haiwei; Choi, Byung-Ok; Horvath, Rita; Chung, Ki-Wha; Zuchner, Stephan; Pareyson, Davide; Harms, Matthew; Reilly, Mary M; Houlden, Henry

    2014-11-01

    Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-μ-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5' region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels. PMID:25439726

  6. Mutation of SIMPLE in Charcot-Marie-Tooth 1C alters production of exosomes.

    PubMed

    Zhu, Hong; Guariglia, Sara; Yu, Raymond Y L; Li, Wenjing; Brancho, Deborah; Peinado, Hector; Lyden, David; Salzer, James; Bennett, Craig; Chow, Chi-Wing

    2013-06-01

    Charcot-Marie-Tooth (CMT) disease is an inherited neurological disorder. Mutations in the small integral membrane protein of the lysosome/late endosome (SIMPLE) account for the rare autosomal-dominant demyelination in CMT1C patients. Understanding the molecular basis of CMT1C pathogenesis is impeded, in part, by perplexity about the role of SIMPLE, which is expressed in multiple cell types. Here we show that SIMPLE resides within the intraluminal vesicles of multivesicular bodies (MVBs) and inside exosomes, which are nanovesicles secreted extracellularly. Targeting of SIMPLE to exosomes is modulated by positive and negative regulatory motifs. We also find that expression of SIMPLE increases the number of exosomes and secretion of exosome proteins. We engineer a point mutation on the SIMPLE allele and generate a physiological mouse model that expresses CMT1C-mutated SIMPLE at the endogenous level. We find that CMT1C mouse primary embryonic fibroblasts show decreased number of exosomes and reduced secretion of exosome proteins, in part due to improper formation of MVBs. CMT1C patient B cells and CMT1C mouse primary Schwann cells show similar defects. Together the data indicate that SIMPLE regulates the production of exosomes by modulating the formation of MVBs. Dysregulated endosomal trafficking and changes in the landscape of exosome-mediated intercellular communications may place an overwhelming burden on the nervous system and account for CMT1C molecular pathogenesis. PMID:23576546

  7. Characteristics of demyelinating Charcot-Marie-Tooth disease with concurrent diabetes mellitus

    PubMed Central

    Yu, Zhiliang; Wu, Xiaohua; Xie, Huijun; Han, Ying; Guan, Yangtai; Qin, Yong; Zheng, Huimin; Jiang, Jianming; Niu, Zhenmin

    2014-01-01

    Purpose: Charcot-Marie-Tooth disease (CMT) is the most common type of inherited peripheral neuropathy and has a high degree of genetic heterogeneity. CMT with concurrent diabetes mellitus (DM) is rare. The purpose of this study is to explore the genetic, clinical and pathological characteristics of the patients with CMT and concurrent DM. Methods: We investigated gene mutations (the peripheral myelin protein 22 gene, myelin protein zero gene, lipopolysaccharide-induced tumor necrosis factor-α factor gene, early growth response gene and the neurofilament light chain gene loci) of a relatively large and typical Chinese family with CMT1 and concurrent DM2. From the literature, we also retrieved all reported families and single cases with CMT and concurrent DM. We comprehensively analyzed the characteristics of total 33 patients with CMT and concurrent DM, and further compared these characteristics with those of patients of diabetic peripheral neuropathy (DPN). Results: Patients with CMT and concurrent DM had some relatively independent characteristics and pathogenic mechanisms. So we designated that kind of characteristic demyelinating CMT which accompanies DM as Yu-Xie syndrome (YXS), a new specific clinical subtype of CMT. Conclusion: CMT is an etiologic factor of DM, even though the intrinsic association between CMT and DM still remains further exploration. PMID:25120817

  8. Heavy ion observations by MARIE in cruise phase and Mars orbit

    NASA Technical Reports Server (NTRS)

    Lee, K. T.; Cleghorn, T.; Cucinotta, F.; Pinsky, L.; Zeitlin, C.

    2004-01-01

    The charged particle spectrum for nuclei from protons to neon, (charge Z=10) was observed during the cruise phase and orbit around Mars by the MARIE charged particle spectrometer on the Odyssey spacecraft. The cruise data were taken between April 23, 2001 and mid-August 2001. The Mars orbit data were taken March 5, 2002 through May 2002 and are scheduled to continue until August 2004. Charge peaks are clearly separated for charges up to Z=10. Especially prominent are the carbon and oxygen peaks, with boron and nitrogen also clearly visible. Although heavy ions are much less abundant than protons in the cosmic ray environment, it is important to determine their abundances because their ionization energy losses (proportional to Z2) are far more dangerous to humans and to instruments. Thus the higher charged nuclei make a significant contribution to dose and dose equivalent received in space. Results of the charged particle spectrum measurements will be reported. c2003 COSPAR. Published by Elsevier Ltd. All rights reserved.

  9. Intermittent fasting alleviates the neuropathic phenotype in a mouse model of Charcot-Marie-Tooth disease

    PubMed Central

    Madorsky, Irina; Opalach, Katherine; Waber, Amanda; Verrier, Jonathan D.; Solmo, Chelsea; Foster, Thomas; Dunn, William A; Notterpek, Lucia

    2009-01-01

    Charcot-Marie-Tooth type 1A (CMT1A) neuropathies linked to the misexpression of peripheral myelin protein 22 (PMP22) are progressive demyelinating disorders of the peripheral nervous system. In this study we asked whether dietary restriction by intermittent fasting (IF) could alleviate the neuropathic phenotype in the Trembler J (TrJ) mouse model of CMT1A. Our results show that neuropathic mice kept on a five month long IF regimen had improved locomotor performance compared to ad libitum (AL) fed littermates. The functional benefits of this dietary intervention are associated with an increased expression of myelin proteins combined with a thicker myelin sheath, less redundant basal lamina, and a reduction in aberrant Schwann cell proliferation. These morphological improvements are accompanied by a decrease in PMP22 protein aggregates, and enhanced expression of cytosolic chaperones and constituents of the autophagy-lysosomal pathway. These results indicate that dietary restriction is beneficial for peripheral nerve function in TrJ neuropathic mice, as it promotes the maintenance of locomotor performance. PMID:19320048

  10. Health-hazard evaluation report HETA 84-033-1576, Airco Carbon, St. Marys, Pennsylvania

    SciTech Connect

    Hartle, R.W.; Morawetz, J.S.

    1985-09-01

    Environmental and breathing-zone samples were analyzed for polynuclear aromatic hydrocarbons (PAH), total particulates, and respirable free silica at the Airco Company (SIC-3624), Saint Marys, Pennsylvania in January, 1984. The evaluation was requested confidentially because of concern over exposures to soot, coal tar pitch volatiles, and sand in the car bottom and sagger bake operations. Forty-three employees were interviewed. Two of 19 total particulate samples exceeded the OSHA standard of 15 milligrams per cubic meter (mg/m3), 17.3 and 32.7 mg/m3. Benzene soluble fractions ranged from 0.5 to 5.0 mg/m3. The OSHA standard for benzene soluble fractions is 0.2 mg/m3. Two of seven samples of silica were above the limit of detection, 0.09 and 0.06 mg/m3. In bulk samples, the benzene soluble fractions ranged from 0.44 to 860 mg/gram and the PAH content from 0 to 26,124 micrograms per gram. Employees working in the bake areas reported a significant excess incidence of symptoms such as skin, nose and eye irritation, cough, sore or dry throat, chest tightness, and breathing difficulty. The authors conclude that a health hazard exists at the facility. Recommendations include enclosing vehicles used in moving electrodes, cleaning up spilled dust, and controlling fumes emitted from the sagger kilns.

  11. A compound heterozygous mutation in HADHB gene causes an axonal Charcot-Marie-tooth disease

    PubMed Central

    2013-01-01

    Background Charcot-Marie-Tooth disease (CMT) is a heterogeneous disorder of the peripheral nervous system. So far, mutations in hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), beta subunit (HADHB) gene exhibit three distinctive phenotypes: severe neonatal presentation with cardiomyopathy, hepatic form with recurrent hypoketotic hypoglycemia, and later-onset axonal sensory neuropathy with episodic myoglobinuria. Methods To identify the causative and characterize clinical features of a Korean family with motor and sensory neuropathies, whole exome study (WES), histopathologic study of distal sural nerve, and lower limb MRIs were performed. Results WES revealed that a compound heterozygous mutation in HADHB is the causative of the present patients. The patients exhibited an early-onset axonal sensorimotor neuropathy without episodic myoglobinuria, and showed typical clinical and electrophysiological features of CMT including predominant distal muscle weakness and atrophy. Histopathologic findings of sural nerve were compatible with an axonal CMT neuropathy. Furthermore, they didn’t exhibit any other symptoms of the previously reported HADHB patients. Conclusions These data implicate that mutation in HADHB gene can also cause early-onset axonal CMT instead of typical manifestations in mitochondrial trifunctional protein (MTP) deficiency. Therefore, this study is the first report of a new subtype of autosomal recessive axonal CMT by a compound heterozygous mutation in HADHB, and will expand the clinical and genetic spectrum of HADHB. PMID:24314034

  12. A pilot study of proximal strength training in Charcot-Marie-Tooth disease.

    PubMed

    Ramdharry, Gita M; Pollard, Alexander; Anderson, Cheryl; Laurá, Matilde; Murphy, Sinead M; Dudziec, Magdalena; Dewar, Elizabeth L; Hutton, Elspeth; Grant, Robert; Reilly, Mary M

    2014-12-01

    Gait analysis of people with Charcot-Marie-Tooth (CMT) disease revealed proximal adaptive gait strategies to compensate for foot drop. We previously demonstrated that hip flexor muscle fatigue can limit walking endurance. This pilot study used a single-blinded cross over design to investigate the effect of a 16-week home-based programme of resistance training on hip flexor muscle strength. Measures of walking endurance, gait speed, exertion, fatigue, and general activity were also recorded. The exercise protocol was based on American College of Sports Medicine recommendations. A mixed effects model was used for analysis. Twenty-six people finished the study, with average reported exercise participation of 93%. No negative effects of exercise were observed. Significant increase in hip flexor muscle strength was observed on the left, but not the right. No changes were observed in walking speed and endurance measures. This pilot study of home-based resistance training showed a modest improvement in hip strength but only on one side. The lack of a more significant improvement and no improvement in walking measures suggests that this training protocol may not be optimal for people with CMT and that patients may need to stratified differently for training studies in CMT. PMID:25582960

  13. Hereditary motor and sensory neuropathies or Charcot-Marie-Tooth diseases: an update.

    PubMed

    Tazir, Meriem; Hamadouche, Tarik; Nouioua, Sonia; Mathis, Stephane; Vallat, Jean-Michel

    2014-12-15

    Hereditary motor and sensory neuropathies (HMSN) or Charcot-Marie-Tooth (CMT) diseases are the most common degenerative disorders of the peripheral nervous system. However, the frequency of the different subtypes varies within distinct populations. Although more than seventy clinical and genetic forms are known to date, more than 80% of CMT patients in Western countries have genetic abnormalities associated with PMP22, MPZ, MFN2 and GJB1. Given the considerable genetic heterogeneity of CMT, we emphasize the interest of both clinical and pathological specific features such that focused genetic testing could be performed. In this regard, peripheral nerve lesions in GDAP1 mutations (AR CMT1A), such as mitochondrial abnormalities, have been newly demonstrated. Otherwise, while demyelinating autosomal recessive CMT used to be classified as CMT4 (A, B, C …), we propose a simplified classification such as AR CMT1 (A, B, C …), and AR CMT2 for axonal forms. Also, we stress that next generation sequencing techniques, now considered to be the most efficient methods of genetic testing in CMT, will be helpful in molecular diagnosis and research of new genes involved. Finally, while no effective therapy is known to date, ongoing new therapeutic trials such as PXT3003 (a low dose combination of the three already approved drugs baclofen, naltrexone, and D-sorbitol) give hopes for potential curative treatment. PMID:25454638

  14. Exacerbation of Charcot-Marie-Tooth type 2E neuropathy following traumatic nerve injury.

    PubMed

    Villalón, Eric; Dale, Jeffrey M; Jones, Maria; Shen, Hailian; Garcia, Michael L

    2015-11-19

    Charcot-Marie-Tooth disease (CMT) is the most commonly inherited peripheral neuropathy. CMT disease signs include distal limb neuropathy, abnormal gait, sensory defects, and deafness. We generated a novel line of CMT2E mice expressing hNF-L(E397K), which displayed muscle atrophy of the lower limbs without denervation, proximal reduction in large caliber axons, and decreased nerve conduction velocity. In this study, we challenged wild type, hNF-L and hNF-L(E397K) mice with crush injury to the sciatic nerve. We analyzed functional recovery by measuring toe spread and analyzed gait using the Catwalk system. hNF-L(E397K) mice demonstrated reduced recovery from nerve injury consistent with increased susceptibility to neuropathy observed in CMT patients. In addition, hNF-L(E397K) developed a permanent reduction in their ability to weight bear, increased mechanical allodynia, and premature gait shift in the injured limb, which led to increasingly disrupted interlimb coordination in hNF-L(E397K). Exacerbation of neuropathy after injury and identification of gait alterations in combination with previously described pathology suggests that hNF-L(E397K) mice recapitulate many of clinical signs associated with CMT2. Therefore, hNF-L(E397K) mice provide a model for determining the efficacy of novel therapies. PMID:26423936

  15. Neural and Molecular Features on Charcot-Marie-Tooth Disease Plasticity and Therapy

    PubMed Central

    Juárez, Paula; Palau, Francesc

    2012-01-01

    In the peripheral nervous system disorders plasticity is related to changes on the axon and Schwann cell biology, and the synaptic formations and connections, which could be also a focus for therapeutic research. Charcot-Marie-Tooth disease (CMT) represents a large group of inherited peripheral neuropathies that involve mainly both motor and sensory nerves and induce muscular atrophy and weakness. Genetic analysis has identified several pathways and molecular mechanisms involving myelin structure and proper nerve myelination, transcriptional regulation, protein turnover, vesicle trafficking, axonal transport and mitochondrial dynamics. These pathogenic mechanisms affect the continuous signaling and dialogue between the Schwann cell and the axon, having as final result the loss of myelin and nerve maintenance; however, some late onset axonal CMT neuropathies are a consequence of Schwann cell specific changes not affecting myelin. Comprehension of molecular pathways involved in Schwann cell-axonal interactions is likely not only to increase the understanding of nerve biology but also to identify the molecular targets and cell pathways to design novel therapeutic approaches for inherited neuropathies but also for most common peripheral neuropathies. These approaches should improve the plasticity of the synaptic connections at the neuromuscular junction and regenerate cell viability based on improving myelin and axon interaction. PMID:22745917

  16. Charcot-Marie-Tooth 1A: A narrative review with clinical and anatomical perspectives.

    PubMed

    McGrath, M C

    2016-07-01

    Charcot-Marie-Tooth 1A (CMT1A) is regarded as the most common hereditary peripheral neurodegenerative disorder. This narrative review highlights perspectives around the historically well-established and characteristic anatomical manifestations of CMT1A seen in the feet, legs and hands, in addition to a clinical diagnosis that may be confirmed by electrophysiology, genetic or molecular markers together with the presence of a typical family history. A less well-known perspective is the potential for systemic manifestations and wider complication. The condition is characterised by a progressive clinical picture with unmistakable anatomical and neurological features that have been described since the late 19th century. There remains no cure although supportive, rehabilitative, and surgical regimes may provide helpful management or amelioration of symptoms. Most recently, the emergence of a pleotherapeutic approach suggests distinct promise. Future research focused on a detailed elucidation of the underlying molecular mechanisms underpinning myelin and axonal function may eventually hold the key to successful treatment of CMT1A. Genetic modification would potentially present a cure. Clin. Anat. 29:547-554, 2016. © 2015 Wiley Periodicals, Inc. PMID:26457477

  17. How do Mutations in GJB1 Cause X-linked Charcot-Marie-Tooth Disease?

    PubMed Central

    Kleopa, Kleopas A.; Abrams, Charles K.; Scherer, Steven S.

    2012-01-01

    The X-linked form of Charcot-Marie-Tooth disease (CMT1X) is the second most common form of hereditary motor and sensory neuropathy. The clinical phenotype is characterized by progressive weakness, atrophy, and sensory abnormalities that are most pronounced in the distal extremities. Some patients have CNS manifestations. Affected males have moderate to severe symptoms, whereas heterozygous females are usually less affected. Neurophysiology shows intermediate slowing of conduction and length-dependent axonal loss. Nerve biopsies show more prominent axonal degeneration than de/remyelination. Mutations in GJB1, the gene that encodes the gap junction (GJ) protein connexin32 (Cx32) cause CMT1X; more than 400 different mutations have been described. Many Cx32 mutants fail to form functional GJs, or form GJs with abnormal biophysical properties. Schwann cells and oligodendrocytes express Cx32, and the GJs formed by Cx32 play an important role in the homeostasis of myelinated axons. Animal models of CMT1X demonstrate that loss of Cx32 in myelinating Schwann cells causes a demyelinating neuropathy. Effective therapies remain to be developed. PMID:22771394

  18. Linkage localization of X-linked Charcot-Marie-Tooth disease

    SciTech Connect

    Bergoffen, J. Univ. of Pennsylvania, Philadelphia ); Trofatter, J.; Haines, J.L. ); Pericak-Vance, M.A. ); Chance, P.F. ); Fischbeck, K.H. )

    1993-02-01

    Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is a heterogeneous group of slowly progressive, degenerative disorders of peripheral nerve. X-linked CMT (CMTX) (McKusick 302800), a subdivision of type I, or demyelinating, CMT is an X-linked dominant condition with variable penetrance. Previous linkage analysis using RFLPs demonstrated linkage to markers on the proximal long and short arms of the X chromosome, with the more likely localization on the proximal long arm of the X chromosome. Available variable simple-sequence repeats (VSSRs) broaden the possibilities for linkage analysis. This paper presents new linkage data and recombination analysis derived from work with four VSSR markers - AR, PGKP1, DXS453, and DXYS1X - in addition to analysis using RFLP markers described elsewhere. These studies localize the CMTX gene to the proximal Xq segment between PGKP1 (Xq11.2-12) and DXS72 (Xq21.1), with a combined maximum multipoint lod score of 15.3 at DXS453 ([theta] = 0). 32 refs., 3 figs., 2 tabs.

  19. Mutational studies in X-linked Charcot-Marie-Tooth disease (CMTX)

    SciTech Connect

    Cherryson, A.K.; Yeung, L.; Kennerson, M.L.; Nicholson, G.A.

    1994-09-01

    Charcot-Marie-Tooth disease, also known as hereditary motor and sensory neuropathy (HMSN), is a heterogeneous group of slowly progressive disorders of the peripheral nerve. X-linked CMT (CMTX) is characterized by slow motor nerve conduction velocities in affected males and the presence of mildly affected or normal carrier females with intermediate or normal nerve conduction velocities. CMTX, which has an incidence of 3.1 per 100,000 and accounts for approximately 10% of CMT cases, has been mapped to Xq13. One of the genes lying in this region, connexin 32, has been found to contain alterations in individuals affected with X-linked CMT. We have identified our X-linked families from dominant type 1 CMT families using the clinical criteria given above. These families were screened for point mutations in connexin 32. We have identified three missense mutations, a G{r_arrow}A transition at amino acid 35 (valine to methionine), a C{r_arrow}G transition at amino acid 158 (proline to alanine) and a T{r_arrow}A transition at amino acid 182 (serine to threonine). Another family showed a 18 bp deletion, which removed the amino acid 111 to 116 inclusive (histidine, glycine, aspartic acid, proline, leucine, histidine).

  20. Two Novel De Novo GARS Mutations Cause Early-Onset Axonal Charcot-Marie-Tooth Disease

    PubMed Central

    Liao, Yi-Chu; Liu, Yo-Tsen; Tsai, Pei-Chien; Chang, Chia-Ching; Huang, Yen-Hua; Soong, Bing-Wen; Lee, Yi-Chung

    2015-01-01

    Background Mutations in the GARS gene have been identified in a small number of patients with Charcot-Marie-Tooth disease (CMT) type 2D or distal spinal muscular atrophy type V, for whom disease onset typically occurs during adolescence or young adulthood, initially manifesting as weakness and atrophy of the hand muscles. The role of GARS mutations in patients with inherited neuropathies in Taiwan remains elusive. Methodology and Principal Findings Mutational analyses of the coding regions of GARS were performed using targeted sequencing of 54 patients with molecularly unassigned axonal CMT, who were selected from 340 unrelated CMT patients. Two heterozygous mutations in GARS, p.Asp146Tyr and p.Met238Arg, were identified; one in each patient. Both are novel de novo mutations. The p.Asp146Tyr mutation is associated with a severe infantile-onset neuropathy and the p.Met238Arg mutation results in childhood-onset disability. Conclusion GARS mutations are an uncommon cause of CMT in Taiwan. The p.Asp146Tyr and p.Met238Arg mutations are associated with early-onset axonal CMT. These findings broaden the mutational spectrum of GARS and also highlight the importance of considering GARS mutations as a disease cause in patients with early-onset neuropathies. PMID:26244500

  1. Linkage localization of X-linked Charcot-Marie-Tooth disease.

    PubMed Central

    Bergoffen, J; Trofatter, J; Pericak-Vance, M A; Haines, J L; Chance, P F; Fischbeck, K H

    1993-01-01

    Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is a heterogeneous group of slowly progressive, degenerative disorders of peripheral nerve. X-linked CMT (CMTX) (McKusick 302800), a subdivision of type I, or demyelinating, CMT is an X-linked dominant condition with variable penetrance. Previous linkage analysis using RFLPs demonstrated linkage to markers on the proximal long and short arms of the X chromosome, with the more likely localization on the proximal long arm of the X chromosome. Available variable simple-sequence repeats (VSSRs) broaden the possibilities for linkage analysis. This paper presents new linkage data and recombination analysis derived from work with four VSSR markers--AR, PGKP1, DXS453, and DXYS1X--in addition to analysis using RFLP markers described elsewhere. These studies localize the CMTX gene to the proximal Xq segment between PGKP1 (Xq11.2-12) and DXS72 (Xq21.1), with a combined maximum multipoint lod score of 15.3 at DXS453 (theta = 0). PMID:8430694

  2. Charged Particle Dose Measurements by the Odyssey/MARIE Instrument in Mars Orbit and Model Calculations

    NASA Technical Reports Server (NTRS)

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

    2004-01-01

    Knowledge of the space radiation environment is crucial both for human space exploration, and robotic space missions. It is likely that human explorers will return to the moon, and then go to Mars within the next thirty years. The radiation environment that they will encounter is a significant obstacle to future exploration, and must be dealt with successfully before longterm human missions outside of the magnetosphere can take place. Shielding technologies and materials must be developed to lower the dose and dose equivalent that human beings will receive on such missions. To begin this development, a fairly complete and accurate understanding of the space environment must be obtained. The major components of the space particle radiation environment that are most hazardous to humans are: galactic cosmic rays (GCR), the particles contained in solar particle events, (SPE), and secondary particles generated in material in the spacecraft itself. The intensity of the GCR varies by roughly a factor of two over the eleven-year solar cycle, inversely with the level of solar activity. These GCR particles are fully stripped nuclei, predominantly protons and helium, but also significant numbers of heavier ions, including carbon, oxygen, and iron. Since the ionization caused by nuclei passing through matter is proportional to the square of its charge (Z=10). The MARIE instrument has been described elsewhere.

  3. Vestibular impairment in Charcot-Marie-Tooth disease type 4C.

    PubMed

    Pérez-Garrigues, Herminio; Sivera, Rafael; Vílchez, Juan Jesús; Espinós, Carmen; Palau, Francesc; Sevilla, Teresa

    2014-07-01

    Charcot-Marie-Tooth disease type 4C (CMT4C) is a hereditary neuropathy with prominent unsteadiness. The objective of the current study is to determine whether the imbalance in CMT4C is caused only by reduced proprioceptive input or if vestibular nerve involvement is an additional factor. We selected 10 CMT4C patients and 10 age-matched and sex-matched controls. We performed a comprehensive evaluation of the vestibular system, including video Head Impulse Test, bithermal caloric test, galvanic stimulation test and skull vibration-induced nystagmus test. None of the patients experienced dizziness, spontaneous or gaze-evoked nystagmus, but all had significant vestibular impairment when tested when compared to controls. Seven had completely unexcitable vestibular systems and abnormal vestibuloocular reflex. There was no correlation between the degree of vestibulopathy and age or clinical severity. Significant vestibular impairment is a consistent finding in CMT4C and is present early in disease evolution. The profound imbalance that is so disabling in these patients may result from a combination of proprioceptive loss and vestibular neuropathy, and this would modify the recommended rehabilitation strategies. PMID:24614092

  4. Integrating research & teaching: the Queen Mary, University of London module in Geodiversity & Geoconservation

    NASA Astrophysics Data System (ADS)

    Gray, M.

    2012-04-01

    The School of Geography at Queen Mary, University of London has been running a Level 6 (undergraduate) module in "Geodiversity & Geoconservation" since 2004. The course is based around the book Geodiversity: valuing and conserving abiotic nature (John Wiley, 2004) but lectures are used to update each topic based on the latest research. The course is divided into 5 parts: 1. Defining and describing geodiversity - which discusses the concept of geodiversity, its definition and the nature of the geodiversity of Planet Earth; 2. Values of, and threats to, geodiversity - a lecture on valuing geodiversity is now based around important research on the role of geodiversity in "ecosystem services" assessments. A second lecture covers the major threats to geodiversity; 3. The protected area approach - lectures here cover geological World Heritage Sites, Global Geoparks, GSSPs, and national geoconservation systems in the UK, USA and other parts of the world; 4. Protecting geodiversity in the wider landscape - the contribution of geology and geomorphology to landscape character are described, together with the role of land-use planning and policy-making in protecting geodiversity. 5. Putting it all together - lectures here emphasize that geodiversity is an important basis for geoconservation, that different geoconservation methods are appropriate to different elements of geodiversity, and that integrated geo/bio conservation is essential. A field trip to three Chalk/Quaternary Sites of Special Scientific Interest in East Sussex is included which discusses some of the planning issues that have arisen at these sites, a theme that is expanded in the lectures.

  5. Conservation Action Planning: Lessons learned from the St. Marys River watershed biodiversity conservation planning process

    USGS Publications Warehouse

    Patterson, Tamatha A.; Grundel, Ralph

    2014-01-01

    Conservation Action Planning (CAP) is an adaptive management planning process refined by The Nature Conservancy (TNC) and embraced worldwide as the Open Standards for the Practice of Conservation. The CAP process facilitates open, multi-institutional collaboration on a common conservation agenda through organized actions and quantified results. While specifically designed for conservation efforts, the framework is adaptable and flexible to multiple scales and can be used for any collaborative planning effort. The CAP framework addresses inception; design and development of goals, measures, and strategies; and plan implementation and evaluation. The specific components of the CAP include defining the project scope and conservation targets; assessing the ecological viability; ascertaining threats and surrounding situation; identifying opportunities and designing strategies for action; and implementing actions and monitoring results. In 2007, TNC and a multidisciplinary graduate student team from the University of Michigan's School of Natural Resources and Environment initiated a CAP for the St. Marys River, the connecting channel between Lake Superior and Lake Huron, and its local watershed. The students not only gained experience in conservation planning, but also learned lessons that notably benefited the CAP process and were valuable for any successful collaborative effort—a dedicated core team improved product quality, accelerated the timeline, and provided necessary support for ongoing efforts; an academic approach in preparation for engagement in the planning process brought applicable scientific research to the forefront, enhanced workshop facilitation, and improved stakeholder participation; and early and continuous interactions with regional stakeholders improved cooperation and built a supportive network for collaboration.

  6. A Mutation in PMP2 Causes Dominant Demyelinating Charcot-Marie-Tooth Neuropathy

    PubMed Central

    Hyun, Young Se; Kwak, Geon; Choi, Yu-Ri; Yeo, Ha Kyung; Jwa, Dong Hwan; Kim, Eun Ja; Mo, Won Min; Nam, Soo Hyun; Kim, Sung Min; Yoo, Jeong Hyun; Koo, Heasoo; Park, Hwan Tae; Chung, Ki Wha; Choi, Byung-Ok

    2016-01-01

    Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of peripheral neuropathies with diverse genetic causes. In this study, we identified p.I43N mutation in PMP2 from a family exhibiting autosomal dominant demyelinating CMT neuropathy by whole exome sequencing and characterized the clinical features. The age at onset was the first to second decades and muscle atrophy started in the distal portion of the leg. Predominant fatty replacement in the anterior and lateral compartment was similar to that in CMT1A caused by PMP22 duplication. Sural nerve biopsy showed onion bulbs and degenerating fibers with various myelin abnormalities. The relevance of PMP2 mutation as a genetic cause of dominant CMT1 was assessed using transgenic mouse models. Transgenic mice expressing wild type or mutant (p.I43N) PMP2 exhibited abnormal motor function. Electrophysiological data revealed that both mice had reduced motor nerve conduction velocities (MNCV). Electron microscopy revealed that demyelinating fibers and internodal lengths were shortened in both transgenic mice. These data imply that overexpression of wild type as well as mutant PMP2 also causes the CMT1 phenotype, which has been documented in the PMP22. This report might expand the genetic and clinical features of CMT and a further mechanism study will enhance our understanding of PMP2-associated peripheral neuropathy. PMID:26828946

  7. Designing long-term fish community assessments in connecting channels: Lessons from the Saint Marys River

    USGS Publications Warehouse

    Schaeffer, Jeff; Rogers, Mark W.; Fielder, David G.; Godby, Neal; Bowen, Anjanette K.; O'Connor, Lisa; Parrish, Josh; Greenwood, Susan; Chong, Stephen; Wright, Greg

    2014-01-01

    Long-term surveys are useful in understanding trends in connecting channel fish communities; a gill net assessment in the Saint Marys River performed periodically since 1975 is the most comprehensive connecting channels sampling program within the Laurentian Great Lakes. We assessed efficiency of that survey, with intent to inform development of assessments at other connecting channels. We evaluated trends in community composition, effort versus estimates of species richness, ability to detect abundance changes for four species, and effects of subsampling yellow perch catches on size and age-structure metrics. Efficiency analysis revealed low power to detect changes in species abundance, whereas reduced effort could be considered to index species richness. Subsampling simulations indicated that subsampling would have allowed reliable estimates of yellow perch (Perca flavescens) population structure, while greatly reducing the number of fish that were assigned ages. Analyses of statistical power and efficiency of current sampling protocols are useful for managers collecting and using these types of data as well as for the development of new monitoring programs. Our approach provides insight into whether survey goals and objectives were being attained and can help evaluate ability of surveys to answer novel questions that arise as management strategies are refined.

  8. Behavioural profiling of a murine Charcot-Marie-Tooth disease type 1A model.

    PubMed

    Norreel, J C; Jamon, M; Riviere, G; Passage, E; Fontes, M; Clarac, F

    2001-04-01

    Different features of motor behaviour were studied on a transgenic mouse model of Charcot-Marie-Tooth's disease (CMT). Mutants with 4 or 7 copies of the human PMP22 gene leading to a phenotype significantly close to CMT's disease type 1A were compared with control animals. The aim of the study was to validate this transgenic model and to characterise the impairments occurring in the various lines. Three main types of analysis were performed in 2-month-old mice without any peculiar visible deficit: (i) a study of standardised clinical tests (SHIRPA protocol) demonstrated that only a few motor deficits were expressed; (ii) a measurement of general spontaneous activity by means of a commercial video-tracking system was performed and revealed that the main spontaneous activities were identical in the three lines with, however, some slight localised modifications; and, (iii) by contrast, the three lines respond very differently to the footprints, grip strength, splay test and rotarod test. Even in lines with a significantly limited copy number of the transgene, we observed and quantified impairments. In conclusion, mutants of CMT1A seem to be a very pertinent model of this human pathology and will certainly be useful for therapeutic procedures and for theoretical studies on this disease. PMID:11328356

  9. Charcot-Marie-Tooth type 1A disease from patient to laboratory.

    PubMed

    Perveen, Shazia; Mannan, Shazia; Hussain, Abrar; Kanwal, Sumaira

    2015-02-01

    Charcot-Marie-Tooth (CMT) disease is a well-known neural or spinal type of muscular atrophy. It is the most familiar disease within a group of conditions called Hereditary Motor and Sensory Neuropathies (HMSN). The disease was discovered by three scientists several years ago. Several genes are involved as the causative agents for the disease. Hundreds of causative mutations have been found and research work for the identification of a novel locus and for the treatment of CMT1A is going on. This review article was planned to gather information on CMT disease and updates on its treatment.National Center for Biotechnology Information (NCBI) and PubMed were searched for data retrieval. Molgen database, which is the exclusive site for CMT mutation, was the other source of articles. Different aspects of the CMT disease were compared.Advancements in the finding of the causative gene, discovery of the novel Loci are the current issues in this regard.CMT disease is incurable, but researchers are trying to get some benefits from different natural compounds and several therapeutic agents.Various groups are working on the treatment projects of CMT1A. Major step forward in CMT research was taken in 2004 when ascorbic acid was used for transgenic mice treatment. Gene therapy for constant neurotrophin-3 (NT- 3) delivery by secretion by muscle cells for the CMT1A is also one of the possible treatments under trial. PMID:25842560

  10. [Phenotypes of Charcot-Marie-Tooth Syndrome and Differential Diagnosis Focused in Inflammatory Neuropathies].

    PubMed

    Iijima, Masahiro

    2016-01-01

    Charcot-Marie-Tooth disease (CMT), the most frequent form of inherited neuropathy, is a genetically heterogeneous syndrome of the peripheral nervous system with a rather homologous clinical phenotype (slowly progressive distal weakness and muscle atrophy, skeletal deformities, and areflexia in each limb). CMT1 is the autosomal-dominant demyelinating form, and CMT1A (mostly PMP22 duplication) is the most frequent subtype, followed by CMTX1, HNPP (hereditary neuropathy with liability to pressure palsies), CMT1B, or CMT2. As CMT is characterized by slowly progressive motor and sensory disturbances in each limb, it could be misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP) occasionally. Some points can distinguish demyelinating CMT from CIDP. CMT1 patients do not show the conduction block that is frequent in CIDP. In addition, ultrasonographic findings are useful because CMT1 suggests diffuse enlargement of peripheral nerves, whereas CIDP is characterized by asymmetrical or focal enlargement of peripheral nerves. Some CMT1 cases show favorable responses to immunomodulating therapeutics such as corticosteroids, IVIg, and plasma exchange. Such CIDP-like CMT1 (especially CMT1B or CMT2A) shows moderate to high levels of cerebrospinal fluid protein and infiltrated inflammatory macrophages. PMID:26764297

  11. [Treatment for Patients with Charcot-Marie-Tooth Disease: Orthopaedic Aspects].

    PubMed

    Watanabe, Kota

    2016-01-01

    The orthopedic manifestations in patients with Charcot-Marie-Tooth disease include deformity and dysfunction of the extremities and spine. Conservative treatment is the first choice. Orthosis and rehabilitation can improve function, and are important for the prevention of joint contractures. Foot problems are most commonly observed and require surgical treatment. Foot deformities include pes cavus, cavovarus, claw toes, or drop foot. Single or combined surgeries selected for soft tissues are plantar release, tendon transfer, or Achilles tendon lengthening, and those for bones are osteotomies and joint fusions. The upper limb initially demonstrates loss of power of the intrinsic hand muscles followed by symmetrical atrophy of the forearm muscle groups. The typical hand deformity is claw hand. Tendon transfer, joint fusion, soft tissue release, or nerve decompression procedures are performed for correction of hand deformities. Acetabular dysplasia in the hip joints is sometimes observed and osteotomy is selected as surgical treatment in such cases. The associated spinal deformity is scoliosis with or without kyphosis. Similar to treatment of idiopathic scoliosis, posterior spinal fusion is performed in patients with progressive spinal deformities. PMID:26764299

  12. Postural stabilization and balance assessment in Charcot-Marie-Tooth 1A subjects.

    PubMed

    Lencioni, T; Rabuffetti, M; Piscosquito, G; Pareyson, D; Aiello, A; Di Sipio, E; Padua, L; Stra, F; Ferrarin, M

    2014-09-01

    The aim of the present study was to assess postural stabilization skill in adult subjects affected by Charcot-Marie-Tooth disease (CMT) type 1A. For this purpose ground reaction force (GRF) was measured by means of a piezoelectric force platform during the sit-to-stand (STS) movement, until a steady state erect posture was achieved. Specific indexes to quantify Centre of Mass acceleration, both during postural stabilization and during quiet standing, were computed using a mathematical model. Forty-seven CMT1A subjects were recruited for the study, and the control group was formed by forty-one age- and sex-matched healthy subjects. The results show that CMT1A subjects are less stable than controls during the quiet stance. Greater difficulty (high values of Yinf, the final instability rate) to maintain erect posture appears to be mainly associated with plantar-flexor muscle weakness, rather than to damage of the proprioceptive system. The worst performances shown by CMT1A subjects in the stabilization phase (high values of I, the global index of postural stabilization performance) seem to be associated with reduced muscle strength and the loss of large sensory nerve fibres. Distal muscle weakness appears to affect both postural stabilization and quiet erect posture. The presented protocol and the analysis of postural stabilization parameters provide useful information on CMT1A balance disorders. PMID:25082324

  13. Global gene expression profiling of a mouse model of ovarian clear cell carcinoma caused by ARID1A and PIK3CA mutations implicates a role for inflammatory cytokine signaling

    PubMed Central

    Chandler, Ronald L.; Raab, Jesse R.; Vernon, Mike; Magnuson, Terry; Schisler, Jonathan C.

    2015-01-01

    Ovarian clear-cell carcinoma (OCCC) is an aggressive form of epithelial ovarian cancer (EOC). OCCC represents 5–25% of all EOC incidences and is the second leading cause of death from ovarian cancer (Glasspool and McNeish, 2013) [1]. A recent publication by Chandler et al. reported the first mouse model of OCCC that resembles human OCCC both genetically and histologically by inducing a localized deletion of ARID1A and the expression of the PIK3CAH1047R substitution mutation (Chandler et al., 2015) [2]. We utilized Affymetrix Mouse Gene 2.1 ST arrays for the global gene expression profiling of mouse primary OCCC tumor samples and animal-matched normal ovaries to identify cancer-dependent gene expression. We describe the approach used to generate the differentially expressed genes from the publicly available data deposited at the Gene Expression Omnibus (GEO) database under the accession number GSE57380. These data were used in cross-species comparisons to publically available human OCCC gene expression data and allowed the identification of coordinately regulated genes in both mouse and human OCCC and supportive of a role for inflammatory cytokine signaling in OCCC pathogenesis (Chandler et al., 2015) [2]. PMID:26484281

  14. Chemical Achievers: The Human Face of the Chemical Sciences (by Mary Ellen Bowden)

    NASA Astrophysics Data System (ADS)

    Kauffman, George B.

    1999-02-01

    Chemical Heritage Foundation: Philadelphia, PA, 1997. viii + 180 pp. 21.6 x 27.8 cm. ISBN 0-941901-15-1. Paper. 20.00 (10.00 for high school teachers who provide documentation). At a 1991 summer workshop sponsored by the Chemical Heritage Foundation and taught by Derek A. Davenport and William B. Jensen, high school and college teachers of introductory chemistry requested a source of pictorial material about famous chemical scientists suitable as a classroom aid. CHF responded by publishing this attractive, inexpensive paperback volume, which reflects the considerable research effort needed to locate appropriate images and to write the biographical essays. Printed on heavy, glossy paper and spiral bound to facilitate conversion to overhead transparencies, it contains 157 images from pictorial collections at CHF and many other institutions on two types of achievers: the historical "greats" most often referred to in introductory courses, and scientists who made contributions in areas of the chemical sciences that are of special relevance to modern life and the career choices students will make. The pictures are intended to provide the "human face" of the book's subtitle- "to point to the human beings who had the insights and made the major advances that [teachers] ask students to master." Thus, for example, Boyle's law becomes less cold and abstract if the student can connect it with the two portraits of the Irish scientist even if his face is topped with a wig. Marie Curie can be seen in the role of wife and mother as well as genius scientist in the photographs of her with her two daughters, one of whom also became a Nobel laureate. And students are reminded of the ubiquity of the contribution of the chemical scientists to all aspects of our everyday life by the stories and pictures of Wallace Hume Carothers' path to nylon, Percy Lavon Julian's work on hormones, and Charles F. Chandler and Rachel Carson's efforts to preserve the environment. In addition to portraits

  15. Tectonic conditions of hydrothermal polymetallic vein-type mineralization, Sainte Marie-aux-Mines, France

    NASA Astrophysics Data System (ADS)

    Hafeznia, Y.; Bourlange, S.; Ohnenstetter, M.

    2012-04-01

    The Sainte-Marie-aux-Mines (SMM) mines host one of the most famous and oldest silver deposits in Europe. The SMM district is located in the central part of the Vosges mountains, France, within gneiss and granites of the Moldanubian zone. The SMM district includes the Neuenberg E-W vein-type Cu-Ag-As/Pb-Zn deposit and the Altenberg N-S vein-type Pb-Zn-Ag deposit. Deposition of the SMM hydrothermal mineralization occurred under a brittle tectonic regime that might be connected to neo-Variscan and/or post-Variscan tectonics, in a similar way as the polymetallic vein deposits of the Black Forest, Germany. A structural study was done in the Neuenberg area, in the vicinity of the Saint-Jacques vein, and within the Gabe Gottes mine, considering the orientation, extent, chronology and density of faults as well as the nature of the infilling minerals. In the Gabe-Gottes mine, the Saint-Jacques vein comprises multiple successive, sub-parallel subvertical veinlets with gangue minerals, mostly carbonates and quartz, and metal-bearing phases, sulfides and sulfosalts. The veinlets are 2 to 50 cm thick and strike N80° to N110°, the earlier veins slightly dipping towards the north, and the latest one, to the south. Seven systems of faults were identified, which may be classified into three major groups formed respectively before, during and after the main stage of ore deposition: a) Pre-mineralization faults - These consist of sinistral NE-SW strike-slip faults, and NW-SE and NE-SW steeply dipping normal faults. These could be related to Carboniferous events considering their relationships with the granitoid intrusives present in the mine area (Brézouard leucogranite ~329 Ma), and the extensional tectonics developed during exhumation processes. b) Faults associated with the main ore-deposition - These faults could be related to late-Hercynian processes from compressional to extensional tectonic regimes. Mineralization controlling faults consist of dextral and sinistral E

  16. Clinical and genetic spectra in a series of Chinese patients with Charcot-Marie-Tooth disease.

    PubMed

    Wang, Rui; He, Jin; Li, Jin-Jing; Ni, Wang; Wu, Zhi-Ying; Chen, Wan-Jin; Wang, Yi

    2015-12-01

    The aim of this study was to determine the clinical features and frequencies of genetic subtypes in a series of patients with Charcot-Marie-Tooth (CMT) disease from Eastern China. Patients were divided into three subtypes, CMT1, CMT2 and hereditary neuropathy with liability to pressure palsy (HNPP), according to their electrophysiological manifestations. Multiplex ligation-dependent probe analysis (MLPA) was performed to detect duplications/deletions in the PMP22 gene. The coding regions and splice sites of the GJB1, MPZ, MFN2 and GDAP-1 genes were determined by direct sequencing. Among the 148 patients in the study, 37.2% of the cases had mutations in genes assessed. The mutation detection rate was higher in patients with family histories than in spontaneous cases. PMP22 duplication (13.5%) was predominant in this group of patients, followed by PMP22 deletion (11.5%), and point mutations in GJB1 (8.8%), MPZ (2.0%) and MFN2 (0.7%). Three novel mutations (c.151T>C and c.310 A>G in GJB1 and c.1516 C>G in MFN2) were detected. A small deletion in PMP22 exon 4 was detected in a patient with severe CMT1. Genetic tests have great value in CMT patients with family histories. The frequency of PMP22 duplications was lower in Asian patients than in others. We suggest that genetic testing strategies in CMT patients should be primarily based on electromyography data. PMID:26454100

  17. Myelin protein zero gene sequencing diagnoses Charcot-Marie-Tooth Type 1B disease

    SciTech Connect

    Su, Y.; Zhang, H.; Madrid, R.

    1994-09-01

    Charcot-Marie-Tooth disease (CMT), the most common genetic neuropathy, affects about 1 in 2600 people in Norway and is found worldwide. CMT Type 1 (CMT1) has slow nerve conduction with demyelinated Schwann cells. Autosomal dominant CMT Type 1B (CMT1B) results from mutations in the myelin protein zero gene which directs the synthesis of more than half of all Schwann cell protein. This gene was mapped to the chromosome 1q22-1q23.1 borderline by fluorescence in situ hybridization. The first 7 of 7 reported CMT1B mutations are unique. Thus the most effective means to identify CMT1B mutations in at-risk family members and fetuses is to sequence the entire coding sequence in dominant or sporadic CMT patients without the CMT1A duplication. Of the 19 primers used in 16 pars to uniquely amplify the entire MPZ coding sequence, 6 primer pairs were used to amplify and sequence the 6 exons. The DyeDeoxy Terminator cycle sequencing method used with four different color fluorescent lables was superior to manual sequencing because it sequences more bases unambiguously from extracted genomic DNA samples within 24 hours. This protocol was used to test 28 CMT and Dejerine-Sottas patients without CMT1A gene duplication. Sequencing MPZ gene-specific amplified fragments identified 9 polymorphic sites within the 6 exons that encode the 248 amino acid MPZ protein. The large number of major CMT1B mutations identified by single strand sequencing are being verified by reverse strand sequencing and when possible, by restriction enzyme analysis. This protocol can be used to distringuish CMT1B patients from othre CMT phenotypes and to determine the CMT1B status of relatives both presymptomatically and prenatally.

  18. Proximal nerve magnetization transfer MRI relates to disability in Charcot-Marie-Tooth diseases

    PubMed Central

    Dethrage, Lindsey M.; Gore, John C.; Smith, Seth A.; Li, Jun

    2014-01-01

    Objective: The objectives of this study were (1) to develop a novel magnetization transfer ratio (MTR) MRI assay of the proximal sciatic nerve (SN), which is inaccessible via current tools for assessing peripheral nerves, and (2) to evaluate the resulting MTR values as a potential biomarker of myelin content changes in patients with Charcot-Marie-Tooth (CMT) diseases. Methods: MTR was measured in the SN of patients with CMT type 1A (CMT1A, n = 10), CMT type 2A (CMT2A, n = 3), hereditary neuropathy with liability to pressure palsies (n = 3), and healthy controls (n = 21). Additional patients without a genetically confirmed subtype (n = 4), but whose family histories and electrophysiologic tests were consistent with CMT, were also included. The relationship between MTR and clinical neuropathy scores was assessed, and the interscan and inter-rater reliability of MTR was estimated. Results: Mean volumetric MTR values were significantly decreased in the SN of patients with CMT1A (33.8 ± 3.3 percent units) and CMT2A (31.5 ± 1.9 percent units) relative to controls (37.2 ± 2.3 percent units). A significant relationship between MTR and disability scores was also detected (p = 0.01 for genetically confirmed patients only, p = 0.04 for all patients). From interscan and inter-rater reliability analyses, proximal nerve MTR values were repeatable at the slicewise and mean volumetric levels. Conclusions: MTR measurements may be a viable biomarker of proximal nerve pathology in patients with CMT. PMID:25253751

  19. Innovative quantitative testing of hand function in Charcot-Marie-Tooth neuropathy.

    PubMed

    Alberti, Maria A; Mori, Laura; Francini, Luca; Poggi, Ilaria; Monti Bragadin, Margherita; Bellone, Emilia; Grandis, Marina; Maggi, Giovanni; Reni, Lizia; Sormani, Maria P; Tacchino, Andrea; Padua, Luca; Prada, Valeria; Bove, Marco; Schenone, Angelo

    2015-12-01

    To describe a new test to quantitatively evaluate hand function in patients affected by Charcot-Marie-Tooth neuropathy (CMT). The sensor-engineered glove test (SEGT) was applied to CMT patients (N: 26) and compared with a cohort of healthy controls (HC, N: 26). CMT patients were further divided into subjects with clinically normal (group 1) or impaired hand (group 2) function. The SEGT parameters evaluated were touch duration, inter-tapping interval, and movement rate parameters of two different sequences: finger tapping (FT) and index-medium-ring-little (IMRL) performed at self-paced mode (SPM) and maximum velocity (MV). Hand function and strength were assessed by the 9-hole peg test (9HPT) and dynamometry. Disability of patients was measured by the CMT neuropathy score. CMT patients had significantly worst performances at SEGT than controls regarding the rate of execution of both FT (at MV) and IMRL sequences (at SPM and MV). The rate parameter at MV in IMRL sequence showed a significant trend of decreasing in its average between HC (n: 26, rate = 3.08 ± 0.52 Hz), group 1 (n: 9, rate = 2.64 ± 0.66 Hz) and group 2 (n: 17, rate = 2.19 ± 0.45 Hz) (p for trend <0.001). No correlations were found with either 9HPT, dynamometry, electrophysiology, and the CMT neuropathy score. The SEGT test is sensitive to show hand dysfunction in CMT patients, with and without clinically impaired hands. PMID:26456943

  20. Clinical, neurophysiological and morphological study of dominant intermediate Charcot-Marie-Tooth type C neuropathy.

    PubMed

    Thomas, Florian P; Guergueltcheva, Velina; Gondim, Francisco A A; Tournev, Ivailo; Rao, Chitharanjan V; Ishpekova, Boryana; Kinsella, Laurence J; Pan, Yi; Geller, Thomas J; Litvinenko, Ivan; De Jonghe, Peter; Scherer, Steven S; Jordanova, Albena

    2016-03-01

    Dominant intermediate Charcot-Marie-Tooth neuropathy subtype C (DI-CMTC) was associated with mutations in the YARS gene, encoding tyrosyl-tRNA synthetase, in two large unrelated Bulgarian and US pedigrees and one sporadic case. Here for the first time we describe the clinical, neurophysiological and histopathological features, and phenotypic differences between these two DI-CMTC families. Twenty-one affected individuals from the US family and 27 from the Bulgarian family were evaluated. The mean age of onset in US subjects was 10.7 years in men and 7.3 years in women, while in the Bulgarian participants it was 18.2 years in men and 33.7 years in women. The course was slowly progressive. Extensor digitorum brevis atrophy was uniform. Atrophy and/or weakness of upper and lower limb muscles were found in over 50 % of the subjects. Nerve conduction studies (NCS) were abnormal in all US adults and five of six children and all Bulgarian patients except one asymptomatic 25-year-old man. Median motor NCS were in the range of 29.5-45.6 m/s in the US family and 24.7-57.8 m/s in the Bulgarian family. Sural sensory nerve action potentials were absent in 14/21 and 4/12 NCS from adult US and Bulgarian participants, respectively. Analysis of sural nerve biopsies from US patients revealed age-dependent morphological changes of axonal degeneration, absence of onion bulbs, and <10 % fibers with segmental remyelination. Our findings provide further insights into the diagnosis and pathology of intermediate CMT. They also extend the phenotypic spectrum of peripheral neuropathies associated with aminoacyl-tRNA synthetase mutations. PMID:26725087