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. 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 ...

  14. 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)

  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. 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.

  20. 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

  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. 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.

  4. 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

  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. 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

  7. 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

  8. 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

  9. 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...

  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. 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

  13. 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

  14. 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

  15. 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 ...

  16. 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…

  17. 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…

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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.

  3. 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.

  4. 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

  5. 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

  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. 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

  9. 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

  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. 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.

  14. 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

  15. 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

  16. 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

  17. 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…

  18. 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…

  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. 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

  1. 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

  2. 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

  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. 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

  7. 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.

  8. 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.

  9. 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

  10. 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

  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. 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

  17. "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…

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

    PubMed Central

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

    2015-01-01

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

  4. 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

  5. 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.

  6. 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

  7. 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

  8. 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

  9. 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

  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. 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

  15. 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

  16. 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.

  17. 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…

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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…

  3. 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,…

  4. 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…

  5. 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…

  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. 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

  15. 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

  16. 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

  17. 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).

  18. 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).

  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. 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

  3. 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 ...

  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 117.373 - 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,...

  8. 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,...

  9. 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,...

  10. 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...

  11. 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...

  12. 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

  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. 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

  16. 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

  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. 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.

  5. 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.

  6. 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.

  7. 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

  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. 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.

  11. 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...

  12. 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 ...

  13. 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

  14. 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

  15. 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.

  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. 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

  2. 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

  3. [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

  4. [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

  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. 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

  7. 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

  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. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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.

  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. 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

  20. 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

  1. 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

  2. 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

  3. 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.

  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. 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...

  6. 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...

  7. 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...

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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...

  14. 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.

  15. 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

  16. 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

  17. 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…

  18. 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…

  19. 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…

  20. 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

  1. 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)

  2. 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 ...

  3. 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…

  4. 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…

  5. 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…

  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. 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)

  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. 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…

  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. 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

  14. 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

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

    NASA Astrophysics Data System (ADS)

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

    2014-10-01

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

  16. 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

  17. 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

  18. 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.

  19. 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

  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. 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

  2. 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

  3. Charcot Marie Tooth disease (CMT): historical perspectives and evolution.

    PubMed

    Kazamel, Mohamed; Boes, Christopher J

    2015-01-01

    Prior to Charcot and Marie's and Tooth's reports, patients with peroneal muscular atrophy had been described by Virchow, Eulenburg, Friedreich, Osler, and others. In February 1886, Charcot and Marie published their original description of five patients who had what they called Progressive Muscular Atrophy. They surmised that the lesion could be in the spinal cord. Three months later, Tooth presented his M.D. degree thesis entitled "Peroneal Type of Progressive Muscular Atrophy", to the University of Cambridge, UK. Tooth localized the pathology to the peripheral nerves. Dyck and Lambert (Arch Neurol 18:619-625, 1968) classified several CMT kinships based on differences in modes of inheritance, natural history, biochemical features, nerve conduction velocity, and pathologic characteristics. This article will focus on historical landmarks and major discoveries pertinent to the disease since its original description through the second half of the twentieth century. PMID:25201224

  4. 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

  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. 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

  14. 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

  15. 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

  16. 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

  17. 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

  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 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....

  20. 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...

  1. "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.…

  2. 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.;...

  3. 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...

  4. 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

  5. 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;...

  6. 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...

  7. 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...

  8. 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...

  9. 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...

  10. 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)...