The protein encoded by the proto-oncogene DEK changes the topology of chromatin and reduces the efficiency of DNA replication in a chromatin-specific manner

DEFF Research Database (Denmark)

Alexiadis, V; Waldmann, T; Andersen, Jens S.

2000-01-01

The structure of chromatin regulates the genetic activity of the underlying DNA sequence. We report here that the protein encoded by the proto-oncogene DEK, which is involved in acute myelogenous leukemia, induces alterations of the superhelical density of DNA in chromatin. The change in topology...

A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia

NARCIS (Netherlands)

Gröschel, Stefan; Sanders, Mathijs A; Hoogenboezem, Remco; de Wit, Elzo; Bouwman, Britta A M; Erpelinck, Claudia; van der Velden, Vincent H J; Havermans, Marije; Avellino, Roberto; van Lom, Kirsten; Rombouts, Elwin J; van Duin, Mark; Döhner, Konstanze; Beverloo, H Berna; Bradner, James E; Döhner, Hartmut; Löwenberg, Bob; Valk, Peter J M; Bindels, Eric M J; de Laat, Wouter; Delwel, Ruud

2014-01-01

Chromosomal rearrangements without gene fusions have been implicated in leukemogenesis by causing deregulation of proto-oncogenes via relocation of cryptic regulatory DNA elements. AML with inv(3)/t(3;3) is associated with aberrant expression of the stem-cell regulator EVI1. Applying functional

Inhibition of carcinogen induced c-Ha-ras and c-fos proto-oncogenes expression by dietary curcumin

Directory of Open Access Journals (Sweden)

Lipigorngoson Suwiwek

2001-01-01

Full Text Available Abstract Background We investigated the chemopreventive action of dietary curcumin on 7,12-dimethylbenz(aanthracene (DMBA-initiated and 12,0-tetradecanoylphorbol-13-acetate (TPA-promoted skin tumor formation in Swiss albino mice. Curcumin, a yellow coloring matter isolated from roots of Curcuma longa Linn, is a phenolic compound possessing antioxidant, free radical scavenger, and antiinflammatory properties. It has been shown by previously reported work that TPA-induced skin tumors were inhibited by topical application of curcumin, and curcumin has been shown to inhibit a variety of biological activities of TPA. Topical application of curcumin was reported to inhibit TPA-induced c-fos, c-jun and c-myc gene expression in mouse skin. This paper reports the effects of orally administered curcumin, which was consumed as a dietary component at concentrations of 0.2 % or 1 %, in ad libitum feeding. Results Animals in which tumors had been initiated with DMBA and promoted with TPA experienced significantly fewer tumors and less tumor volume if they ingested either 0.2% or 1% curcumin diets. Also, the dietary consumption of curcumin resulted in a significantly decreased expression of ras and fos proto-oncogenes in the tumorous skin, as measured by enhanced chemiluminesence Western blotting detection system (Amersham. Conclusions Whereas earlier work demonstrated that topical application of curcumin to mouse skin inhibited TPA-induced expression of c-fos, c-jun and c-myc oncogenes, our results are the first to show that orally consumed curcumin significantly inhibited DMBA- and TPA-induced ras and fos gene expression in mouse skin.

Inhibition of carcinogen induced c-Ha-ras and c-fos proto-oncogenes expression by dietary curcumin

International Nuclear Information System (INIS)

Limtrakul, Porn-ngarm; Anuchapreeda, Songyot; Lipigorngoson, Suwiwek; Dunn, Floyd W

2001-01-01

We investigated the chemopreventive action of dietary curcumin on 7,12-dimethylbenz(a)anthracene (DMBA)-initiated and 12,0-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor formation in Swiss albino mice. Curcumin, a yellow coloring matter isolated from roots of Curcuma longa Linn, is a phenolic compound possessing antioxidant, free radical scavenger, and antiinflammatory properties. It has been shown by previously reported work that TPA-induced skin tumors were inhibited by topical application of curcumin, and curcumin has been shown to inhibit a variety of biological activities of TPA. Topical application of curcumin was reported to inhibit TPA-induced c-fos, c-jun and c-myc gene expression in mouse skin. This paper reports the effects of orally administered curcumin, which was consumed as a dietary component at concentrations of 0.2 % or 1 %, in ad libitum feeding. Animals in which tumors had been initiated with DMBA and promoted with TPA experienced significantly fewer tumors and less tumor volume if they ingested either 0.2% or 1% curcumin diets. Also, the dietary consumption of curcumin resulted in a significantly decreased expression of ras and fos proto-oncogenes in the tumorous skin, as measured by enhanced chemiluminesence Western blotting detection system (Amersham). Whereas earlier work demonstrated that topical application of curcumin to mouse skin inhibited TPA-induced expression of c-fos, c-jun and c-myc oncogenes, our results are the first to show that orally consumed curcumin significantly inhibited DMBA- and TPA-induced ras and fos gene expression in mouse skin

Characterization of ERAS, a putative novel human oncogene, in skin and breast

Energy Technology Data Exchange (ETDEWEB)

Peña Avalos, B.L. de la

2014-07-01

Most human tumors have mutations in genes of the RAS small GTPase protein family. RAS works as a molecular switch for signaling pathways that modulate many aspects of cell behavior, including proliferation, differentiation, motility and death. Oncogenic mutations in RAS prevent GTP hydrolysis, locking RAS in a permanently active state, being the most common mutations in HRAS, KRAS and NRAS. The human RAS family consists of at least 36 different genes, many of which have been scarcely studied. One of these relatively unknown genes is ERAS (ES cell-expressed RAS), which is a constitutively active RAS protein, localized in chromosome X and expressed only in embryonic cells, being undetectable in adult tissues. New high throughput technologies have made it possible to screen complete cancer genomes for identification of mutations associated to cancer. Using the Sleeping Beauty (SB) transposon system, ERAS was identified as a putative novel oncogene in non-melanoma skin and breast cancers. The major aim of this project is to determine the general characteristics of ERAS as a putative novel human oncogene in skin and breast cells. Forced expression of ERAS results in drastic changes in cell shape, proliferation and motility. When ERAS is overexpressed in skin and breast human cells it is mainly localized in the cytoplasmic membrane. ERAS activates the phosphatidylinositol-3-OH kinase (PI3K) pathway but not the mitogen-activated protein kinase (MAPK) pathway. ERAS-expressing cells suffer spontaneous morphologic and phenotypic EMT-like changes, including cytoskeleton reorganization, vimentin and N-cadherin up-regulation and down-regulation of E-cadherin, which can be associated with increased malignancy, and invasive and metastatic potential. Our results suggest that inappropriate expression of ERAS lead to transformation of human cells. (Author)

Primary structure of the human fgr proto-oncogene product p55/sup c-fgr/

Energy Technology Data Exchange (ETDEWEB)

Katamine, S.; Notario, V.; Rao, C.D.; Miki, T.; Cheah, M.S.C.; Tronick, S.R.; Robbins, K.C.

1988-01-01

Normal human c-fgr cDNA clones were constructed by using normal peripheral blood mononuclear cell mRNA as a template. Nucleotide sequence analysis of two such clones revealed a 1,587-base-pair-long open reading frame which predicted the primary amino acid sequence of the c-fgr translational product. Homology of this protein with the v-fgr translational product stretched from codons 128 to 516, where 32 differences among 388 codons were observed. Sequence similarity with human c-src, c-yes, and fyn translations products began at amino acid position 76 of the predicted c-fgr protein and extended nearly to its C-terminus. In contrast, the stretch of 75 amino acids at the N-terminus demonstrated a greatly reduced degree of relatedness to these same proteins. To verify the deduced amino acid sequence, antibodies were prepared against peptides representing amino- and carboxy-terminal regions of the predicted c-fgr translational product. Both antibodies specifically recognized a 55-kilodalton protein expressed in COS-1 cells transfected with a c-fgr cDNA expression plasmid. Moreover, the same protein was immunoprecipitated from an Epstein-Barr virus-infected Burkitt's lymphoma cell line which expressed c-fgr mRNA but not in its uninfected fgr mRNA-negative counterpart. These findings identified the 55-kilodalton protein as the product of the human fgr proto-oncogene.

Methamphetamine induces apoptosis in immortalized neural cells: protection by the proto-oncogene, bcl-2.

Science.gov (United States)

Cadet, J L; Ordonez, S V; Ordonez, J V

1997-02-01

Methamphetamine (METH) is an amphetamine analog that produces degeneration of the dopaminergic system in mammals. The neurotoxic effects of the drug are thought to be mediated by oxygen-based free radicals. In the present report, we have used immortalized neural cells obtained from rat mesencephalon in order to further assess the role of oxidative stress in METH-induced neurotoxicity. We thus tested if the anti-death proto-oncogene, bcl-2 could protect against METH-induced cytotoxicity. METH caused dose-dependent loss of cellular viability in control cells while bcl-2-expressing cells were protected against these deleterious effects. Using flow cytometry, immunofluorescent staining, and DNA electrophoresis, we also show that METH exposure can cause DNA strand breaks, chromatin condensation, nuclear fragmentation, and DNA laddering. All these changes were prevented by bcl-2 expression. These observations provide further support for the involvement of oxidative stress in the toxic effects of amphetamine analogs. They also document that METH-induced cytotoxicity is secondary to apoptosis. These findings may be of relevance to the cause(s) of Parkinson's disease which involves degeneration of the nigrostriatal dopaminergic pathway.

The putative oncogene Pim-1 in the mouse: its linkage and variation among t haplotypes.

Science.gov (United States)

Nadeau, J H; Phillips, S J

1987-11-01

Pim-1, a putative oncogene involved in T-cell lymphomagenesis, was mapped between the pseudo-alpha globin gene Hba-4ps and the alpha-crystallin gene Crya-1 on mouse chromosome 17 and therefore within the t complex. Pim-1 restriction fragment variants were identified among t haplotypes. Analysis of restriction fragment sizes obtained with 12 endonucleases demonstrated that the Pim-1 genes in some t haplotypes were indistinguishable from the sizes for the Pim-1b allele in BALB/c inbred mice. There are now three genes, Pim-1, Crya-1 and H-2 I-E, that vary among independently derived t haplotypes and that have indistinguishable alleles in t haplotypes and inbred strains. These genes are closely linked within the distal inversion of the t complex. Because it is unlikely that these variants arose independently in t haplotypes and their wild-type homologues, we propose that an exchange of chromosomal segments, probably through double crossingover, was responsible for indistinguishable Pim-1 genes shared by certain t haplotypes and their wild-type homologues. There was, however, no apparent association between variant alleles of these three genes among t haplotypes as would be expected if a single exchange introduced these alleles into t haplotypes. If these variant alleles can be shown to be identical to the wild-type allele, then lack of association suggests that multiple exchanges have occurred during the evolution of the t complex.

Mutation analysis of the RET proto-oncogene in Dutch families with MEN 2A, MEN 2B and FMTC : Two novel mutations and one de novo mutation for MEN 2A

NARCIS (Netherlands)

Landsvater, RM; Jansen, RPM; Hofstra, RMW; Buys, CHCM; Lips, CJM; vanAmstel, HKP

Hereditary C-cell carcinoma is encountered in multiple endocrine neoplasia type 2A (MEN 2A), MEN 2B, and familial medullary thyroid carcinoma (FMTC). Mutations of the RET proto-oncogene are associated with all three diseases. To obtain an insight into the molecular heterogeneity of MEN 2 syndromes

Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer.

Science.gov (United States)

Slamon, D J; Godolphin, W; Jones, L A; Holt, J A; Wong, S G; Keith, D E; Levin, W J; Stuart, S G; Udove, J; Ullrich, A

1989-05-12

Carcinoma of the breast and ovary account for one-third of all cancers occurring in women and together are responsible for approximately one-quarter of cancer-related deaths in females. The HER-2/neu proto-oncogene is amplified in 25 to 30 percent of human primary breast cancers and this alteration is associated with disease behavior. In this report, several similarities were found in the biology of HER-2/neu in breast and ovarian cancer, including a similar incidence of amplification, a direct correlation between amplification and over-expression, evidence of tumors in which overexpression occurs without amplification, and the association between gene alteration and clinical outcome. A comprehensive study of the gene and its products (RNA and protein) was simultaneously performed on a large number of both tumor types. This analysis identified several potential shortcomings of the various methods used to evaluate HER-2/neu in these diseases (Southern, Northern, and Western blots, and immunohistochemistry) and provided information regarding considerations that should be addressed when studying a gene or gene product in human tissue. The data presented further support the concept that the HER-2/neu gene may be involved in the pathogenesis of some human cancers.

The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease.

Science.gov (United States)

Singbrant, Sofie; Wall, Meaghan; Moody, Jennifer; Karlsson, Göran; Chalk, Alistair M; Liddicoat, Brian; Russell, Megan R; Walkley, Carl R; Karlsson, Stefan

2014-04-01

The proto-oncogene SKI is highly expressed in human myeloid leukemia and also in murine hematopoietic stem cells. However, its operative relevance in these cells remains elusive. We have over-expressed SKI to define its intrinsic role in hematopoiesis and myeloid neoplasms, which resulted in a robust competitive advantage upon transplantation, a complete dominance of the stem and progenitor compartments, and a marked enhancement of myeloid differentiation at the expense of other lineages. Accordingly, enforced expression of SKI induced a gene signature associated with hematopoietic stem cells and myeloid differentiation, as well as hepatocyte growth factor signaling. Here we demonstrate that, in contrast to what has generally been assumed, the significant impact of SKI on hematopoiesis is independent of its ability to inhibit TGF-beta signaling. Instead, myeloid progenitors expressing SKI are partially dependent on functional hepatocyte growth factor signaling. Collectively our results demonstrate that SKI is an important regulator of hematopoietic stem cell activity and its overexpression leads to myeloproliferative disease.

Proto-oncogene FBI-1 (Pokemon/ZBTB7A) Represses Transcription of the Tumor Suppressor Rb Gene via Binding Competition with Sp1 and Recruitment of Co-repressors*S⃞

Science.gov (United States)

Jeon, Bu-Nam; Yoo, Jung-Yoon; Choi, Won-Il; Lee, Choong-Eun; Yoon, Ho-Geun; Hur, Man-Wook

2008-01-01

FBI-1 (also called Pokemon/ZBTB7A) is a BTB/POZ-domain Krüppel-like zinc-finger transcription factor. Recently, FBI-1 was characterized as a proto-oncogenic protein, which represses tumor suppressor ARF gene transcription. The expression of FBI-1 is increased in many cancer tissues. We found that FBI-1 potently represses transcription of the Rb gene, a tumor suppressor gene important in cell cycle arrest. FBI-1 binds to four GC-rich promoter elements (FREs) located at bp –308 to –188 of the Rb promoter region. The Rb promoter also contains two Sp1 binding sites: GC-box 1 (bp –65 to –56) and GC-box 2 (bp –18 to –9), the latter of which is also bound by FBI-1. We found that FRE3 (bp –244 to –236) is also a Sp1 binding element. FBI-1 represses transcription of the Rb gene not only by binding to the FREs, but also by competing with Sp1 at the GC-box 2 and the FRE3. By binding to the FREs and/or the GC-box, FBI-1 represses transcription of the Rb gene through its POZ-domain, which recruits a co-repressor-histone deacetylase complex and deacetylates histones H3 and H4 at the Rb gene promoter. FBI-1 inhibits C2C12 myoblast cell differentiation by repressing Rb gene expression. PMID:18801742

Aubergine and piRNAs promote germline stem cell self-renewal by repressing the proto-oncogene Cbl.

Science.gov (United States)

Rojas-Ríos, Patricia; Chartier, Aymeric; Pierson, Stéphanie; Simonelig, Martine

2017-11-02

PIWI proteins play essential roles in germ cells and stem cell lineages. In Drosophila , Piwi is required in somatic niche cells and germline stem cells (GSCs) to support GSC self-renewal and differentiation. Whether and how other PIWI proteins are involved in GSC biology remains unknown. Here, we show that Aubergine (Aub), another PIWI protein, is intrinsically required in GSCs for their self-renewal and differentiation. Aub needs to be loaded with piRNAs to control GSC self-renewal and acts through direct mRNA regulation. We identify the Cbl proto-oncogene, a regulator of mammalian hematopoietic stem cells, as a novel GSC differentiation factor. Aub stimulates GSC self-renewal by repressing Cbl mRNA translation and does so in part through recruitment of the CCR4-NOT complex. This study reveals the role of piRNAs and PIWI proteins in controlling stem cell homeostasis via translational repression and highlights piRNAs as major post-transcriptional regulators in key developmental decisions. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

The crucial role of the proto-oncogene c-mos in regulation of oocyte maturation

Directory of Open Access Journals (Sweden)

Irena Jałocha

2010-12-01

Full Text Available Meiosis arrest before fertilization is a common and unique feature of oogenesis in many animal species. On account of the unclear biological significance of meiosis arrest at various stages and for different durations in different animal species, this process and its regulation are the subject of many scientific studies. Studies on the development of ovarian teratomas proved to be helpful in defining the role of particular genes and biochemical cycles in control of the cell cycle in animals. These benign tumors are a valuable source of information on oocyte maturation. The [i]c-mos[/i] proto-oncogene, which is specifically expressed in female and male germ cells, plays a crucial role in control of meiotic cell division in mammals. Its product – Mos protein kinase – acting through mitogen-activated protein kinases (MAPKs regulates critical cellular functions required for homeostasis and decides about cell survival or apoptosis. The MAPK kinase kinase – MAPK kinase – MAPK (MKKK-MKK-MAPK phosphorelay system, in view of its role in cells, seems to be the ideal target for therapeutic intervention in cancer and other diseases. The recent research on human oocytes suggests that the basic mechanisms regulating various stages of oocyte maturation are similar to those described in animals.

Mutation and genomic amplification of the PIK3CA proto-oncogene in pituitary adenomas

International Nuclear Information System (INIS)

Murat, C.B.; Braga, P.B.S.; Fortes, M.A.H.Z.; Bronstein, M.D.; Corrêa-Giannella, M.L.C.; Giorgi, R.R.

2012-01-01

The tumorigenesis of pituitary adenomas is poorly understood. Mutations of the PIK3CA proto-oncogene, which encodes the p110-α catalytic subunit of PI3K, have been reported in various types of human cancers regarding the role of the gene in cell proliferation and survival through activation of the PI3K/Akt signaling pathway. Only one Chinese study described somatic mutations and amplification of the PIK3CA gene in a large series of pituitary adenomas. The aim of the present study was to determine genetic alterations of PIK3CA in a second series that consisted of 33 pituitary adenomas of different subtypes diagnosed by immunohistochemistry: 6 adrenocorticotropic hormone-secreting microadenomas, 5 growth hormone-secreting macroadenomas, 7 prolactin-secreting macroadenomas, and 15 nonfunctioning macroadenomas. Direct sequencing of exons 9 and 20 assessed by qPCR was employed to investigate the presence of mutations and genomic amplification defined as a copy number ≥4. Previously identified PIK3CA mutations (exon 20) were detected in four cases (12.1%). Interestingly, the Chinese study reported mutations only in invasive tumors, while we found a PIK3CA mutation in one noninvasive corticotroph microadenoma. PIK3CA amplification was observed in 21.2% (7/33) of the cases. This study demonstrates the presence of somatic mutations and amplifications of the PIK3CA gene in a second series of pituitary adenomas, corroborating the previously described involvement of the PI3K/Akt signaling pathway in the tumorigenic process of this gland

Mutation and genomic amplification of the PIK3CA proto-oncogene in pituitary adenomas

Energy Technology Data Exchange (ETDEWEB)

Murat, C.B.; Braga, P.B.S.; Fortes, M.A.H.Z. [Laboratório de Endocrinologia Celular e Molecular (LIM-25), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Bronstein, M.D. [Unidade de Neuroendocrinologia, Serviço de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Corrêa-Giannella, M.L.C.; Giorgi, R.R. [Laboratório de Endocrinologia Celular e Molecular (LIM-25), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil)

2012-07-13

The tumorigenesis of pituitary adenomas is poorly understood. Mutations of the PIK3CA proto-oncogene, which encodes the p110-α catalytic subunit of PI3K, have been reported in various types of human cancers regarding the role of the gene in cell proliferation and survival through activation of the PI3K/Akt signaling pathway. Only one Chinese study described somatic mutations and amplification of the PIK3CA gene in a large series of pituitary adenomas. The aim of the present study was to determine genetic alterations of PIK3CA in a second series that consisted of 33 pituitary adenomas of different subtypes diagnosed by immunohistochemistry: 6 adrenocorticotropic hormone-secreting microadenomas, 5 growth hormone-secreting macroadenomas, 7 prolactin-secreting macroadenomas, and 15 nonfunctioning macroadenomas. Direct sequencing of exons 9 and 20 assessed by qPCR was employed to investigate the presence of mutations and genomic amplification defined as a copy number ≥4. Previously identified PIK3CA mutations (exon 20) were detected in four cases (12.1%). Interestingly, the Chinese study reported mutations only in invasive tumors, while we found a PIK3CA mutation in one noninvasive corticotroph microadenoma. PIK3CA amplification was observed in 21.2% (7/33) of the cases. This study demonstrates the presence of somatic mutations and amplifications of the PIK3CA gene in a second series of pituitary adenomas, corroborating the previously described involvement of the PI3K/Akt signaling pathway in the tumorigenic process of this gland.

Expression of proto-oncogene KIT is up-regulated in subset of human meningiomas

Directory of Open Access Journals (Sweden)

Saini Masum

2012-06-01

Full Text Available Abstract Background KIT is a proto-oncogene involved in diverse neoplastic processes. Aberrant kinase activity of the KIT receptor has been targeted by tyrosine kinase inhibitor (TKI therapy in different neoplasias. In all the earlier studies, KIT expression was reported to be absent in meningiomas. However, we observed KIT mRNA expression in some meningioma cases. This prompted us to undertake its detailed analyses in meningioma tissues resected during 2008–2009. Methods Tumor tissues and matched peripheral blood samples collected from meningioma patients were used for detailed molecular analyses. KIT expression was ascertained immunohistochemically and validated by immunoblotting. KIT and KITLG transcript levels were discerned by reverse transcription quantitative real-time PCR (RT-qPCR. Similarly, KIT amplification and allele loss were assessed by quantitative real-time (qPCR and validated by fluorescence in situ hybridization (FISH on the neoplastic tissues. Possible alterations of the gene at the nucleotide level were analyzed by sequencing. Results Contrary to earlier reports, KIT expression, was detected immunohistochemically in 20.6% meningioma cases (n = 34. Receptor (KIT and ligand (KITLG transcripts monitored by RT-qPCR were found to co-express (p = 0.048 in most of the KIT immunopositive tumors. 1/7 KIT positive meningiomas showed allele loss corroborated by reduced FISH signal in the corresponding neoplastic tissue. Sequence analysis of KIT showed M541L substitution in exon 10, in one of the immunopositive cases. However, its biological consequence remains to be uncovered. Conclusions This study clearly demonstrates KIT over-expression in the human meningiomas. The data suggest that up-regulated KIT transcription (p  0.05, is a likely mechanism responsible for altered KIT expression. Thus, KIT is a potential candidate for detailed investigation in the context of meningioma pathogenesis.

Expression of proto-oncogene KIT is up-regulated in subset of human meningiomas

International Nuclear Information System (INIS)

Saini, Masum; Jha, Ajaya Nand; Abrari, Andleeb; Ali, Sher

2012-01-01

KIT is a proto-oncogene involved in diverse neoplastic processes. Aberrant kinase activity of the KIT receptor has been targeted by tyrosine kinase inhibitor (TKI) therapy in different neoplasias. In all the earlier studies, KIT expression was reported to be absent in meningiomas. However, we observed KIT mRNA expression in some meningioma cases. This prompted us to undertake its detailed analyses in meningioma tissues resected during 2008–2009. Tumor tissues and matched peripheral blood samples collected from meningioma patients were used for detailed molecular analyses. KIT expression was ascertained immunohistochemically and validated by immunoblotting. KIT and KITLG transcript levels were discerned by reverse transcription quantitative real-time PCR (RT-qPCR). Similarly, KIT amplification and allele loss were assessed by quantitative real-time (qPCR) and validated by fluorescence in situ hybridization (FISH) on the neoplastic tissues. Possible alterations of the gene at the nucleotide level were analyzed by sequencing. Contrary to earlier reports, KIT expression, was detected immunohistochemically in 20.6% meningioma cases (n = 34). Receptor (KIT) and ligand (KITLG) transcripts monitored by RT-qPCR were found to co-express (p = 0.048) in most of the KIT immunopositive tumors. 1/7 KIT positive meningiomas showed allele loss corroborated by reduced FISH signal in the corresponding neoplastic tissue. Sequence analysis of KIT showed M541L substitution in exon 10, in one of the immunopositive cases. However, its biological consequence remains to be uncovered. This study clearly demonstrates KIT over-expression in the human meningiomas. The data suggest that up-regulated KIT transcription (p < 0.001), instead of gene amplification (p > 0.05), is a likely mechanism responsible for altered KIT expression. Thus, KIT is a potential candidate for detailed investigation in the context of meningioma pathogenesis

A sparse regulatory network of copy-number driven gene expression reveals putative breast cancer oncogenes.

Science.gov (United States)

Yuan, Yinyin; Curtis, Christina; Caldas, Carlos; Markowetz, Florian

2012-01-01

Copy number aberrations are recognized to be important in cancer as they may localize to regions harboring oncogenes or tumor suppressors. Such genomic alterations mediate phenotypic changes through their impact on expression. Both cis- and transacting alterations are important since they may help to elucidate putative cancer genes. However, amidst numerous passenger genes, trans-effects are less well studied due to the computational difficulty in detecting weak and sparse signals in the data, and yet may influence multiple genes on a global scale. We propose an integrative approach to learn a sparse interaction network of DNA copy-number regions with their downstream transcriptional targets in breast cancer. With respect to goodness of fit on both simulated and real data, the performance of sparse network inference is no worse than other state-of-the-art models but with the advantage of simultaneous feature selection and efficiency. The DNA-RNA interaction network helps to distinguish copy-number driven expression alterations from those that are copy-number independent. Further, our approach yields a quantitative copy-number dependency score, which distinguishes cis- versus trans-effects. When applied to a breast cancer data set, numerous expression profiles were impacted by cis-acting copy-number alterations, including several known oncogenes such as GRB7, ERBB2, and LSM1. Several trans-acting alterations were also identified, impacting genes such as ADAM2 and BAGE, which warrant further investigation. An R package named lol is available from www.markowetzlab.org/software/lol.html.

Germline mutation of RET proto-oncogene’s exons 17 and 18 in Iranian medullary thyroid carcinoma patients

Directory of Open Access Journals (Sweden)

Marjan Zarif Yeganeh

2017-03-01

Full Text Available Background: Thyroid carcinoma is the most common endocrine malignancy. Medullary thyroid carcinoma (MTC approximately accounts for 5-10% of all thyroid carcinoma. Nowadays, it is obviously, the mutations in REarranged during transfection (RET proto-oncogene, especially, mutations in exons 10, 11 and 16 are associated with MTC pathogenesis and occurrence. Thus, early diagnosis of MTC by mutation detection in RET proto-oncogene allows to identify patients who do not have any developed symptoms. The aim of this study was to screening of germline mutations in RET proto-oncogene exons 17 and 18 in MTC patients and their first degree relatives in Iranian population. Methods: In this cross-sectional study, three hundred eleven participates (190 patients, 121 their relatives were referred to endocrine research center, Shahid Beheshti University of Medical Science during September 2013 until September 2015. The inclusion criteria were pathological and clinical diagnosis. After whole blood sampling, genomic DNA was extracted from peripheral blood leucocytes using the standard Salting Out/Proteinase K method. Nucleotide change detection in exons 17 and 18 was performed using PCR and direct DNA sequencing methods. Results: In this study, twenty missense mutations [CGC>TGC, c.2944C>T, p.Arg982Cys (rs17158558] which included 16 heterozygote and 4 homozygote mutations were found in codon 982 (exon 18. In the present study, 154 G>A (rs2742236 and 4 C>T (rs370072408 nucleotide changes were detected in exons 18 and intron 17 respectively. There was no mutation in exon 17. Conclusion: It seems that because of arginine to cysteine substitutions in RET tyrosine kinase protein structure and its polyphen score (0.955 and SIFT score (0.01 the mutation in codon 982 (exon 18 could be have pathogenic effects. On the other hands, the mentioned mutation frequency was 6.4% among MTC patients, so this mutation of exon 18 could be checked in genetic screening tests of RET

Targeting of the tumor suppressor GRHL3 by a miR-21-dependent proto-oncogenic network results in PTEN loss and tumorigenesis.

Science.gov (United States)

Darido, Charbel; Georgy, Smitha R; Wilanowski, Tomasz; Dworkin, Sebastian; Auden, Alana; Zhao, Quan; Rank, Gerhard; Srivastava, Seema; Finlay, Moira J; Papenfuss, Anthony T; Pandolfi, Pier Paolo; Pearson, Richard B; Jane, Stephen M

2011-11-15

Despite its prevalence, the molecular basis of squamous cell carcinoma (SCC) remains poorly understood. Here, we identify the developmental transcription factor Grhl3 as a potent tumor suppressor of SCC in mice, and demonstrate that targeting of Grhl3 by a miR-21-dependent proto-oncogenic network underpins SCC in humans. Deletion of Grhl3 in adult epidermis evokes loss of expression of PTEN, a direct GRHL3 target, resulting in aggressive SCC induced by activation of PI3K/AKT/mTOR signaling. Restoration of Pten expression completely abrogates SCC formation. Reduced levels of GRHL3 and PTEN are evident in human skin, and head and neck SCC, associated with increased expression of miR-21, which targets both tumor suppressors. Our data define the GRHL3-PTEN axis as a critical tumor suppressor pathway in SCC. 2011 Elsevier Inc. All rights reserved.

Oncogenic K-Ras Activates p38 to Maintain Colorectal Cancer Cell Proliferation during MEK Inhibition

Directory of Open Access Journals (Sweden)

Winan J. van Houdt

2010-01-01

Full Text Available Background: Colon carcinomas frequently contain activating mutations in the K-ras proto-oncogene. K-ras itself is a poor drug target and drug development efforts have mostly focused on components of the classical Ras-activated MEK/ERK pathway. Here we have studied whether endogenous oncogenic K-ras affects the dependency of colorectal tumor cells on MEK/ERK signaling.

Microsatellite instability and B-type Raf proto-oncogene mutation in colorectal cancer: Clinicopathological characteristics and effects on survival

Directory of Open Access Journals (Sweden)

Sebnem Batur

2016-11-01

Full Text Available Prognostic significance of microsatellite instability (MSI status and B-type Raf proto-oncogene (BRAF mutation in colorectal cancer is controversial. The aim of this study was to examine the clinical and pathological characteristics associated with microsatellite stability and the effect of MSI and BRAF mutation on the survival of patients with colorectal cancer. The study included 145 colorectal cancer cases. All the patients were examined for DNA mismatch repair (MMR proteins with an immunohistochemical method. Molecular assessment of MSI was available in a subset of 41 patients. In addition, BRAF mutation analysis was performed in 30 cases. Immunohistochemically, MMR deficiency was present in 28 (19.3% patients. Female gender (p = 0.001, lesion size ≥5 cm (p = 0.013, Crohn-like response (p = 0.035, and right-sided localization (p < 0.001 were significantly more frequent among MMR-deficient patients. The overall survival was 44.1 ± 5.1 months (95% confidence interval [CI], 33.7-54.4. Multivariate analyses identified only high tumor grade as an independent predictor of poor overall survival: odd ratio, 6.7 (95% CI 2.1-21.7, p = 0.002. In the subset of patients with available BRAF assessment (n = 30, a negative BRAF status was associated with better survival when compared to a positive BRAF status (36.7 ± 2.1 vs. 34.1 ± 7.2 months, p = 0.048. The sensitivity and specificity of the immunohistochemical method in predicting positive MSI status, with the molecular method as a reference, were 85.7% (95% CI: 56.2%-97.5% and 88.9% (95% CI: 69.7%-97.1%, respectively. BRAF appears to be a significant predictor of a worse outcome in patients with colorectal cancer. Further studies with a large spectrum of clinical and biological variables are warranted.

Sequence analysis of the MYC oncogene involved in the t(8;14)(q24;q11) chromosome translocation in a human leukemia T-cell line indicates that putative regulatory regions are not altered

International Nuclear Information System (INIS)

Finver, S.N.; Nishikura, K.; Finger, L.R.; Haluska, F.G.; Finan, J.; Nowell, P.C.; Croce, C.M.

1988-01-01

The authors cloned the translocation-associated and homologous normal MYC alleles from SKW-3, a leukemia T-cell line with the t(8; 14)(q24; q11) translocation, and determined the sequence of the MYC oncogene first exon and flanking 5' putative regulatory regions. S1 nuclease protection experiments utilizing a MYC first exon probe demonstrated transcriptional deregulation of the MYC gene associated with the T-cell receptor α locus on the 8q + chromosome of SKW-3 cells. Nucleotide sequence analysis of the translocation-associated (8q +) MYC allele identified a single base substitution within the upstream flanking region; the homologous nontranslocated allele contained an additional substitution and a two-base deletion. None of the deletions or substitutions localized to putative 5' regulatory regions. The MYC first exon sequence was germ line in both alleles. These results demonstrate that alterations within the putative 5' MYC regulatory regions are not necessarily involved in MYC deregulation in T-cell leukemias, and they show that juxtaposition of the T-cell receptor α locus to a germ-line MYC oncogene results in MYC deregulation

CRM1-mediated nuclear export is required for 26 S proteasome-dependent degradation of the TRIP-Br2 proto-oncoprotein.

Science.gov (United States)

Cheong, Jit Kong; Gunaratnam, Lakshman; Hsu, Stephen I-Hong

2008-04-25

Overexpression of the proto-oncogene TRIP-Br2 (SERTAD2) has been shown to induce E2F activity and promote tumorigenesis, whereas ablation of TRIP-Br2 arrests cell proliferation. Timely degradation of many cell cycle regulators is fundamental to the maintenance of proper cell cycle progression. Here we report novel mechanism(s) that govern the tight regulation of TRIP-Br2 levels during cell cycle progression. TRIP-Br2 was observed to be a short-lived protein in which the expression level peaks at the G(1)/S boundary. TRIP-Br2 accumulated in cells treated with 26 S proteasome inhibitors. Co-immunoprecipitation studies revealed that TRIP-Br2 forms ubiquitin conjugates. In silico analysis identified a putative leucine-rich nuclear export signal (NES) motif that overlaps with the PHD-Bromo interaction domain in the acidic C-terminal transactivation domain (TAD) of TRIP-Br2. This NES motif is highly conserved in widely divergent species and in all TRIP-Br family members. TRIP-Br2 was shown to be stabilized in G(2)/M phase cells through nuclear entrapment, either by deletion of the acidic C-terminal TAD, which includes the NES motif, or by leptomycin B-mediated inhibition of the CRM1-dependent nuclear export machinery. Mutation of leucine residue 238 of this NES motif abolished the interaction between CRM1 and TRIP-Br2, as well as the nuclear export of TRIP-Br2 and its subsequent 26 S proteasome-dependent degradation. These data suggest that CRM1-mediated nuclear export may be required for the proper execution of ubiquitin-proteasome-dependent degradation of TRIP-Br2.

The proto-oncogene product c-Crk associates with insulin receptor substrate-1 and 4PS. Modulation by insulin growth factor-I (IGF) and enhanced IGF-I signaling.

Science.gov (United States)

Beitner-Johnson, D; Blakesley, V A; Shen-Orr, Z; Jimenez, M; Stannard, B; Wang, L M; Pierce, J; LeRoith, D

1996-04-19

The Crk proto-oncogene product is an SH2 and SH3 domain-containing adaptor protein which we have previously shown to become rapidly tyrosine phosphorylated in response to stimulation with insulin-like growth factor I (IGF-I) in NIH-3T3 cells. In order to further characterize the role of Crk in the IGF-I signaling pathway, NIH-3T3 and 293 cells were stably transfected with an expression vector containing the Crk cDNA. The various resultant 3T3-Crk clones expressed Crk at approximately 2-15-fold higher levels than parental 3T3 cells. In 3T3-Crk cells, Crk immunoreactivity was detected in insulin receptor substrate-1 (IRS-1) immunoprecipitates. Stimulation with IGF-I resulted in a dissociation of Crk protein from IRS-1. In contrast, the association of the related adaptor protein Grb2 with IRS-1 was enhanced by IGF-I stimulation. Similar results were obtained in stably transfected 293-Crk cells, which express both IRS-1 and the IRS-1-related signaling protein 4PS. In these cells, IRS-1 and 4PS both associated with Crk, and this association was also decreased by IGF-I treatment, whereas the association of Grb2 with IRS-1 and 4PS was enhanced by IGF-I. Overexpression of Crk also enhanced IGF-I-induced mitogenesis of NIH-3T3 cells, as measured by [3H]thymidine incorporation. The levels of IGF-I-induced mitogenesis were proportional to the level of Crk expression. These results suggest that Crk is a positive effector of IGF-I signaling, and may mediate its effects via interaction with IRS-1 and/or 4PS.

Formaldehyde-induced histone H3 phosphorylation via JNK and the expression of proto-oncogenes

International Nuclear Information System (INIS)

Yoshida, Ikuma; Ibuki, Yuko

2014-01-01

Graphical abstract: - Highlights: • Formaldehyde modified histones. • The phosphorylation of H3S10 was increased at the promoter regions of proto-oncogenes. • The phosphorylation of H2AXS139 was attributed to FA-induced DNA damage. • The FA-induced initiation and promotion of cancer could be judged by these modifications. - Abstract: Formaldehyde (FA) is a very reactive compound that forms DNA adducts and DNA-protein crosslinks, which are known to contribute to FA-induced mutations and carcinogenesis. Post-translational modifications to histones have recently attracted attention due to their link with cancer. In the present study, we examined histone modifications following a treatment with FA. FA significantly phosphorylated histone H3 at serine 10 (H3S10), and at serine 28 (H3S28), the time-course of which was similar to the phosphorylation of H2AX at serine 139 (γ-H2AX), a marker of DNA double strand breaks. The temporal deacetylation of H3 was observed due to the reaction of FA with the lysine residues of histones. The phosphorylation mechanism was then analyzed by focusing on H3S10. The nuclear distribution of the phosphorylation of H3S10 and γ-H2AX did not overlap, and the phosphorylation of H3S10 could not be suppressed with an inhibitor of ATM/ATR, suggesting that the phosphorylation of H3S10 was independent of the DNA damage response. ERK and JNK in the MAPK pathways were phosphorylated by the treatment with FA, in which the JNK pathway was the main target for phosphorylation. The phosphorylation of H3S10 increased at the promoter regions of c-fos and c-jun, indicating a relationship between FA-induced tumor promotion activity and phosphorylation of H3S10. These results suggested that FA both initiates and promotes cancer, as judged by an analysis of histone modifications

Formaldehyde-induced histone H3 phosphorylation via JNK and the expression of proto-oncogenes

Energy Technology Data Exchange (ETDEWEB)

Yoshida, Ikuma; Ibuki, Yuko, E-mail: ibuki@u-shizuoka-ken.ac.jp

2014-12-15

Graphical abstract: - Highlights: • Formaldehyde modified histones. • The phosphorylation of H3S10 was increased at the promoter regions of proto-oncogenes. • The phosphorylation of H2AXS139 was attributed to FA-induced DNA damage. • The FA-induced initiation and promotion of cancer could be judged by these modifications. - Abstract: Formaldehyde (FA) is a very reactive compound that forms DNA adducts and DNA-protein crosslinks, which are known to contribute to FA-induced mutations and carcinogenesis. Post-translational modifications to histones have recently attracted attention due to their link with cancer. In the present study, we examined histone modifications following a treatment with FA. FA significantly phosphorylated histone H3 at serine 10 (H3S10), and at serine 28 (H3S28), the time-course of which was similar to the phosphorylation of H2AX at serine 139 (γ-H2AX), a marker of DNA double strand breaks. The temporal deacetylation of H3 was observed due to the reaction of FA with the lysine residues of histones. The phosphorylation mechanism was then analyzed by focusing on H3S10. The nuclear distribution of the phosphorylation of H3S10 and γ-H2AX did not overlap, and the phosphorylation of H3S10 could not be suppressed with an inhibitor of ATM/ATR, suggesting that the phosphorylation of H3S10 was independent of the DNA damage response. ERK and JNK in the MAPK pathways were phosphorylated by the treatment with FA, in which the JNK pathway was the main target for phosphorylation. The phosphorylation of H3S10 increased at the promoter regions of c-fos and c-jun, indicating a relationship between FA-induced tumor promotion activity and phosphorylation of H3S10. These results suggested that FA both initiates and promotes cancer, as judged by an analysis of histone modifications.

Characterization of a human cell line stably over-expressing the candidate oncogene, dual specificity phosphatase 12.

Directory of Open Access Journals (Sweden)

Erica L Cain

2011-04-01

Full Text Available Analysis of chromosomal rearrangements within primary tumors has been influential in the identification of novel oncogenes. Identification of the "driver" gene(s within cancer-derived amplicons is, however, hampered by the fact that most amplicons contain many gene products. Amplification of 1q21-1q23 is strongly associated with liposarcomas and microarray-based comparative genomic hybridization narrowed down the likely candidate oncogenes to two: the activating transcription factor 6 (atf6 and the dual specificity phosphatase 12 (dusp12. While atf6 is an established transcriptional regulator of the unfolded protein response, the potential role of dusp12 in cancer remains uncharacterized.To evaluate the oncogenic potential of dusp12, we established stable cell lines that ectopically over-express dusp12 in isolation and determined whether this cell line acquired properties frequently associated with transformed cells. Here, we demonstrate that cells over-expressing dusp12 display increased cell motility and resistance to apoptosis. Additionally, over-expression of dusp12 promoted increased expression of the c-met proto-oncogene and the collagen and laminin receptor intergrin alpha 1 (itga1 which is implicated in metastasis.Collectively, these results suggest that dusp12 is oncologically relevant and exposes a potential association between dusp12 and established oncogenes that could be therapeutically targeted.

Expression of the proto-oncogene Pokemon in colorectal cancer--inhibitory effects of an siRNA.

Science.gov (United States)

Zhao, Gan-Ting; Yang, Li-Juan; Li, Xi-Xia; Cui, Hui-Lin; Guo, Rui

2013-01-01

This study aimed to investigate expression of the proto-oncogene POK erythroid myeloid ontogenic factor (Pokemon) in colorectal cancer (CRC), and assess inhibitory effects of a small interference RNA (siRNA) expression vector in SW480 and SW620 cells. Semi-quantitative reverse transcription-polymerase chain reaction (PCR) and immunohistochemistry were performed to determine mRNA and protein expression levels of Pokemon in CRC tissues. Indirect immunofluorescence staining was applied to investigate the location of Pokemon in SW480 and SW620 cells. The siRNA expression vectors that were constructed to express a short hairpin RNA against Pokemon were transfected to the SW480 and SW620 cells with a liposome. Expression levels of Pokemon mRNA and protein were examined by real-time quantitative-fluorescent PCR and western blot analysis. The effects of Pokemon silencing on proliferation of SW480 and SW620 cells were evaluated with reference to growth curves with MTT assays. The mRNA expression level of Pokemon in tumor tissues (0.845 ± 0.344) was significantly higher than that in adjacent tumor specimens (0.321 ± 0.197). The positive expression ratio of Pokemon protein in CRC (87.0%) was significantly higher than that in the adjacent tissues (19.6%). Strong fluorescence staining of Pokemon protein was observed in the cytoplasm of the SW480 and SW620 cells. The inhibition ratios of Pokemon mRNA and protein in the SW480 cells were 83.1% and 73.5% at 48 and 72 h, respectively, compared with those of the negative control cells with the siRNA. In the SW620 cells, the inhibition ratios of Pokemon mRNA and protein were 76.3% and 68.7% at 48 and 72 h, respectively. MTT showed that Pokemon gene silencing inhibited the proliferation of SW480 and SW620 cells. Overexpression of Pokemon in CRC may have a function in carcinogenesis and progression. siRNA expression vectors could effectively inhibit mRNA and protein expression of Pokemon in SW480 and SW620 cells, thereby reducing

Analysis of nucleo-cytoplasmic shuttling of the proto-oncogene SET/I2PP2A

NARCIS (Netherlands)

Lam, B. Daniel; Anthony, Eloise C.; Hordijk, Peter L.

2012-01-01

SET/I2PP2A is a nuclear protein that was initially identified as an oncogene in human undifferentiated acute myeloid leukemia, fused to the nuclear porin Nup-214. In addition, SET is a potent inhibitior of the phosphatase PP2A. Previously, we proposed a model in which the small GTPase Rac1 recruits

Targeting MET Amplification as a New Oncogenic Driver

International Nuclear Information System (INIS)

Kawakami, Hisato; Okamoto, Isamu; Okamoto, Wataru; Tanizaki, Junko; Nakagawa, Kazuhiko; Nishio, Kazuto

2014-01-01

Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as “oncogene addiction”. A new generation of drugs that selectively target such “driver oncogenes” manifests a clinical efficacy greater than that of conventional chemotherapy in appropriate genetically defined patients. MET is a proto-oncogene that encodes a receptor tyrosine kinase, and aberrant activation of MET signaling occurs in a subset of advanced cancers as result of various genetic alterations including gene amplification, polysomy, and gene mutation. Our preclinical studies have shown that inhibition of MET signaling either with the small-molecule MET inhibitor crizotinib or by RNA interference targeted to MET mRNA resulted in marked antitumor effects in cancer cell lines with MET amplification both in vitro and in vivo. Furthermore, patients with non-small cell lung cancer or gastric cancer positive for MET amplification have shown a pronounced clinical response to crizotinib. Accumulating preclinical and clinical evidence thus suggests that MET amplification is an “oncogenic driver” and therefore a valid target for treatment. However, the prevalence of MET amplification has not been fully determined, possibly in part because of the difficulty in evaluating gene amplification. In this review, we provide a rationale for targeting this genetic alteration in cancer therapy

Targeting MET Amplification as a New Oncogenic Driver

Energy Technology Data Exchange (ETDEWEB)

Kawakami, Hisato [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Okamoto, Isamu, E-mail: okamotoi@kokyu.med.kyushu-u.ac.jp [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Center for Clinical and Translational Research, Kyushu University Hospital, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582 (Japan); Okamoto, Wataru [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Division of Transrlational Research, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577 (Japan); Tanizaki, Junko [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, HIM223, 450 Brookline Avenue, Boston, MA 02215 (United States); Nakagawa, Kazuhiko [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Nishio, Kazuto [Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511 (Japan)

2014-07-22

Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as “oncogene addiction”. A new generation of drugs that selectively target such “driver oncogenes” manifests a clinical efficacy greater than that of conventional chemotherapy in appropriate genetically defined patients. MET is a proto-oncogene that encodes a receptor tyrosine kinase, and aberrant activation of MET signaling occurs in a subset of advanced cancers as result of various genetic alterations including gene amplification, polysomy, and gene mutation. Our preclinical studies have shown that inhibition of MET signaling either with the small-molecule MET inhibitor crizotinib or by RNA interference targeted to MET mRNA resulted in marked antitumor effects in cancer cell lines with MET amplification both in vitro and in vivo. Furthermore, patients with non-small cell lung cancer or gastric cancer positive for MET amplification have shown a pronounced clinical response to crizotinib. Accumulating preclinical and clinical evidence thus suggests that MET amplification is an “oncogenic driver” and therefore a valid target for treatment. However, the prevalence of MET amplification has not been fully determined, possibly in part because of the difficulty in evaluating gene amplification. In this review, we provide a rationale for targeting this genetic alteration in cancer therapy.

Proteome-wide analysis of protein abundance and turnover remodelling during oncogenic transformation of human breast epithelial cells [version 1; referees: 2 approved, 1 approved with reservations

Directory of Open Access Journals (Sweden)

Tony Ly

2018-05-01

Full Text Available Background: Viral oncogenes and mutated proto-oncogenes are potent drivers of cancer malignancy. Downstream of the oncogenic trigger are alterations in protein properties that give rise to cellular transformation and the acquisition of malignant cellular phenotypes. Developments in mass spectrometry enable large-scale, multidimensional characterisation of proteomes. Such techniques could provide an unprecedented, unbiased view of how oncogene activation remodels a human cell proteome. Methods: Using quantitative MS-based proteomics and cellular assays, we analysed how transformation induced by activating v-Src kinase remodels the proteome and cellular phenotypes of breast epithelial (MCF10A cells. SILAC MS was used to comprehensively characterise the MCF10A proteome and to measure v-Src-induced changes in protein abundance across seven time-points (1-72 hrs. We used pulse-SILAC MS (Boisvert et al., 2012, to compare protein synthesis and turnover in control and transformed cells. Follow-on experiments employed a combination of cellular and functional assays to characterise the roles of selected Src-responsive proteins. Results: Src-induced transformation changed the expression and/or turnover levels of ~3% of proteins, affecting ~1.5% of the total protein molecules in the cell. Transformation increased the average rate of proteome turnover and disrupted protein homeostasis. We identify distinct classes of protein kinetics in response to Src activation. We demonstrate that members of the polycomb repressive complex 1 (PRC1 are important regulators of invasion and migration in MCF10A cells. Many Src-regulated proteins are present in low abundance and some are regulated post-transcriptionally. The signature of Src-responsive proteins is highly predictive of poor patient survival across multiple cancer types. Open access to search and interactively explore all these proteomic data is provided via the EPD database (www.peptracker.com/epd. Conclusions

Aberrant status and clinicopathologic characteristic associations of 11 target genes in 1,321 Chinese patients with lung adenocarcinoma.

Science.gov (United States)

Zhao, Mengnan; Zhan, Cheng; Li, Ming; Yang, Xiaodong; Yang, Xinyu; Zhang, Yong; Lin, Miao; Xia, Yifeng; Feng, Mingxiang; Wang, Qun

2018-01-01

The aberrant status of target genes and their associations with clinicopathologic characteristics are still unclear in primary lung adenocarcinoma. The common mutations and translocations of nine target genes were evaluated in 1,247 specimens of surgically-resected primary lung adenocarcinoma. Immunohistochemistry was used to analyze the expressions of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) in 731 specimens. The frequency of the aberrations and their associations with clinicopathologic characteristics were analyzed. Overall, 952 (76.3%) of 1,247 patients harbored at least one target mutation or translocation: epidermal growth factor receptor ( EGFR ) (729, 58.5%), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS ) (83, 6.7%), human epidermal growth factor receptor 2 ( HER2 ) (82, 6.6%), anaplastic lymphoma kinase ( ALK) (23, 1.8%), phosphoinositide-3-kinase catalytic alpha polypeptide ( PIK3CA ) (20, 1.6%), Ret proto-oncogene RET (15, 1.2%), ROS proto-oncogene 1 receptor tyrosine kinase ( ROS1 ) (12, 1.0%), B-raf proto-oncogene ( BRAF ) (9, 0.7%), neuroblastoma RAS viral (v-ras) oncogene homolog ( NRAS ) (3, 0.2%). Fourteen (1.9%) of 731 patients were PD-1 positive and 95 (13.0%) were PD-L1 positive in tumor cells. In men and smokers, there were more frequent KRAS mutations (both Ppatients, while HER2 (Ppatients with EGFR mutations (all Ppatients with primary lung adenocarcinoma harbored target gene aberrations. The frequency of each alteration differed in patients depending on clinicopathologic characteristics.

Characteristics of lentiviral vectors harboring the proximal promoter of the vav proto-oncogene: a weak and efficient promoter for gene therapy.

Science.gov (United States)

Almarza, Elena; Río, Paula; Meza, Nestor W; Aldea, Montserrat; Agirre, Xabier; Guenechea, Guillermo; Segovia, José C; Bueren, Juan A

2007-08-01

Recent published data have shown the efficacy of gene therapy treatments of certain monogenic diseases. Risks of insertional oncogenesis, however, indicate the necessity of developing new vectors with weaker or cell-restricted promoters to minimize the trans-activation activity of integrated proviruses. We have inserted the proximal promoter of the vav proto-oncogene into self-inactivating lentiviral vectors (vav-LVs) and investigated the expression pattern and therapeutic efficacy of these vectors. Compared with other LVs frequently used in gene therapy, vav-LVs mediated a weak, though homogeneous and stable, expression in in vitro-cultured cells. Transplantation experiments using transduced mouse bone marrow and human CD34(+) cells confirmed the stable activity of the promoter in vivo. To investigate whether the weak activity of this promoter was compatible with a therapeutic effect, a LV expressing the Fanconi anemia A (FANCA) gene was constructed (vav-FANCA LV). Although this vector induced a low expression of FANCA, compared to the expression induced by a LV harboring the spleen focus-forming virus (SFFV) promoter, the two vectors corrected the phenotype of cells from a patient with FA-A with the same efficacy. We propose that self-inactivating vectors harboring weak promoters, such as the vav promoter, will improve the safety of gene therapy and will be of particular interest for the treatment of diseases where a high expression of the transgene is not required.

Canabinoides sintéticos: drogas de abuso emergentes

Directory of Open Access Journals (Sweden)

Audrei de Oliveira Alves

2012-01-01

Full Text Available CONTEXTO: A Cannabis sativa (cannabis, maconha, marijuana é uma droga de abuso com efeitos psicoativos e potencial terapêutico bastante conhecidos. Um grande número de canabinoides foi sintetizado na tentativa de excluir ou minimizar os efeitos psicotrópicos e mantendo as aplicações terapêuticas. Os canabinoides sintéticos representam o mais recente avanço das designer drugs. OBJETIVOS: Este trabalho busca trazer informações sobre a utilização de canabinoides sintéticos como drogas de abuso emergentes, principalmente sob a forma de spice ou herbal blends. MÉTODOS: Foi realizada uma pesquisa bibliográfica na base de dados PubMed utilizando os descritores de assunto "synthetic cannabinoids", "spice", "legal highs", "herbal blends", "psychosis cannabis" e suas combinações. RESULTADOS: Foram encontrados canabinoides sintéticos nos produtos Spice, confirmando que os incensos herbais realmente surgiram como drogas de abuso emergentes. CONCLUSÃO: Não está claro se a utilização de canabinoides sintéticos e de Spice é uma moda passageira ou se irá se estabelecer em nossa sociedade. No entanto, o fenômeno das designer drugs, especialmente canabinoides sintéticos, representa um desafio presente para o sistemas de saúde no mundo globalizado, tornando-se necessária a pesquisa clínica e forense desses produtos.

Caucho natural y caucho sintético

OpenAIRE

Bekkedahl, Norman

2012-01-01

El Dr. Bekkedahl escribió así: ¿Cuál es el mejor caucho, el natural o el sintético? ¿Puede el caucho natural competir con el caucho sintético? Estas son dos importantes preguntas que se hacen frecuentemente. Las respuestas son demasiado complejas para poderlas explicar en pocas palabras. Esta charla tendrá como fin la consideración de estas cuestiones en sus varios aspectos para tratar luego de sacar algunas conclusiones.

Caucho Natural y Caucho Sintético

Directory of Open Access Journals (Sweden)

Bekkedahl Norman

1946-04-01

Full Text Available El Dr. Bekkedahl escribió así: ¿Cuál es el mejor caucho, el natural o el sintético? ¿Puede el caucho natural competir con el caucho sintético? Estas son dos importantes preguntas que se hacen frecuentemente. Las respuestas son demasiado complejas para poderlas explicar en pocas palabras. Esta charla tendrá como fin la consideración de estas cuestiones en sus varios aspectos para tratar luego de sacar algunas conclusiones.

Suppression of bcr-abl synthesis by siRNAs or tyrosine kinase activity by Glivec alters different oncogenes, apoptotic/antiapoptotic genes and cell proliferation factors (microarray study).

Science.gov (United States)

Zhelev, Zhivko; Bakalova, Rumiana; Ohba, Hideki; Ewis, Ashraf; Ishikawa, Mitsuru; Shinohara, Yasuo; Baba, Yoshinobu

2004-07-16

Short 21-mer double-stranded/small-interfering RNAs (ds/siRNAs) were designed to target bcr-abl mRNA in chronic myelogenous leukemia. The ds/siRNAs were transfected into bcr-abl-positive K-562 (derived from blast crisis chronic myelogenous leukemia), using lipofectamine. Penetrating of ds/siRNAs into the cells was detected by fluorescent confocal microscopy, using fluorescein-labeled ds/siRNAs. The cells were treated with mix of three siRNA sequences (3 x 60 nM) during 6 days with three repetitive transfections. The siRNA-treatment was accompanied with significant reduction of bcr-abl mRNA, p210, protein tyrosine kinase activity and cell proliferation index. Treatment of cells with Glivec (during 8 days with four repetitive doses, 180 nM single dose) resulted in analogous reduction of cell proliferation activity, stronger suppression of protein tyrosine kinase activity, and very low reduction of p210. siRNA-mix and Glivec did not affect significantly the viability of normal lymphocytes. Microarray analysis of siRNA- and Glivec-treated K-562 cells demonstrated that both pathways of bcr-abl suppression were accompanied with overexpression and suppression of many different oncogenes, apoptotic/antiapoptotic and cell proliferation factors. The following genes of interest were found to decrease in relatively equal degree in both siRNA- and Glivec-treated cells: Bcd orf1 and orf2 proto-oncogene, chromatin-specific transcription elongation factor FACT 140-kDa subunit mRNA, gene encoding splicing factor SF1, and mRNA for Tec protein tyrosine kinase. siRNA-mix and Glivec provoked overexpression of the following common genes: c-jun proto-oncogene, protein kinase C-alpha, pvt-1 oncogene homologue (myc activator), interleukin-6, 1-8D gene from interferon-inducible gene family, tumor necrosis factor receptor superfamily (10b), and STAT-induced STAT inhibitor.

Proto-planetary nebulae

International Nuclear Information System (INIS)

Zuckerman, B.

1978-01-01

A 'proto-planetary nebula' or a 'planetary nebula progenitor' is the term used to describe those objects that are losing mass at a rate >approximately 10 -5 Msolar masses/year (i.e. comparable to mass loss rates in planetary nebulae with ionized masses >approximately 0.2 Msolar masses) and which, it is believed, will become planetary nebulae themselves within 5 years. It is shown that most proto-planetary nebulae appear as very red objects although a few have been 'caught' near the middle of the Hertzsprung-Russell diagram. The precursors of these proto-planetaries are the general red giant population, more specifically probably Mira and semi-regular variables. (Auth.)end

Amplification of the Ect2 proto-oncogene and over-expression of Ect2 mRNA and protein in nickel compound and methylcholanthrene-transformed 10T1/2 mouse fibroblast cell lines

International Nuclear Information System (INIS)

Clemens, Farrah; Verma, Rini; Ramnath, Jamuna; Landolph, Joseph R.

2005-01-01

Occupational exposure of humans to mixtures of insoluble and soluble nickel (Ni) compounds correlates with increased incidences of lung, sinus, and pharyngeal tumors. Specific insoluble Ni compounds are carcinogenic to animals by inhalation and induce morphological and neoplastic transformation of cultured rodent cells. Our objectives were to (1) understand mechanisms of nickel ion-induced cell transformation, hence carcinogenesis and (2) develop biomarkers of nickel ion exposure and nickel ion-induced cell transformation. We isolated mRNAs from green nickel oxide (NiO), crystalline nickel monosulfide (NiS), and 3-methylcholanthrene (MCA) transformed C3H/10T1/2 Cl 8 cell lines, and determined by mRNA differential display that nine mRNA fragments were differentially expressed between Ni transformed and non-transformed 10T1/2 cell lines. Fragment R2-5 was expressed at higher steady-state levels in the transformed cell lines. R2-5 had 100% sequence identity to part of the coding region of Ect2, a mouse proto-oncogene encoding a GDP-GTP exchange factor. The 3.9-kb Ect2 transcript was expressed at 1.6- to 3.6-fold higher steady-state levels in four Ni transformed, and in two MCA-transformed, cell lines. Ect2 protein was expressed at 3.0- to 4.5-fold higher steady-state levels in Ni-transformed and in MCA-transformed cell lines. The Ect2 gene was amplified by 3.5- to 10-fold in Ni transformed, and by 2.5- to 3-fold in MCA transformed cell lines. Binding of nickel ions to enzymes of DNA synthesis likely caused amplification of the Ect2 gene. Ect2 gene amplification and over-expression of Ect2 mRNA and protein can cause microtubule disassembly and cytokinesis, contributing to induction and maintenance of morphological, anchorage-independent, and neoplastic transformation of these cell lines. Over-expression of Ect2 protein is a useful biomarker to detect exposure to nickel compounds and nickel ion-induced morphological and neoplastic cell transformation

Mutant p53 - heat shock response oncogenic cooperation: a new mechanism of cancer cell survival

Directory of Open Access Journals (Sweden)

Evguenia eAlexandrova

2015-04-01

Full Text Available The main tumor suppressor function of p53 as a ‘guardian of the genome’ is to respond to cellular stress by transcriptional activation of apoptosis, growth arrest or senescence in damaged cells. Not surprisingly, mutations in the p53 gene are the most frequent genetic alteration in human cancers. Importantly, mutant p53 (mutp53 proteins not only lose their wild-type tumor suppressor activity, but also can actively promote tumor development. Two main mechanisms accounting for mutp53 proto-oncogenic activity are inhibition of the wild-type p53 in a dominant-negative fashion and gain of additional oncogenic activities known as gain-of-function (GOF. Here we discuss a novel mechanism of mutp53 GOF, which relies on its oncogenic cooperation with the heat shock machinery. This coordinated adaptive mechanism renders cancer cells more resistant to proteotoxic stress and provides both, a strong survival advantage to cancer cells and a promising means for therapeutic intervention.

Activating mutation in MET oncogene in familial colorectal cancer

Directory of Open Access Journals (Sweden)

Schildkraut Joellen M

2011-10-01

Full Text Available Abstract Background In developed countries, the lifetime risk of developing colorectal cancer (CRC is 5%, and it is the second leading cause of death from cancer. The presence of family history is a well established risk factor with 25-35% of CRCs attributable to inherited and/or familial factors. The highly penetrant inherited colon cancer syndromes account for approximately 5%, leaving greater than 20% without clear genetic definition. Familial colorectal cancer has been linked to chromosome 7q31 by multiple affected relative pair studies. The MET proto-oncogene which resides in this chromosomal region is considered a candidate for genetic susceptibility. Methods MET exons were amplified by PCR from germline DNA of 148 affected sibling pairs with colorectal cancer. Amplicons with altered sequence were detected with high-resolution melt-curve analysis using a LightScanner (Idaho Technologies. Samples demonstrating alternative melt curves were sequenced. A TaqMan assay for the specific c.2975C >T change was used to confirm this mutation in a cohort of 299 colorectal cancer cases and to look for allelic amplification in tumors. Results Here we report a germline non-synonymous change in the MET proto-oncogene at amino acid position T992I (also reported as MET p.T1010I in 5.2% of a cohort of sibling pairs affected with CRC. This genetic variant was then confirmed in a second cohort of individuals diagnosed with CRC and having a first degree relative with CRC at prevalence of 4.1%. This mutation has been reported in cancer cells of multiple origins, including 2.5% of colon cancers, and in Conclusions Although the MET p.T992I genetic mutation is commonly found in somatic colorectal cancer tissues, this is the first report also implicating this MET genetic mutation as a germline inherited risk factor for familial colorectal cancer. Future studies on the cancer risks associated with this mutation and the prevalence in different at-risk populations will

Inside ProtoDune

CERN Multimedia

Brice, Maximilien

2017-01-01

The protoDUNE experimental program is designed to test and validate the technologies and design that will be applied to the construction of the DUNE Far Detector at the Sanford Underground Research Facility (SURF). The protoDUNE detectors will be run in a dedicated beam line at the CERN SPS accelerator complex. The rate and volume of data produced by these detectors will be substantial and will require extensive system design and integration effort. As of Fall 2015, "protoDUNE" is the official name for the two apparatuses to be used in CERN beam test: single-phase and dual-phase LArTPC detectors. Each received a formal CERN experiment designation: NP02 for the dual-phase detector. NP04 for single-phase detector.

Fusion peptides from oncogenic chimeric proteins as putative specific biomarkers of cancer.

Science.gov (United States)

Conlon, Kevin P; Basrur, Venkatesha; Rolland, Delphine; Wolfe, Thomas; Nesvizhskii, Alexey I; MacCoss, Michael J; Lim, Megan S; Elenitoba-Johnson, Kojo S J

2013-10-01

Chromosomal translocations encoding chimeric fusion proteins constitute one of the most common mechanisms underlying oncogenic transformation in human cancer. Fusion peptides resulting from such oncogenic chimeric fusions, though unique to specific cancer subtypes, are unexplored as cancer biomarkers. Here we show, using an approach termed fusion peptide multiple reaction monitoring mass spectrometry, the direct identification of different cancer-specific fusion peptides arising from protein chimeras that are generated from the juxtaposition of heterologous genes fused by recurrent chromosomal translocations. Using fusion peptide multiple reaction monitoring mass spectrometry in a clinically relevant scenario, we demonstrate the specific, sensitive, and unambiguous detection of a specific diagnostic fusion peptide in clinical samples of anaplastic large cell lymphoma, but not in a diverse array of benign lymph nodes or other forms of primary malignant lymphomas and cancer-derived cell lines. Our studies highlight the utility of fusion peptides as cancer biomarkers and carry broad implications for the use of protein biomarkers in cancer detection and monitoring.

N-gramas sintácticos y su uso en la lingüistica computacional

Directory of Open Access Journals (Sweden)

Grigori Sidorov

2013-05-01

Full Text Available En este artículo, estamos introduciendo un nuevo concepto que se utilizará en la lingüística computacional, se llama n-gramas sintácticos: son n-gramas que se construyen siguiendo un árbol sintáctico. Es equivalente a introducir la información sintáctica en los métodos de aprendizaje automático, que siempre era un problema muy difícil. Discutimos los elementos que pueden formar estos n-gramas: palabras, clases gramaticales (POS tags, nombres de relaciones sintácticas, caracteres. Consideramos dos ejemplos de cómo se puede obtener los n-gramas sintácticos basándonos en un árbol sintáctico, tanto para el español como para el inglés. Adicionalmente, presentamos un modelo más utilizando de solución de problemas de la lingüística computacional, específicamente, el modelo de espacio vectorial.

Pokemon proto-oncogene in oral cancer: potential role in the early phase of tumorigenesis.

Science.gov (United States)

Sartini, D; Lo Muzio, L; Morganti, S; Pozzi, V; Di Ruscio, G; Rocchetti, R; Rubini, C; Santarelli, A; Emanuelli, M

2015-05-01

Oral squamous cell carcinoma (OSCC) represents about 90% of all oral neoplasms with a poor clinical prognosis. To improve survival of OSCC patients, it is fundamental to understand the basic molecular mechanisms characterizing oral carcinogenesis. Dysregulation of oncogenes and tumor suppressor genes seems to play a central role in tumorigenesis, including malignant transformation of the oral cavity. We analyzed the expression levels of the pro-oncogenic transcription factor Pokemon through real-time PCR, Western blot and immunohistochemistry in tumor, and normal oral tissue samples obtained from 22 patients with OSCC. The relationship between tumor characteristics and the level of Pokemon intratumor expression was also analyzed. Pokemon was significantly downregulated in OSCC. In particular, both mRNA and protein levels (tumor vs normal tissue) inversely correlated with histological grading, suggesting its potential role as a prognostic factor for OSCC. Moreover, a significant inverse correlation was found between Pokemon protein expression levels (OSCC vs normal oral mucosa) and tumor size, supporting the hypothesis that Pokemon could play an important role in the early phase of tumor expansion. This work shows that reduced expression of Pokemon is a peculiar feature of OSCC. Additional studies may establish the effective role of Pokemon in oral tumorigenesis. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Consideraciones sobre la naturaleza de los núcleos sintácticos. Hacia una representación sintáctica de dependencias

Directory of Open Access Journals (Sweden)

Marina Lloberes

2012-01-01

Full Text Available En el análisis sintáctico automático, la definición de criterios lingüísticos para gramáticas basadas en conocimiento lingüístico permite de desarrollar recursos coherentes y consistentes. La construcción de EsTxala y CaTxala, dos gramáticas de dependencias del español y del catalán para FreeLing (un entorno de herramientas de Procesamiento del Lenguaje Natural, se ha llevado a cabo según el diseño previo de un repertorio de criterios ecléctico y crítico en relación con algunos de los formalismos lingüísticos implementados en el análisis automático del lenguaje, la Gramática de Dependencias y la Gramática Generativa. El objetivo de dicho repertorio es facilitar la coherencia y la consistencia de la representación sintáctica en el desarrollo de gramáticas para el análisis sintáctico automático.

MHD stability studies in the Proto S-1 A/B device

International Nuclear Information System (INIS)

Munson, C.; Janos, A.; Newhouse, M.; Salberta, E.; Wysocki, F.; Yamada, M.

1982-01-01

An experimental study of the gross MHD stability properties of Spheromak plasmas in the Proto S-1 A/B device is presented. Utilizing the previously demonstrated S-1 slow formation technique, plasmas have been produced which exhibit the predicted tilting instability in a regime of slightly negative field index. A relatively simple passive coil system suggested by numerical stability studies has proven to be effective in stabilizing the observed tilting mode

PROTO-II: a short pulse water insulated accelerator

International Nuclear Information System (INIS)

Martin, T.H.; VanDevender, J.P.; Johnson, D.L.; McDaniel, D.H.; Aker, M.

1975-01-01

A new accelerator, designated Proto-II, is presently under construction at Sandia Laboratories. Proto-II will have a nominal output of 100 kJ into a two-sided diode at a voltage of 1.5 MV and a total current of over 6 MA for 24 ns. This accelerator will be utilized for electron beam fusion experiments and for pulsed power and developmental studies leading to a proposed further factor of five scale-up in power. The design of Proto-II is based upon recent water switching developments and represents a 10-fold extrapolation of those results. Initial testing of Proto-II is scheduled to begin in 1976. Proto-II power flow starts with eight Marx generators which charge 16 water-insulated storage capacitors. Eight triggered, 3 MV, SF 6 gas-insulated switches next transfer the energy through oil-water interfaces into the first stage of 16 parallel lines. Next, the 16 first stages transfer their energy into the pulse forming lines and fast switching sections.The energy is then delivered to two converging, back-to-back, disk-shaped transmission line. Two back-to-back diodes then form the electron beams which are focused onto a common anode

Change of mitotic cycle and DNA repair in embryonic cells of rat, immortalized by E1 A oncogene and transformated by E1 A and c-Ha-Ras oncogenes under ionizing radiation action

International Nuclear Information System (INIS)

Kirillova, T.V.

1997-01-01

Comparison investigation into the repair of mitotic cycle and the reunion of DN single- and double-strand breaks in gamma-ray irradiated initial E1 A oncogene immortalized and E1 A and c-Ha-Ras oncogene transformed (mutant form) lines of rat embryonic fibroblasts was carried out. Possible involvement of Ras gene product in DNA repair speed governing and absence of tumor suppression function of p 53 protein in the embryonic and E1 A oncogene immortalized cells of rat fibroblast, as well as, presence of the mentioned function of p 53 protein in E1 A and c-Ha-Ras oncogene transformed cells were studied [ru

Oncogenic activation of v-kit involves deletion of a putative tyrosine-substrate interaction site.

Science.gov (United States)

Herbst, R; Munemitsu, S; Ullrich, A

1995-01-19

The transforming gene of the Hardy-Zuckerman-4 strain of feline sarcoma virus, v-kit, arose by transduction of the cellular c-kit gene, which encodes the receptor tyrosine kinase (RTK) p145c-kit. To gain insight into the molecular basis of the v-kit transforming potential, we characterized the feline c-kit by cDNA cloning. Comparison of the feline v-kit and c-kit sequences revealed, in addition to deletions of the extracellular and transmembrane domains, three additional mutations in the v-kit oncogene product: deletion of tyrosine-569 and valine-570, the exchange of aspartate at position 761 to glycine, and replacement of the C-terminal 50 amino acids by five unrelated residues. Examinations of individual v-kit mutations in the context of chimeric receptors yielded inhibitory effects for some mutants on both autophosphorylation and substrate phosphorylation functions. In contrast, deletion of tyrosine-569 and valine-570 significantly enhanced transforming and mitogenic activities of p145c-kit, while the other mutations had no significant effects. Conservation in subclass III RTKs and the identification of the corresponding residue in beta PDGF-R, Y579, as a binding site for src family tyrosine kinases suggests an important role for Y568 in kit signal regulation and the definition of its oncogenic potential. Repositioning of Y571 by an inframe two codon deletion may be the crucial alteration resulting in enhancement of v-kit oncogenic activity.

Oncogenic Notch signaling in T-cell and B-cell lymphoproliferative disorders.

Science.gov (United States)

Chiang, Mark Y; Radojcic, Vedran; Maillard, Ivan

2016-07-01

This article highlights recent discoveries about Notch activation and its oncogenic functions in lymphoid malignancies, and discusses the therapeutic potential of Notch inhibition. NOTCH mutations arise in a broad spectrum of lymphoid malignancies and are increasingly scrutinized as putative therapeutic targets. In T-cell acute lymphoblastic leukemia (T-ALL), NOTCH1 mutations affect the extracellular negative regulatory region and lead to constitutive Notch activation, although mutated receptors remain sensitive to Notch ligands. Other NOTCH1 mutations in T-ALL and NOTCH1/2 mutations in multiple B-cell malignancies truncate the C-terminal proline (P), glutamic acid (E), serine (S), threonine (T)-rich (PEST) domain, leading to decreased Notch degradation after ligand-mediated activation. Thus, targeting Notch ligand-receptor interactions could provide therapeutic benefits. In addition, we discuss recent reports on clinical testing of Notch inhibitors in T-ALL that influenced contemporary thinking on the challenges of targeting Notch in cancer. We review advances in the laboratory to address these challenges in regards to drug targets, the Notch-driven metabolome, and the sophisticated protein-protein interactions at Notch-dependent superenhancers that underlie oncogenic Notch functions. Notch signaling is a recurrent oncogenic pathway in multiple T- and B-cell lymphoproliferative disorders. Understanding the complexity and consequences of Notch activation is critical to define optimal therapeutic strategies targeting the Notch pathway.

Ludwik Fleck on proto-ideas in medicine

DEFF Research Database (Denmark)

Brorson, S

2000-01-01

and his nominalist view on medical taxonomy. Finally, I discuss four philosophical problems implied by Fleck's concept of proto-ideas: (a) the problem of combining two conflicting perspectives on the history of science (b) the problem of accounting for the notion of 'continuity' within a nonrealist theory......'Proto-idea' was a central concept in the thinking of the Polish microbiologist and philosopher of science Ludwik Fleck (1896-1961). Based on studies of the origin of the modern concept of syphilis, Fleck claimed that many established scientific facts are best understood as interpretations...... of prescientific, somewhat hazy 'proto-ideas' in the framework of a certain 'thought-style'. As an example, Fleck saw the modern knowledge of infection as an interpretation of the ancient proto-idea of diseases as caused by minute 'animalcules'. However, the epistemological aspects of the concept of proto-ideas...

Copy Number Analysis of 24 Oncogenes: MDM4 Identified as a Putative Marker for Low Recurrence Risk in Non Muscle Invasive Bladder Cancer

Directory of Open Access Journals (Sweden)

Samanta Salvi

2014-07-01

Full Text Available Patients with non-muscle invasive bladder cancer (NMIBC generally have a high risk of relapsing locally after primary tumor resection. The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease. We studied the copy number variations (CNVs of 24 oncogenes (MDM4, MYCN, ALK, PDGFRA, KIT, KDR, DHFR, EGFR, MET, SMO, FGFR1, MYC, ABL1, RET, CCND1, CCND2, CDK4, MDM2, AURKB, ERBB2, TOP2A, AURKA, AR and BRAF using multiplex ligation probe amplification technique to verify their role as predictive markers of recurrence. Formalin-fixed paraffin-embedded tissue samples from 43 patients who underwent transurethral resection of the bladder (TURB were used; 23 patients had relapsed and 20 were disease-free after 5 years. Amplification frequencies were analyzed for all genes and MDM4 was the only gene that showed significantly higher amplification in non recurrent patients than in recurrent ones (0.65 vs. 0.3; Fisher’s test p = 0.023. Recurrence-free survival analysis confirmed the predictive role of MDM4 (log-rank test p = 0.041. Our preliminary results indicate a putative role for the MDM4 gene in predicting local recurrence of bladder cancer. Confirmation of this hypothesis is needed in a larger cohort of NMIBC patients.

Intragenic origins due to short G1 phases underlie oncogene-induced DNA replication stress.

Science.gov (United States)

Macheret, Morgane; Halazonetis, Thanos D

2018-03-01

Oncogene-induced DNA replication stress contributes critically to the genomic instability that is present in cancer. However, elucidating how oncogenes deregulate DNA replication has been impeded by difficulty in mapping replication initiation sites on the human genome. Here, using a sensitive assay to monitor nascent DNA synthesis in early S phase, we identified thousands of replication initiation sites in cells before and after induction of the oncogenes CCNE1 and MYC. Remarkably, both oncogenes induced firing of a novel set of DNA replication origins that mapped within highly transcribed genes. These ectopic origins were normally suppressed by transcription during G1, but precocious entry into S phase, before all genic regions had been transcribed, allowed firing of origins within genes in cells with activated oncogenes. Forks from oncogene-induced origins were prone to collapse, as a result of conflicts between replication and transcription, and were associated with DNA double-stranded break formation and chromosomal rearrangement breakpoints both in our experimental system and in a large cohort of human cancers. Thus, firing of intragenic origins caused by premature S phase entry represents a mechanism of oncogene-induced DNA replication stress that is relevant for genomic instability in human cancer.

O tecido sintático "Tecendo a manhã"

Directory of Open Access Journals (Sweden)

Mercedes Sanfelice Risso

2001-02-01

Full Text Available

O artigo é uma análise do poema "Tecendo a Manhã", de João Cabral de Melo Neto, em que a organização sintática é tomada como principal fator verbal caracterizadorda construção da mensagem poética e dlrecionador de outros constituintes lingüísticos a ele assimilados. A tessitura sintática, apoiada em mecanismos variados de coesão e remontagem de estruturas, é vista como expressão forte do artesanato poético a revelar, plasticamente, um outro trabalho artesanal: o dos galos unidos na composição solidária e gradativa da manhã.

Oncogenic events associated with endometrial and ovarian cancers are rare in endometriosis

DEFF Research Database (Denmark)

Vestergaard, Anna Lindeløv; Thorup, Katrine; Knudsen, Ulla Breth

2011-01-01

Endometriosis displays some features that resemble malignant processes, including invasive growth, resistance to apoptosis, and distant implantation. The objective of this study was to investigate whether gene alterations that are frequent in endometrial and/or ovarian cancers contribute to the p......Endometriosis displays some features that resemble malignant processes, including invasive growth, resistance to apoptosis, and distant implantation. The objective of this study was to investigate whether gene alterations that are frequent in endometrial and/or ovarian cancers contribute...... to the pathogenesis of endometriosis. Biopsies were obtained from ectopic endometriosis lesions from 23 patients with revised American Fertility Score (rAFS) stage 1 (N=1), 2 (N=10), 3 (N=11), or 4 (N=1) endometriosis. Six genes (APC, CDKN2A, PYCARD, RARB, RASSF1, and ESR1) were analyzed for promoter hypermethylation...... in a single lesion. No gene alterations were found in the remaining samples. Our data suggest that genetic and epigenetic events contributing to endometrial and ovarian cancers are rare in endometriosis. However, other proto-oncogenes and tumor suppressor genes should be tested for alterations in order...

Effects of 12-O-tetradecanoyl-phorbol-13-acetate [corrected] and sodium lauryl sulfate on the production and expression of cytokines and proto-oncogenes in photoaged and intrinsically aged human keratinocytes.

Science.gov (United States)

Suh, D H; Youn, J I; Eun, H C

2001-11-01

Skin aging may be divided into photoaging and intrinsic aging. The purpose of this study was to investigate the effects of 12-O-tetradecanoyl-phorbol-13-acetate and sodium lauryl sulfate on the production and expression of cytokines and proto-oncogenes in photoaged and intrinsically aged skin, compared with young skin. Keratinocytes were taken from newborns, young adults in their twenties, and from the forearm and thigh of volunteers in their fifties and seventies. Interleukin-1alpha and -6, and interleukin-1 receptor antagonist, c-fos and c-myc were measured after cultured keratinocytes had been treated with 12-O-tetradecanoyl-phorbol-13-acetate and sodium lauryl sulfate. There has been no report concerning the dependence of cytokine production by sodium lauryl sulfate upon photoaging and intrinsic aging. This study also involves the first investigation of the effects of aging on c-myc expression by 12-O-tetradecanoyl-phorbol-13-acetate treatment. Cytokine production decreased markedly with age. These results suggest the progressive decline of cellular function with age. The ratio of cytokine production in the irritant-treated group compared with that in the control group showed a different pattern in photoaging and intrinsic aging. With the significant difference between photoaging and intrinsic aging, T/C ratio decreased in interleukin-1alpha and interleukin-1 receptor antagonist upon aging, whereas it increased in interleukin-6. S/C ratio was uniquely elevated on photoaged skin in the 50 y age group. It is suggested that photoaged skin shows an exaggerated reaction to surfactant. Compared with the control, c-fos expression in 12-O-tetradecanoyl-phorbol-13-acetate-treated keratinocytes decreased with age in the thigh, but increased in the photoaged skin of forearm. The increased c-fos expression in 12-O-tetradecanoyl-phorbol-13-acetate-treated keratinocytes could be relevant for the predisposition of photoaged keratinocytes to malignant transformation.

Chikungunya virus outbreak in Sint Maarten, 2013–2014

Directory of Open Access Journals (Sweden)

Maria Henry

2017-08-01

Full Text Available ABSTRACT This report describes the outbreak of chikungunya virus (CHIKV in Sint Maarten, a constituent country of Kingdom of the Netherlands comprising the southern part of the Caribbean island of Saint Martin, from 22 December 2013 (first reported case through 5 December 2014. The outbreak was first reported by the French overseas collectivity of Saint-Martin in the northern part of the island—the first site in the Americas to report autochthonous transmission of CHIKV. By 5 December 2014, Sint Maarten had reported a total of 658 cases—an overall attack rate of 1.76%. Actual prevalence may have been higher, as some cases may have been misdiagnosed as dengue. Fever and arthralgia affected 71% and 69% of reported cases respectively. Of the 390 laboratory-confirmed cases, 61% were female and the majority were 20–59 years old (mean: 42; range: 4–92. The spread of CHIKV to Sint Maarten was inevitable given the ease of movement of people, and the vector, island-wide. Continuing their history of collaboration, the French and Dutch parts of the island coordinated efforts for prevention and control of the disease. These included a formal agreement to exchange epidemiological information on a regular basis and provide alerts in a timely manner; collaboration among personnel through joint island-wide planning of mosquito control activities, especially along borders; notification of all island visitors, upon their arrival at airports and seaports, of preventative measures to avoid being bitten by mosquitoes; dissemination of educational materials to the public; and island-wide public awareness campaigns, particularly in densely populated areas, for both residents and visitors. The information provided in this report could help increase understanding of the epidemiological characteristics of CHIKV and guide other countries dealing with vector-borne epidemics.

Proto-cooperation

DEFF Research Database (Denmark)

Herbert-Read, James E; Romanczuk, Pawel; Krause, Stefan

2016-01-01

beneficial if the cost of attacking is high, and only then when waiting times are short. Our findings provide evidence that cooperative benefits can be realized through the facilitative effects of individuals' hunting actions without spatial coordination of attacks. Such 'proto-cooperation' may be the pre...

Characteristics of the mouse genomic histamine H1 receptor gene

Energy Technology Data Exchange (ETDEWEB)

Inoue, Isao; Taniuchi, Ichiro; Kitamura, Daisuke [Kyushu Univ., Fukuoka (Japan)] [and others

1996-08-15

We report here the molecular cloning of a mouse histamine H1 receptor gene. The protein deduced from the nucleotide sequence is composed of 488 amino acid residues with characteristic properties of GTP binding protein-coupled receptors. Our results suggest that the mouse histamine H1 receptor gene is a single locus, and no related sequences were detected. Interspecific backcross analysis indicated that the mouse histamine H1 receptor gene (Hrh1) is located in the central region of mouse Chromosome 6 linked to microphthalmia (Mitfmi), ras-related fibrosarcoma oncogene 1 (Raf1), and ret proto-oncogene (Ret) in a region of homology with human chromosome 3p. 12 refs., 3 figs.

The Emergence of a Proto-institution

DEFF Research Database (Denmark)

Boxenbaum, Eva

2004-01-01

of inter-organizational networks, and actors embedded in multiple fields. The making of the proto-institution is intentional, yet the institutional building blocks and the apparent interests of actors are institutionally embedded. The results from this micro-dynamic analysis suggest revisions to current...... conceptualizations of institutional change processes. Keywords: Institutional change, proto-institution, cognition, institutional entrepreneurship, innovation, collaborative networks....

The Homeodomain Transcription Factor Cdx1 Does Not Behave as an Oncogene in Normal Mouse Intestine1

Science.gov (United States)

Crissey, Mary Ann S; Guo, Rong-Jun; Fogt, Franz; Li, Hong; Katz, Jonathan P; Silberg, Debra G; Suh, Eun Ran; Lynch, John P

2008-01-01

The Caudal-related homeobox genes Cdx1 and Cdx2 are intestine-specific transcription factors that regulate differentiation of intestinal cell types. Previously, we have shown Cdx1 to be antiproliferative and to promote cell differentiation. However, other studies have suggested that Cdx1 may be an oncogene. To test for oncogenic behavior, we used the murine villin promoter to ectopically express Cdx1 in the small intestinal villi and colonic surface epithelium. No changes in intestinal architecture, cell differentiation, or lineage selection were observed with expression of the transgene. Classic oncogenes enhance proliferation and induce tumors when ectopically expressed. However, the Cdx1 transgene neither altered intestinal proliferation nor induced spontaneous intestinal tumors. In a murine model for colitis-associated cancer, the Cdx1 transgene decreased, rather than increased, the number of adenomas that developed. In the polyps, the expression of the endogenous and the transgenic Cdx1 proteins was largely absent, whereas endogenous Villin expression was retained. This suggests that transgene silencing was specific and not due to a general Villin inactivation. In conclusion, neither the ectopic expression of Cdx1 was associated with changes in intestinal cell proliferation or differentiation nor was there increased intestinal cancer susceptibility. Our results therefore suggest that Cdx1 is not an oncogene in normal intestinal epithelium. PMID:18231635

Suppressor of cytokine signaling 1 interacts with oncogenic lymphocyte-specific protein tyrosine kinase.

Science.gov (United States)

Venkitachalam, Srividya; Chueh, Fu-Yu; Leong, King-Fu; Pabich, Samantha; Yu, Chao-Lan

2011-03-01

Lymphocyte-specific protein tyrosine kinase (Lck) plays a key role in T cell signal transduction and is tightly regulated by phosphorylation and dephosphorylation. Lck can function as an oncoprotein when overexpressed or constantly activated by mutations. Our previous studies showed that Lck-induced cellular transformation could be suppressed by enforced expression of suppressor of cytokine signaling 1 (SOCS1), a SOCS family member involved in the negative feedback control of cytokine signaling. We observed attenuated Lck kinase activity in SOCS1-expressing cells, suggesting an important role of SOCS in regulating Lck functions. It remains largely unknown whether and how SOCS proteins interact with the oncogenic Lck kinase. Here, we report that among four SOCS family proteins, SOCS1, SOCS2, SOCS3 and CIS (cytokine-inducible SH2 domain containing protein), SOCS1 has the highest affinity in binding to the oncogenic Lck kinase. We identified the positive regulatory phosphotyrosine 394 residue in the kinase domain as the key interacting determinant in Lck. Additionally, the Lck kinase domain alone is sufficient to bind SOCS1. While the SH2 domain in SOCS1 is important in its association with the oncogenic Lck kinase, other functional domains may also contribute to overall binding affinity. These findings provide important mechanistic insights into the role of SOCS proteins as tumor suppressors in cells transformed by oncogenic protein tyrosine kinases.

Relaxation and particle diffusion in the Proto S-1/C spheromak

International Nuclear Information System (INIS)

Meyerhofer, D.D.

1987-01-01

The relationship between relaxation and particle diffusion in the Proto S-1C spheromak has been studied. The plasma was formed in a magnetic configuration which was not the minimum-energy Taylor state, and went through a period of relaxation before its magnetic configuration was that of the Taylor state. Early in the relaxation phase, the internal and external magnetic fluctuations were correlated and it was found that, at the time of peak amplitude, they had a radial structure of a tearing mode. After the reconnection of these modes, the plasma continued to evolve towards the Taylor state with only small magnetic fluctuations at the center of plasma. The local particle diffusion coefficient was measured in these Proto S-1C discharges, the technique used was to inject a delta-function source of impurities into the plasma and observe the motion of the impurities relative to the flux surface. It was found that, during the decay phase of the spheromak discharge, when the plasma was in a Taylor state, the carbon diffusion coefficient was explained classically. While the plasma was relaxing towards the Taylor state, the diffusion coefficient was 2 ∼ 4a times larger than classical. At this time, the plasma was not yet force-free. This nonclassical diffusion appears to have been caused by v/sub ExB/ velocities due to correlations between the fluctuating electric field and density. Because the v/sub ExB/ velocity acts on all of the plasma species similarly, the anomalous hydrogen-particle diffusion coefficient should have been as large as that of carbon

Characterization of LAF-4, a Putative Proto-Oncogene Involved in the Development of Breast Cancer

National Research Council Canada - National Science Library

Andrulis, Irene

2001-01-01

The long range goal of our research is to identify genes involved in the early stages of breast cancer development, specifically genes involved in the transition from hyperplasia to ductal carcinoma in-situ (DCIS...

Identifying Breast Cancer Oncogenes

Science.gov (United States)

2011-10-01

cells we observed that it promoted transformation of HMLE cells, suggesting a tumor suppressive role of Merlin in breast cancer (Figure 4B). A...08-1-0767 TITLE: Identifying Breast Cancer Oncogenes PRINCIPAL INVESTIGATOR: Yashaswi Shrestha...Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 W81XWH-08-1-0767 Identifying Breast Cancer Oncogenes Yashaswi Shrestha Dana-Farber

Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL.

Science.gov (United States)

Della Gatta, Giusy; Palomero, Teresa; Perez-Garcia, Arianne; Ambesi-Impiombato, Alberto; Bansal, Mukesh; Carpenter, Zachary W; De Keersmaecker, Kim; Sole, Xavier; Xu, Luyao; Paietta, Elisabeth; Racevskis, Janis; Wiernik, Peter H; Rowe, Jacob M; Meijerink, Jules P; Califano, Andrea; Ferrando, Adolfo A

2012-02-26

The TLX1 and TLX3 transcription factor oncogenes have a key role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). Here we used reverse engineering of global transcriptional networks to decipher the oncogenic regulatory circuit controlled by TLX1 and TLX3. This systems biology analysis defined T cell leukemia homeobox 1 (TLX1) and TLX3 as master regulators of an oncogenic transcriptional circuit governing T-ALL. Notably, a network structure analysis of this hierarchical network identified RUNX1 as a key mediator of the T-ALL induced by TLX1 and TLX3 and predicted a tumor-suppressor role for RUNX1 in T cell transformation. Consistent with these results, we identified recurrent somatic loss-of-function mutations in RUNX1 in human T-ALL. Overall, these results place TLX1 and TLX3 at the top of an oncogenic transcriptional network controlling leukemia development, show the power of network analyses to identify key elements in the regulatory circuits governing human cancer and identify RUNX1 as a tumor-suppressor gene in T-ALL.

Protos2CPN: using colored Petri nets for confuguring and testing business processes

NARCIS (Netherlands)

Gottschalk, F.; Aalst, van der W.M.P.; Vullers - Jansen, M.H.; Verbeek, H.M.W.

2008-01-01

Protos is a popular tool for business process modelling used in more than 1,500 organizations. It has a built-in Petri-net-based simulation engine which shows key performance indicators for the modelled processes. Reference process models offered for Protos reduce modelling efforts by providing

Energy Transition Initiative: Island Energy Snapshot - Saint Martin/Sint Maarten

Energy Technology Data Exchange (ETDEWEB)

2015-09-01

This profile provides a snapshot of the energy landscape of the northeast Caribbean island Saint Martin. The island is divided between two nations, France in the north (Saint-Martin) and the Netherlands in the south (Sint Maarten).

An analysis of community perceptions of mosquito-borne disease control and prevention in Sint Eustatius, Caribbean Netherlands.

NARCIS (Netherlands)

Leslie, Teresa E; Carson, Marianne; Coeverden, Els van; De Klein, Kirsten; Braks, Marieta; Krumeich, Anja

2017-01-01

In the Caribbean, mosquito-borne diseases are a public health threat. In Sint Eustatius, dengue, Chikungunya and Zika are now endemic. To control and prevent mosquito-borne diseases, the Sint Eustatius Public Health Department relies on the community to assist with the control of Aedes aegypti

Transforming properties of Felis catus papillomavirus type 2 E6 and E7 putative oncogenes in vitro and their transcriptional activity in feline squamous cell carcinoma in vivo

Energy Technology Data Exchange (ETDEWEB)

Altamura, Gennaro, E-mail: gennaro.altamura@unina.it [Department of Veterinary Medicine and Animal Productions, General Pathology and Pathological Anatomy Unit, University of Naples Federico II, Via Delpino 1, 80137 Naples (Italy); Corteggio, Annunziata, E-mail: ancorteg@unina.it [Department of Veterinary Medicine and Animal Productions, General Pathology and Pathological Anatomy Unit, University of Naples Federico II, Via Delpino 1, 80137 Naples (Italy); Pacini, Laura, E-mail: PaciniL@students.iarc.fr [Infections and Cancer Biology Group, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon (France); Conte, Andrea, E-mail: andreaconte88@hotmail.it [Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Pansini 5, 80131 Naples (Italy); Pierantoni, Giovanna Maria, E-mail: gmpieran@unina.it [Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Pansini 5, 80131 Naples (Italy); Tommasino, Massimo, E-mail: tommasinom@iarc.fr [Infections and Cancer Biology Group, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon (France); Accardi, Rosita, E-mail: accardir@iarc.fr [Infections and Cancer Biology Group, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon (France); Borzacchiello, Giuseppe, E-mail: borzacch@unina.it [Department of Veterinary Medicine and Animal Productions, General Pathology and Pathological Anatomy Unit, University of Naples Federico II, Via Delpino 1, 80137 Naples (Italy)

2016-09-15

Felis catus papillomavirus type 2 (FcaPV2) DNA is found in feline cutaneous squamous cell carcinomas (SCCs); however, its biological properties are still uncharacterized. In this study, we successfully expressed FcaPV2 E6 and E7 putative oncogenes in feline epithelial cells and demonstrated that FcaPV2 E6 binds to p53, impairing its protein level. In addition, E6 and E7 inhibited ultraviolet B (UVB)-triggered accumulation of p53, p21 and pro-apoptotic markers such as Cleaved Caspase3, Bax and Bak, suggesting a synergistic action of the virus with UV exposure in tumour pathogenesis. Furthermore, FcaPV2 E7 bound to feline pRb and impaired pRb levels, resulting in upregulation of the downstream pro-proliferative genes Cyclin A and Cdc2. Importantly, we demonstrated mRNA expression of FcaPV2 E2, E6 and E7 in feline SCC samples, strengthening the hypothesis of a causative role in the development of feline SCC. - Highlights: • FcaPV2 E6 binds to and deregulates feline p53 protein. • FcaPV2 E7 binds to and deregulates feline pRb protein. • FcaPV2 oncogenes inhibit UVB-induced apoptosis. • FcaPV2 E6E7 and E7 increase the lifespan of primary cells. • FcaPV2 E2, E6 and E7 are expressed at the mRNA level in feline SCC in vivo.

Descoloração de efluentes têxteis sintéticos por catálise enzimática

OpenAIRE

Silva, Maria Cristina; Corrêa, Angelita D.; Amorim, M. T. Pessoa de; Oliveira, Sara L. C.; Duarte, António A. L. Sampaio; Torres, Juliana A.

2010-01-01

Peroxidases podem ser utilizadas em processos de descoloração no tratamento de efluentes têxteis. Há um interesse crescente por novas fontes desta enzima, e por processos de obtenção viáveis economicamente.1Neste trabalho o potencial de descoloração de efluentes têxteis sintéticos por peroxidase extraída de nabo (Brassica campestre ssp. rapifera) é avaliado. Para a obtenção da enzima de baixa pureza utiliza-se um processo de baixo custo, Os efluentes utilizados nos ensaios são efluentes sinté...

Human microRNA oncogenes and tumor suppressors show significantly different biological patterns: from functions to targets.

Directory of Open Access Journals (Sweden)

Dong Wang

Full Text Available MicroRNAs (miRNAs are small noncoding RNAs which play essential roles in many important biological processes. Therefore, their dysfunction is associated with a variety of human diseases, including cancer. Increasing evidence shows that miRNAs can act as oncogenes or tumor suppressors, and although there is great interest in research into these cancer-associated miRNAs, little is known about them. In this study, we performed a comprehensive analysis of putative human miRNA oncogenes and tumor suppressors. We found that miRNA oncogenes and tumor suppressors clearly show different patterns in function, evolutionary rate, expression, chromosome distribution, molecule size, free energy, transcription factors, and targets. For example, miRNA oncogenes are located mainly in the amplified regions in human cancers, whereas miRNA tumor suppressors are located mainly in the deleted regions. miRNA oncogenes tend to cleave target mRNAs more frequently than miRNA tumor suppressors. These results indicate that these two types of cancer-associated miRNAs play different roles in cancer formation and development. Moreover, the patterns identified here can discriminate novel miRNA oncogenes and tumor suppressors with a high degree of accuracy. This study represents the first large-scale bioinformatic analysis of human miRNA oncogenes and tumor suppressors. Our findings provide help for not only understanding of miRNAs in cancer but also for the specific identification of novel miRNAs as miRNA oncogenes and tumor suppressors. In addition, the data presented in this study will be valuable for the study of both miRNAs and cancer.

Oncogenes, radiation and cancer; Oncogenes, radiacion y cancer

Energy Technology Data Exchange (ETDEWEB)

Michelin, S C

1999-12-31

The discovery of the oncogenic virus and the analysis of its nucleic acid, together with the development of new biochemical technology have permitted the partial knowledge of the molecular mechanisms responsible for the cellular neoplastic transformation. This work, besides describing the discovery of the first oncogenic virus and the experiments to demonstrate the existence of the oncogenes, summarizes its activation mechanisms and its intervention in cellular metabolisms. Ionizing radiation is among the external agents that induce the neoplastic process. Its participation in the genesis of this process and the contribution of oncogenes to the cellular radioresistance are among the topics, which are referred to another topic that makes reference. At the same time as the advancement of theoretical knowledge, lines of investigation for the application of the new concepts in diagnosis, prognosis and therapeutical treatment, were developed. An example of this, is the study of the participation of the oncogen c-erbB-2 in human breast cancer and its implications on the anti tumoral therapy. (author) 87 refs., 7 figs., 3 tabs. [Espanol] El descubrimiento de los virus oncogenicos y el analisis de su acido nucleico, junto con el desarrollo de nuevas tecnicas bioquimicas, ha permitido conocer parcialmente los mecanismos moleculares responsables de la transformacion de una celula normal en neoplasica. En este trabajo, ademas de describir el descubrimiento de los primeros virus oncogenicos y las experiencias para demostrar la existencia de los oncogenes, se resumen sus mecanismos de activacion y su intervencion en el metabolismo celular. Entre los agentes expernos que inducen un proceso oncogenico, se encuentran las radiaciones ionizantes. Su participacion en la genesis de este proceso y la contribucion de los oncogenes a la radioresistencia de las celulas tumorales, es otro de los temas a que se hace referencia. Paralelamente al avance del conocimiento teorico, se

First results from the Thomson scattering diagnostic on proto-MPEX

Energy Technology Data Exchange (ETDEWEB)

Biewer, T. M., E-mail: biewertm@ornl.gov; Meitner, S.; Rapp, J. [Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831 (United States); Ray, H.; Shaw, G. [Bredesen Center, University of Tennessee, Knoxville, Tennessee 37996 (United States)

2016-11-15

A Thomson scattering (TS) diagnostic has been successfully implemented on the prototype Material Plasma Exposure eXperiment (Proto-MPEX) at Oak Ridge National Laboratory. The diagnostic collects the light scattered by plasma electrons and spectroscopically resolves the Doppler shift imparted to the light by the velocity of the electrons. The spread in velocities is proportional to the electron temperature, while the total number of photons is proportional to the electron density. TS is a technique used on many devices to measure the electron temperature (T{sub e}) and electron density (n{sub e}) of the plasma. A challenging aspect of the technique is to discriminate the small number of Thomson scattered photons against the large peak of background photons from the high-power laser used to probe the plasma. A variety of methods are used to mitigate the background photons in Proto-MPEX, including Brewster angled windows, viewing dumps, and light baffles. With these methods, first results were measured from argon plasmas in Proto-MPEX, indicating T{sub e} ∼ 2 eV and n{sub e} ∼ 1 × 10{sup 19} m{sup −3}. The configuration of the Proto-MPEX TS diagnostic will be described and plans for improvement will be given.

ProtoMD: A prototyping toolkit for multiscale molecular dynamics

Science.gov (United States)

Somogyi, Endre; Mansour, Andrew Abi; Ortoleva, Peter J.

2016-05-01

ProtoMD is a toolkit that facilitates the development of algorithms for multiscale molecular dynamics (MD) simulations. It is designed for multiscale methods which capture the dynamic transfer of information across multiple spatial scales, such as the atomic to the mesoscopic scale, via coevolving microscopic and coarse-grained (CG) variables. ProtoMD can be also be used to calibrate parameters needed in traditional CG-MD methods. The toolkit integrates 'GROMACS wrapper' to initiate MD simulations, and 'MDAnalysis' to analyze and manipulate trajectory files. It facilitates experimentation with a spectrum of coarse-grained variables, prototyping rare events (such as chemical reactions), or simulating nanocharacterization experiments such as terahertz spectroscopy, AFM, nanopore, and time-of-flight mass spectroscopy. ProtoMD is written in python and is freely available under the GNU General Public License from github.com/CTCNano/proto_md.

Proto-2 seduces America

CERN Multimedia

2002-01-01

Proto-2, an ALICE detector prototype, overcame its prototype status to become a real part of the STAR experiment at the US Brookhaven National Laboratory. After more than two years across the ocean, it has just arrived back at CERN.

The role of hypoxia inducible factor-1 alpha in bypassing oncogene-induced senescence.

Directory of Open Access Journals (Sweden)

Mehtap Kilic Eren

Full Text Available Oncogene induced senescence (OIS is a sustained anti-proliferative response acutely induced in primary cells via activation of mitogenic oncogenes such as Ras/BRAF. This mechanism acts as an initial barrier preventing normal cells transformation into malignant cell. Besides oncogenic activation and DNA damage response (DDR, senescence is modulated by a plethora of other factors, and one of the most important one is oxygen tension of the tissue. The aim of this study was to determine the impact of hypoxia on RasV12-induced senescence in human diploid fibroblasts (HDFs. We showed here that hypoxia prevents execution of oncogene induced senescence (OIS, through a strong down-regulation of senescence hallmarks, such as SA- β-galactosidase, H3K9me3, HP1γ, p53, p21CIP1 and p16INK4a in association with induction of hypoxia inducible factor-1α (HIF-1α. In addition, hypoxia also decreased marks of H-RasV12-induced DDR in both cell lines through down-regulation of ATM/ATR, Chk1 and Chk2 phosphorylation as well as decreased γ-H2AX positivity. Utilizing shRNA system targeting HIF-1α we show that HIF-1α is directly involved in down regulation of p53 and its target p21CIP1 but not p16INK4a. In line with this finding we found that knock down of HIF-1α leads to a strong induction of apoptotic response, but not restoration of senescence in Ras expressing HDFs in hypoxia. This indicates that HIF-1α is an important player in early steps of tumorigenesis, leading to suppression of senescence through its negative regulation of p53 and p21CIP1. In our work we describe a mechanism through which hypoxia and specifically HIF-1α preclude cells from maintaining senescence-driven anti proliferative response. These findings indicate the possible mechanism through which hypoxic environment helps premalignant cells to evade impingement of cellular failsafe pathways.

[Inheritable phenotypic normalization of rodent cells transformed by simian adenovirus SA7 E1 oncogenes by singled-stranded oligonucleotides complementary to a long region of integrated oncogenes].

Science.gov (United States)

Grineva, N I; Borovkova, T V; Sats, N V; Kurabekova, R M; Rozhitskaia, O S; Solov'ev, G Ia; Pantin, V I

1995-08-01

G11 mouse cells and SH2 rat cells transformed with simian adenovirus SA7 DNA showed inheritable oncogen-specific phenotypic normalization when treated with sense and antisense oligonucleotides complementary to long RNA sequences, plus or minus strands of the integrated adenovirus oncogenes E1A and E1B. Transitory treatment of the cells with the oligonucleotides in the absence of serum was shown to cause the appearance of normalized cell lines with fibroblastlike morphology, slower cell proliferation, and lack of ability to form colonies in soft agar. Proliferative activity and adhesion of the normalized cells that established cell lines were found to depend on the concentration of growth factors in the cultural medium. In some of the cell lines, an inhibition of transcription of the E1 oncogenes was observed. The normalization also produced cells that divided 2 - 5 times and died and cells that reverted to a transformed phenotype in 2 - 10 days. The latter appeared predominantly upon the action of the antisense oligonucleotides.

Large-scale analysis by SAGE reveals new mechanisms of v-erbA oncogene action

Directory of Open Access Journals (Sweden)

Faure Claudine

2007-10-01

Full Text Available Abstract Background: The v-erbA oncogene, carried by the Avian Erythroblastosis Virus, derives from the c-erbAα proto-oncogene that encodes the nuclear receptor for triiodothyronine (T3R. v-ErbA transforms erythroid progenitors in vitro by blocking their differentiation, supposedly by interference with T3R and RAR (Retinoic Acid Receptor. However, v-ErbA target genes involved in its transforming activity still remain to be identified. Results: By using Serial Analysis of Gene Expression (SAGE, we identified 110 genes deregulated by v-ErbA and potentially implicated in the transformation process. Bioinformatic analysis of promoter sequence and transcriptional assays point out a potential role of c-Myb in the v-ErbA effect. Furthermore, grouping of newly identified target genes by function revealed both expected (chromatin/transcription and unexpected (protein metabolism functions potentially deregulated by v-ErbA. We then focused our study on 15 of the new v-ErbA target genes and demonstrated by real time PCR that in majority their expression was activated neither by T3, nor RA, nor during differentiation. This was unexpected based upon the previously known role of v-ErbA. Conclusion: This paper suggests the involvement of a wealth of new unanticipated mechanisms of v-ErbA action.

The Homeodomain Transcription Factor Cdx1 Does Not Behave as an Oncogene in Normal Mouse Intestine

Directory of Open Access Journals (Sweden)

Mary Ann S. Crissey

2008-01-01

Full Text Available The Caudal-related homeobox genes Cdx1 and Cdx2 are intestine-specific transcription factors that regulate differentiation of intestinal cell types. Previously, we have shown Cdx1 to be antiproliferative and to promote cell differentiation. However, other studies have suggested that Cdx1 may be an oncogene. To test for oncogenic behavior, we used the murine villin promoter to ectopically express Cdx1 in the small intestinal villi and colonic surface epithelium. No changes in intestinal architecture, cell differentiation, or lineage selection were observed with expression of the transgene. Classic oncogenes enhance proliferation and induce tumors when ectopically expressed. However, the Cdx1 transgene neither altered intestinal proliferation nor induced spontaneous intestinal tumors. In a murine model for colitis-associated cancer, the Cdx1 transgene decreased, rather than increased, the number of adenomas that developed. In the polyps, the expression of the endogenous and the transgenic Cdx1 proteins was largely absent, whereas endogenous Villin expression was retained. This suggests that transgene silencing was specific and not due to a general Villin inactivation. In conclusion, neither the ectopic expression of Cdx1 was associated with changes in intestinal cell proliferation or differentiation nor was there increased intestinal cancer susceptibility. Our results therefore suggest that Cdx1 is not an oncogene in normal intestinal epithelium.

WSB1 overcomes oncogene-induced senescence by targeting ATM for degradation

Science.gov (United States)

Kim, Jung Jin; Lee, Seung Baek; Yi, Sang-Yeop; Han, Sang-Ah; Kim, Sun-Hyun; Lee, Jong-Min; Tong, Seo-Yun; Yin, Ping; Gao, Bowen; Zhang, Jun; Lou, Zhenkun

2017-01-01

Oncogene-induced senescence (OIS) or apoptosis through the DNA-damage response is an important barrier of tumorigenesis. Overcoming this barrier leads to abnormal cell proliferation, genomic instability, and cellular transformation, and finally allows cancers to develop. However, it remains unclear how the OIS barrier is overcome. Here, we show that the E3 ubiquitin ligase WD repeat and SOCS box-containing protein 1 (WSB1) plays a role in overcoming OIS. WSB1 expression in primary cells helps the bypass of OIS, leading to abnormal proliferation and cellular transformation. Mechanistically, WSB1 promotes ATM ubiquitination, resulting in ATM degradation and the escape from OIS. Furthermore, we identify CDKs as the upstream kinase of WSB1. CDK-mediated phosphorylation activates WSB1 by promoting its monomerization. In human cancer tissue and in vitro models, WSB1-induced ATM degradation is an early event during tumorigenic progression. We suggest that WSB1 is one of the key players of early oncogenic events through ATM degradation and destruction of the tumorigenesis barrier. Our work establishes an important mechanism of cancer development and progression in premalignant lesions. PMID:27958289

The Protos mandate a scientific novel

CERN Document Server

Kanas, Nick

2014-01-01

In the 25th Century, the effects of overpopulation and global warming on Earth have led to the formation of human colonies on the Moon, Mars and elsewhere in the Solar System, yet the limited number of viable places forces humanity to look to the stars. A crash program has been developed to send Protos 1, a giant multigenerational starship, to a newly discovered Earth-like planet orbiting a nearby star. The plan is for awake crewmembers to run the ship, and for people in suspended animation to be roused before planetfall to use their skills in exploration and colony formation. To fulfill the goals of the mission and ensure that the in-flight population does not deplete the limited resources, the Protos Mandate is set up to govern a tightly controlled social system for the duration of the journey, which will take several generations.  But problems threaten to sabotage the mission during its launch and transit, and what finally awaits the crewmembers shocks them in an unpredictable way.  This novel chronicl...

Curtimento de peles de peixe com taninos vegetal e sintético = Tanning fish skins using vegetable and synthetic tannins

Directory of Open Access Journals (Sweden)

Ariana Martins Vieira

2008-07-01

Full Text Available No presente experimento objetivou-se avaliar a resistência das peles de peixes submetidas ao curtimento com taninos vegetal e sintético. As peles foram distribuídas em um delineamento inteiramente casualizado, com seis tratamentos aplicados na etapa decurtimento (T1 = 10% tanino vegetal; T2=10% tanino sintético; T3 = 5% tanino vegetal + 5% sintético; T4 = 12% tanino vegetal; T5 = 12% tanino sintético; T6 = 6% tanino vegetal + 6% sintético e dez repetições por tratamento, sendo o couro a unidade experimental.Para os testes de resistência à tração, alongamento e rasgamento, foi utilizado o dinamômetro EMIC. O curtimento com tanino vegetal, sintético e/ou sua combinação, assim como os níveis utilizados dentro de cada técnica de curtimento, interferiu no teste de tração, no entanto não influenciou No teste de alongamento e rasgamento progressivo. Portanto, a técnica de curtimento interfere na resistência dos couros de peixes. As peles de tilápia, quando curtidas e recurtidas apenas com tanino sintético, independentemente da concentração (10 ou 12%, apresentaram pior resistência à tração. Quando comparados com os que receberam 10% de taninos (vegetal e a combinação dos taninos, esses couros não apresentaram diferença na resistência.The objective of the present experiment was to evaluate the resistance of fish skins submitted to tanning using vegetable and synthetic tannins. Skins were distributed in a completelyrandomized design, with six treatments applied in the tanning stage (T1 = 10% vegetable tannin; T2 = 10% synthetic tannin; T3 = 5% vegetable tannin + 5% synthetic tannin; T4 = 12% vegetable tannin; T5 = 12% synthetic tannin; T6 = 6% vegetable tannin + 6% synthetic. Ten repetitions per treatment were conducted, and the leather was theexperimental unit. For the tests of tensile strength, lengthening and progressive tearing resistance, an EMIC dynamometer was used. Tanning with vegetable tannin, synthetic

Flight performance of an advanced CZT imaging detector in a balloon-borne wide-field hard X-ray telescope-ProtoEXIST1

Energy Technology Data Exchange (ETDEWEB)

Hong, J., E-mail: jaesub@head.cfa.harvard.edu [Harvard-Smithsonian Center for Astrophysics, Cambridge, MA 02138 (United States); Allen, B.; Grindlay, J. [Harvard-Smithsonian Center for Astrophysics, Cambridge, MA 02138 (United States); Barthelemy, S.; Baker, R. [NASA Goddard Space Flight Center, Greenbelt, MD 20771 (United States); Garson, A.; Krawczynski, H. [Washington University in St. Louis and the McDonnell Center for the Space Sciences, St. Louis, MO 63130 (United States); Apple, J.; Cleveland, W.H. [NASA Marshall Space Flight Center and Universities Space Research Association, Huntsville, AL 35812 (United States)

2011-10-21

We successfully carried out the first high-altitude balloon flight of a wide-field hard X-ray coded-aperture telescope ProtoEXIST1, which was launched from the Columbia Scientific Balloon Facility at Ft. Sumner, New Mexico on October 9, 2009. ProtoEXIST1 is the first implementation of an advanced CdZnTe (CZT) imaging detector in our ongoing program to establish the technology required for next generation wide-field hard X-ray telescopes such as the High Energy Telescope (HET) in the Energetic X-ray Imaging Survey Telescope (EXIST). The CZT detector plane in ProtoEXIST1 consists of an 8x8 array of closely tiled 2 cmx2 cmx0.5 cm thick pixellated CZT crystals, each with 8x8 pixels, mounted on a set of readout electronics boards and covering a 256 cm{sup 2} active area with 2.5 mm pixels. A tungsten mask, mounted at 90 cm above the detector provides shadowgrams of X-ray sources in the 30-600 keV band for imaging, allowing a fully coded field of view of 9{sup o}x9{sup o} (and 19{sup o}x19{sup o} for 50% coding fraction) with an angular resolution of 20'. In order to reduce the background radiation, the detector is surrounded by semi-graded (Pb/Sn/Cu) passive shields on the four sides all the way to the mask. On the back side, a 26 cmx26 cmx2 cm CsI(Na) active shield provides signals to tag charged particle induced events as well as {>=}100keV background photons from below. The flight duration was only about 7.5 h due to strong winds (60 knots) at float altitude (38-39 km). Throughout the flight, the CZT detector performed excellently. The telescope observed Cyg X-1, a bright black hole binary system, for {approx}1h at the end of the flight. Despite a few problems with the pointing and aspect systems that caused the telescope to track about 6.4{sup o} off the target, the analysis of the Cyg X-1 data revealed an X-ray source at 7.2{sigma} in the 30-100 keV energy band at the expected location from the optical images taken by the onboard daytime star camera. The

Relationship of ultrasonic shear wave velocity with oncogene and tumor suppressor gene expression in primary liver cancer lesions as well as angiogenesis factor contents

Directory of Open Access Journals (Sweden)

Xing Yin1

2017-06-01

Full Text Available Objective: To discuss the relationship of ultrasonic shear wave velocity (SWV with oncogene and tumor suppressor gene expression in primary liver cancer lesions as well as angiogenesis factor contents. Methods: 100 patients with primary liver cancer who underwent surgical treatment in our hospital between March 2014 and September 2016 were collected as observation group, and 50 healthy subjects who received physical examination in our hospital during the same period were collected as normal control group. The ultrasonic SWV levels of two groups of subjects were measured before the operation, and the observation groups were further divided into high SWV group and low SWV group, 50 cases in each group. Intraoperative tumor tissue samples were kept and fluorescence quantitative PCR was used to determine the mRNA expression of oncogenes and tumor suppressor genes. Enzymelinked immunosorbent assay was used to determine serum contents of angiogenesis factors in observation group before operation. Results: Hepatic ultrasonic SWV level in observation group was significantly higher than that in normal control group; proto-oncogene CK, Ki67, Gly-3, Survivin and Pokemon mRNA expression in tumor tissue of high SWV group were higher than those of low SWV group while tumor suppressor genes Tg737, p16, p27, PTEN and runx3 mRNA expression were lower than those of low SWV group; serum angiogenesis factors VEGF, MMP-9 and IGF-1R contents were higher than those in low SWV group. Conclusion: The hepatic ultrasonic SWV level increases in patients with primary liver cancer, and the SWV level is directly correlated with oncogene and tumor suppressor gene expression as well as angiogenesis factor contents.

Targeting Self-Binding Peptides as a Novel Strategy To Regulate Protein Activity and Function: A Case Study on the Proto-oncogene Tyrosine Protein Kinase c-Src.

Science.gov (United States)

Bai, Zhengya; Hou, Shasha; Zhang, Shilei; Li, Zhongyan; Zhou, Peng

2017-04-24

Previously, we have reported a new biomolecular phenomenon spanning between protein folding and binding, termed as self-binding peptides (SBPs), where a short peptide segment in monomeric protein functions as a molecular switch by dynamically binding to/unbinding from its cognate domain in the monomer (Yang et al. J. Chem. Inf. 2015, 55, 329-342). Here, we attempt to raise the SBP as a new class of druggable targets to regulate the biological activity and function of proteins. A case study was performed on the proto-oncogene nonreceptor tyrosine kinase, c-Src, which contains two SBPs that bind separately to SH3 and SH2 domains of the kinase. State-of-the-art molecular dynamics (MD) simulations and post binding energetics analysis revealed that disrupting the kinase-intramolecular interactions of SH3 and SH2 domains with their cognate SBP ligands can result in totally different effects on the structural dynamics of c-Src kinase architecture; targeting the SH2 domain unlocks the autoinhibitory form of the kinase-this is very similar to the pTyr527 dephosphorylation that functionally activates the kinase, whereas targeting the SH3 domain can only release the domain from the tightly packed kinase but has a moderate effect on the kinase activity. Subsequently, based on the cognate SBP sequence we computationally designed a number of SH2-binding phosphopeptides using a motif grafting strategy. Fluorescence polarization (FP) assay observed that most of the designed phosphopeptides have higher binding affinity to SH2 domain as compared to the native SBP segment (K d = 53 nM). Kinase assay identified a typical dose-response relationship of phosphopeptides against kinase activation, substantiating that disruption of SH2-SBP interaction can mimic c-Src dephosphorylation and activate the kinase. Two rationally designed phosphopeptides, namely EPQpYEEIEN and EPQpYEELEN, were determined as strong binders of SH2 domain (K d = 8.3 and 15 nM, respectively) and potent activators of

Oncogene mutational profile in nasopharyngeal carcinoma

Directory of Open Access Journals (Sweden)

Zhang ZC

2014-03-01

Full Text Available Zi-Chen Zhang,1,* Sha Fu,1,* Fang Wang,1 Hai-Yun Wang,1 Yi-Xin Zeng,2 Jian-Yong Shao11Department of Molecular Diagnostics, 2Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, People's Republic of China *These authors contributed equally to this work Abstract: Nasopharyngeal carcinoma (NPC is a common tumor in Southern China, but the oncogene mutational status of NPC patients has not been clarified. Using time-of-flight mass spectrometry, 238 mutation hotspots in 19 oncogenes were examined in 123 NPC patients. The relationships between mutational status and clinical data were assessed with a χ2 or Fisher's exact test. Survival analysis was performed using the Kaplan–Meier method with the log-rank test. In 123 patients, 21 (17.1% NPC tumors were positive for mutations in eight oncogenes: six patients had PIK3CA mutations (4.9%, five NRAS mutations (4.1%, four KIT mutations (3.3%, two PDGFRA mutations (1.6%, two ABL mutations (1.6%, and one with simultaneous mutations in HRAS, EGFR, and BRAF (1%. Patients with mutations were more likely to relapse or develop metastasis than those with wild-type alleles (P=0.019. No differences or correlations were found in other clinical characteristics or in patient survival. No mutations were detected in oncogenes AKT1, AKT2, CDK, ERBB2, FGFR1, FGFR3, FLT3, JAK2, KRAS, MET, and RET. These results demonstrate an association between NPC and mutations in NRAS, KIT, PIK3CA, PDGFRA, and ABL, which are associated with patient relapse and metastasis. Keywords: NPC, oncogene, mutation

Human Mut T Homolog 1 (MTH1): a roadblock for the tumor-suppressive effects of oncogenic RAS-induced ROS.

Science.gov (United States)

Rai, Priyamvada

2012-01-01

Oncogenic RAS-induced reactive oxygen species (ROS) trigger barriers to cell transformation and cancer progression through tumor-suppressive responses such as cellular senescence or cell death. We have recently shown that oncogenic RAS-induced DNA damage and attendant premature senescence can be prevented by overexpressing human MutT Homolog 1 (MTH1), the major mammalian detoxifier of the oxidized DNA precursor, 8-oxo-dGTP. Paradoxically, RAS-induced ROS are also able to participate in tumor progression via transformative processes such as mitogenic signaling, the epithelial-mesenchymal transition (EMT), anoikis inhibition, and PI3K/Akt-mediated survival signaling. Here we provide a preliminary insight into the influence of MTH1 levels on the EMT phenotype and Akt activation in RAS-transformed HMLE breast epithelial cells. Within this context, we will discuss the implications of MTH1 upregulation in oncogenic RAS-sustaining cells as a beneficial adaptive change that inhibits ROS-mediated cell senescence and participates in the maintenance of ROS-associated tumor-promoting mechanisms. Accordingly, targeting MTH1 in RAS-transformed tumor cells will not only induce proliferative defects but also potentially enhance therapeutic cytotoxicity by shifting cellular response away from pro-survival mechanisms.

Proto-ribosome: a theoretical approach based on RNA relics

OpenAIRE

Demongeot, Jacques

2017-01-01

We describe in this paper, based on already published articles, a contribution to the theory postulating the existence of a proto-ribosome, which could have appeared early at the origin of life and we discuss the interest of this notion in an evolutionary perspective, taking into account the existence of possible RNA relics of this proto-ribosome.

Could a Proto-Ribosome Emerge Spontaneously in the Prebiotic World?

Directory of Open Access Journals (Sweden)

Ilana C. Agmon

2016-12-01

Full Text Available An indispensable prerequisite for establishing a scenario of life emerging by natural processes is the requirement that the first simple proto-molecules could have had a realistic probability of self-assembly from random molecular polymers in the prebiotic world. The vestige of the proto-ribosome, which is believed to be still embedded in the contemporary ribosome, is used to assess the feasibility of such spontaneous emergence. Three concentric structural elements of different magnitudes, having a dimeric nature derived from the symmetrical region of the ribosomal large subunit, were suggested to constitute the vestige of the proto-ribosome. It is assumed to have materialized spontaneously in the prebiotic world, catalyzing non-coded peptide bond formation and simple elongation. Probabilistic and energetic considerations are applied in order to evaluate the suitability of the three contenders for being the initial proto-ribosome. The analysis points to the simplest proto-ribosome, comprised of a dimer of tRNA-like molecules presently embedded in the core of the symmetrical region, as the only one having a realistic statistical likelihood of spontaneous emergence from random RNA chains. Hence it offers a feasible starting point for a continuous evolutionary path from the prebiotic matter, through natural processes, into the intricate modern translation system.

The proto-oncogenic protein TAL1 controls TGF-β1 signaling through interaction with SMAD3

Directory of Open Access Journals (Sweden)

Jean-Michel Terme

2016-06-01

Full Text Available TGF-β1 is involved in many aspects of tissue development and homeostasis including hematopoiesis. The TAL1 transcription factor is also an important player of this latter process and is expressed very early in the myeloid and erythroid lineages. We previously established a link between TGF-β1 signaling and TAL1 by showing that the cytokine was able to induce its proteolytic degradation by the ubiquitin proteasome pathway. In this manuscript we show that TAL1 interacts with SMAD3 that acts in the pathway downstream of TGF-β1 association with its receptor. TAL1 expression strengthens the positive or negative effect of SMAD3 on various genes. Both transcription factors activate the inhibitory SMAD7 factor through the E box motif present in its transcriptional promoter. DNA precipitation assays showed that TAL1 present in Jurkat or K562 cells binds to this SMAD binding element in a SMAD3 dependent manner. SMAD3 and TAL1 also inhibit several genes including ID1, hTERT and TGF-β1 itself. In this latter case TAL1 and SMAD3 can impair the positive effect exerted by E47. Our results indicate that TAL1 expression can modulate TGF-β1 signaling by interacting with SMAD3 and by increasing its transcriptional properties. They also suggest the existence of a negative feedback loop between TAL1 expression and TGF-β1 signaling.

protoDUNE-Single Phase and protDUNE-DualPhase

CERN Multimedia

Brice, Maximilien

2016-01-01

At the EHN1 two big 8m x 8m x8m detector prototypes (protoDUNE-Single Phase and protDUNE-DualPhase) are being constructed. The aim is to test technologies and detector performances for DUNE, a new generation of LBN neutr

Initial proto II pulsed power tests

International Nuclear Information System (INIS)

Johnson, D.L.

1976-01-01

The Proto II electron beam accelerator is being developed by Sandia Laboratories to study engineering and physics aspects of electron beam pellet fusion. Currently the Marx generator-water capacitor portion of Proto II is undergoing high voltage testing and timing measurements. Eight 112 kJ Marx generators form the primary energy storage system. Each Marx generator pulse charges two parallel 7.5 nF water capacitors to 3 MV. The water capacitors act as intermediate energy storage elements and will transfer their energy to the water insulated pulse-forming lines in 250 ns by means of eight SF 6 gas insulated, trigatron switches. Test data and design considerations of the trigger systems, Marx generators, water capacitors, and trigatron switches are presented

Tiled Array of Pixelated CZT Imaging Detectors for ProtoEXIST2 and MIRAX-HXI

Science.gov (United States)

Hong, Jaesub; Allen, Branden; Grindlay, Jonathan; Rodrigues, Barbara; Ellis, Jon Robert; Baker, Robert; Barthelmy, Scott; Mao, Peter; Miyasaka, Hiromasa; Apple, Jeff

2013-12-01

We have assembled a tiled array (220 cm2) of fine pixel (0.6 mm) imaging CZT detectors for a balloon borne wide-field hard X-ray telescope, ProtoEXIST2. ProtoEXIST2 is a prototype experiment for a next generation hard X-ray imager MIRAX-HXI on board Lattes, a spacecraft from the Agencia Espacial Brasilieira. MIRAX will survey the 5 to 200 keV sky of Galactic bulge, adjoining southern Galactic plane and the extragalactic sky with 6 ' angular resolution. This survey will open a vast discovery space in timing studies of accretion neutron stars and black holes. The ProtoEXIST2 CZT detector plane consists of 64 of 5 mm thick 2 cm × 2 cm CZT crystals tiled with a minimal gap. MIRAX will consist of 4 such detector planes, each of which will be imaged with its own coded-aperture mask. We present the packaging architecture and assembly procedure of the ProtoEXIST2 detector. On 2012, Oct 10, we conducted a successful high altitude balloon experiment of the ProtoEXIST1 and 2 telescopes, which demonstrates their technology readiness for space application. During the flight both telescopes performed as well as on the ground. We report the results of ground calibration and the initial results for the detector performance in the balloon flight.

FOXO1 is a direct target of EWS-Fli1 oncogenic fusion protein in Ewing's sarcoma cells

International Nuclear Information System (INIS)

Yang, Liu; Hu, Hsien-Ming; Zielinska-Kwiatkowska, Anna; Chansky, Howard A.

2010-01-01

Research highlights: → Inducible and reversible siRNA knockdown of an oncogenic fusion protein such as EWS-Fli1 is feasible and more advantageous than other siRNA methods. → The tumor suppressor gene FOXO1 is a new EWS-Fli1 target. → While trans-activators are known for the FOXO1 gene, there has been no report on negative regulators of FOXO1 transcription. → This study provides first evidence that the EWS-Fli1 oncogenic fusion protein can function as a transcriptional repressor of the FOXO1 gene. -- Abstract: Ewing's family tumors are characterized by a specific t(11;22) chromosomal translocation that results in the formation of EWS-Fli1 oncogenic fusion protein. To investigate the effects of EWS-Fli1 on gene expression, we carried out DNA microarray analysis after specific knockdown of EWS-Fli1 through transfection of synthetic siRNAs. EWS-Fli1 knockdown increased expression of genes such as DKK1 and p57 that are known to be repressed by EWS-Fli1 fusion protein. Among other potential EWS-Fli1 targets identified by our microarray analysis, we have focused on the FOXO1 gene since it encodes a potential tumor suppressor and has not been previously reported in Ewing's cells. To better understand how EWS-Fli1 affects FOXO1 expression, we have established a doxycycline-inducible siRNA system to achieve stable and reversible knockdown of EWS-Fli1 in Ewing's sarcoma cells. Here we show that FOXO1 expression in Ewing's cells has an inverse relationship with EWS-Fli1 protein level, and FOXO1 promoter activity is increased after doxycycline-induced EWS-Fli1 knockdown. In addition, we have found that direct binding of EWS-Fli1 to FOXO1 promoter is attenuated after doxycycline-induced siRNA knockdown of the fusion protein. Together, these results suggest that suppression of FOXO1 function by EWS-Fli1 fusion protein may contribute to cellular transformation in Ewing's family tumors.

The Earliest Chinese Proto-Porcelain Excavated from Kiln Sites: An Elemental Analysis

OpenAIRE

Li, Yu; Zhang, Bin; Cheng, Huansheng; Zheng, Jianming

2015-01-01

In June 2012, the Piaoshan kiln site was excavated in Huzhou, Zhejiang Province, which hitherto proved to be the earliest known Chinese proto-porcelain kiln. Judging from the decorative patterns of unearthed impressed stoneware and proto-porcelain sherds, the site was determined to date to the late Xia (c. 2070-c. 1600 BC), the first dynasty of China. Here, we report on proton-induced X-ray emission analyses of 118 proto-porcelain and 35 impressed stoneware sherds from Piaoshan and five subse...

Oncogenes, radiation and cancer

International Nuclear Information System (INIS)

Michelin, S.C.

1998-01-01

The discovery of the oncogenic virus and the analysis of its nucleic acid, together with the development of new biochemical technology have permitted the partial knowledge of the molecular mechanisms responsible for the cellular neoplastic transformation. This work, besides describing the discovery of the first oncogenic virus and the experiments to demonstrate the existence of the oncogenes, summarizes its activation mechanisms and its intervention in cellular metabolisms. Ionizing radiation is among the external agents that induce the neoplastic process. Its participation in the genesis of this process and the contribution of oncogenes to the cellular radioresistance are among the topics, which are referred to another topic that makes reference. At the same time as the advancement of theoretical knowledge, lines of investigation for the application of the new concepts in diagnosis, prognosis and therapeutical treatment, were developed. An example of this, is the study of the participation of the oncogen c-erbB-2 in human breast cancer and its implications on the anti tumoral therapy. (author) [es

Helicon normal modes in Proto-MPEX

Science.gov (United States)

Piotrowicz, P. A.; Caneses, J. F.; Green, D. L.; Goulding, R. H.; Lau, C.; Caughman, J. B. O.; Rapp, J.; Ruzic, D. N.

2018-05-01

The Proto-MPEX helicon source has been operating in a high electron density ‘helicon-mode’. Establishing plasma densities and magnetic field strengths under the antenna that allow for the formation of normal modes of the fast-wave are believed to be responsible for the ‘helicon-mode’. A 2D finite-element full-wave model of the helicon antenna on Proto-MPEX is used to identify the fast-wave normal modes responsible for the steady-state electron density profile produced by the source. We also show through the simulation that in the regions of operation in which core power deposition is maximum the slow-wave does not deposit significant power besides directly under the antenna. In the case of a simulation where a normal mode is not excited significant edge power is deposited in the mirror region. ).

The APC/C E3 Ligase Complex Activator FZR1 Restricts BRAF Oncogenic Function.

Science.gov (United States)

Wan, Lixin; Chen, Ming; Cao, Juxiang; Dai, Xiangpeng; Yin, Qing; Zhang, Jinfang; Song, Su-Jung; Lu, Ying; Liu, Jing; Inuzuka, Hiroyuki; Katon, Jesse M; Berry, Kelsey; Fung, Jacqueline; Ng, Christopher; Liu, Pengda; Song, Min Sup; Xue, Lian; Bronson, Roderick T; Kirschner, Marc W; Cui, Rutao; Pandolfi, Pier Paolo; Wei, Wenyi

2017-04-01

BRAF drives tumorigenesis by coordinating the activation of the RAS/RAF/MEK/ERK oncogenic signaling cascade. However, upstream pathways governing BRAF kinase activity and protein stability remain undefined. Here, we report that in primary cells with active APC FZR1 , APC FZR1 earmarks BRAF for ubiquitination-mediated proteolysis, whereas in cancer cells with APC-free FZR1, FZR1 suppresses BRAF through disrupting BRAF dimerization. Moreover, we identified FZR1 as a direct target of ERK and CYCLIN D1/CDK4 kinases. Phosphorylation of FZR1 inhibits APC FZR1 , leading to elevation of a cohort of oncogenic APC FZR1 substrates to facilitate melanomagenesis. Importantly, CDK4 and/or BRAF/MEK inhibitors restore APC FZR1 E3 ligase activity, which might be critical for their clinical effects. Furthermore, FZR1 depletion cooperates with AKT hyperactivation to transform primary melanocytes, whereas genetic ablation of Fzr1 synergizes with Pten loss, leading to aberrant coactivation of BRAF/ERK and AKT signaling in mice. Our findings therefore reveal a reciprocal suppression mechanism between FZR1 and BRAF in controlling tumorigenesis. Significance: FZR1 inhibits BRAF oncogenic functions via both APC-dependent proteolysis and APC-independent disruption of BRAF dimers, whereas hyperactivated ERK and CDK4 reciprocally suppress APC FZR1 E3 ligase activity. Aberrancies in this newly defined signaling network might account for BRAF hyperactivation in human cancers, suggesting that targeting CYCLIN D1/CDK4, alone or in combination with BRAF/MEK inhibition, can be an effective anti-melanoma therapy. Cancer Discov; 7(4); 424-41. ©2017 AACR. See related commentary by Zhang and Bollag, p. 356 This article is highlighted in the In This Issue feature, p. 339 . ©2017 American Association for Cancer Research.

UniProt search blastx result: AK289170 [KOME

Lifescience Database Archive (English)

Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Neofelis nebulosa (Clouded leopard) 1.00E-18 ...

Education Policy as Proto-Fascism: The Aesthetics of Racial Neo-Liberalism

Science.gov (United States)

Webb, P. Taylor; Gulson, Kalervo N.

2011-01-01

We argue that neo-liberal educational policy has emerged as a proto-fascist governmentality. This contemporary technology relies on State racisms and racial orderings manifested from earlier liberal and neo-liberal practices of biopower. As a proto-fascist technology, education policy, and school choice policies in particular, operate within a…

The Single-Phase ProtoDUNE Technical Design Report

Energy Technology Data Exchange (ETDEWEB)

Abi, B. [Univ. of Padova (Italy); et al.

2017-06-21

ProtoDUNE-SP is the single-phase DUNE Far Detector prototype that is under construction and will be operated at the CERN Neutrino Platform (NP) starting in 2018. ProtoDUNE-SP, a crucial part of the DUNE effort towards the construction of the first DUNE 10-kt fiducial mass far detector module (17 kt total LAr mass), is a significant experiment in its own right. With a total liquid argon (LAr) mass of 0.77 kt, it represents the largest monolithic single-phase LArTPC detector to be built to date. It's technical design is given in this report.

Single-phase ProtoDUNE, the Prototype of a Single-Phase Liquid Argon TPC for DUNE at the CERN Neutrino Platform

CERN Document Server

Cavanna, F; Touramanis, C

2017-01-01

ProtoDUNE-SP is the single-phase DUNE Far Detector prototype that is under construction and will be operated at the CERN Neutrino Platform (NP) starting in 2018. It was proposed to the CERN SPSC in June 2015 (SPSC-P-351) and was approved in December 2015 as experiment NP04 (ProtoDUNE). ProtoDUNE-SP, a crucial part of the DUNE effort towards the construction of the first DUNE 10-kt fiducial mass far detector module (17 kt total LAr mass), is a significant experiment in its own right. With a total liquid argon (LAr) mass of 0.77 kt, it represents the largest monolithic single phase LArTPC detector to be built to date. It is housed in an extension to the EHN1 hall in the North Area, where the CERN NP is providing a new dedicated charged-particle test beamline. ProtoDUNE-SP aims to take its first beam data before the LHC long shutdown (LS2) at the end of 2018. ProtoDUNE-SP prototypes the designs of most of the single-phase DUNE far detector module (DUNE-SP) components at a 1:1 scale, with an extrapolation of abo...

Heat flux estimates of power balance on Proto-MPEX with IR imaging

Energy Technology Data Exchange (ETDEWEB)

Showers, M., E-mail: mshower1@vols.utk.edu [Bredesen Center, University of Tennessee, Knoxville, Tennessee 37996 (United States); Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831 (United States); Biewer, T. M.; Caughman, J. B. O.; Goulding, R. H.; Rapp, J. [Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831 (United States); Donovan, D. C. [Bredesen Center, University of Tennessee, Knoxville, Tennessee 37996 (United States)

2016-11-15

The Prototype Material Plasma Exposure eXperiment (Proto-MPEX) at Oak Ridge National Laboratory (ORNL) is a precursor linear plasma device to the Material Plasma Exposure eXperiment (MPEX), which will study plasma material interactions (PMIs) for future fusion reactors. This paper will discuss the initial steps performed towards completing a power balance on Proto-MPEX to quantify where energy is lost from the plasma, including the relevant diagnostic package implemented. Machine operating parameters that will improve Proto-MPEX’s performance may be identified, increasing its PMI research capabilities.

Heat flux estimates of power balance on Proto-MPEX with IR imaging

International Nuclear Information System (INIS)

Showers, M.; Biewer, T. M.; Caughman, J. B. O.; Goulding, R. H.; Rapp, J.; Donovan, D. C.

2016-01-01

The Prototype Material Plasma Exposure eXperiment (Proto-MPEX) at Oak Ridge National Laboratory (ORNL) is a precursor linear plasma device to the Material Plasma Exposure eXperiment (MPEX), which will study plasma material interactions (PMIs) for future fusion reactors. This paper will discuss the initial steps performed towards completing a power balance on Proto-MPEX to quantify where energy is lost from the plasma, including the relevant diagnostic package implemented. Machine operating parameters that will improve Proto-MPEX’s performance may be identified, increasing its PMI research capabilities.

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

Directory of Open Access Journals (Sweden)

Saliha Ece Acuner Ozbabacan

2014-02-01

Full Text Available Interleukin-1 (IL-1 is a large cytokine family closely related to innate immunity and inflammation. IL-1 proteins are key players in signaling pathways such as apoptosis, TLR, MAPK, NLR and NF-κB. The IL-1 pathway is also associated with cancer, and chronic inflammation increases the risk of tumor development via oncogenic mutations. Here we illustrate that the structures of interfaces between proteins in this pathway bearing the mutations may reveal how. Proteins are frequently regulated via their interactions, which can turn them ON or OFF. We show that oncogenic mutations are significantly at or adjoining interface regions, and can abolish (or enhance the protein-protein interaction, making the protein constitutively active (or inactive, if it is a repressor. We combine known structures of protein-protein complexes and those that we have predicted for the IL-1 pathway, and integrate them with literature information. In the reconstructed pathway there are 104 interactions between proteins whose three dimensional structures are experimentally identified; only 15 have experimentally-determined structures of the interacting complexes. By predicting the protein-protein complexes throughout the pathway via the PRISM algorithm, the structural coverage increases from 15% to 71%. In silico mutagenesis and comparison of the predicted binding energies reveal the mechanisms of how oncogenic and single nucleotide polymorphism (SNP mutations can abrogate the interactions or increase the binding affinity of the mutant to the native partner. Computational mapping of mutations on the interface of the predicted complexes may constitute a powerful strategy to explain the mechanisms of activation/inhibition. It can also help explain how an oncogenic mutation or SNP works.

Characterization of sur-2, a Novel Ras-Mediated Signal Transduction Component in C. elegans

National Research Council Canada - National Science Library

DesJardins, Edward

1998-01-01

... (oncogenes). A subset of proto-oncogenes comprise the RAS signal transduction pathway. Vulval development in the nematode worm Caenorhabditis elegans is controlled by a RAS signal transduction pathway...

Expression of oncogen c-erbB-2 (neu/HER-2) in human breast cancer

International Nuclear Information System (INIS)

Michelin, Severino C.; Mayo, Jose

2000-01-01

Breast cancer continues to be one of the leading causes of death from cancer among women and represents the most serious challenge to therapeutic control. Amplification and overexpression of the c-erbB-2 proto-oncogene occurs in as many as 30 % of all breast cancers and has been correlated with lymph node metastasis and poor prognosis in breast cancer patients. This gene know as neu, HER-2 or c-erbB-2 in among those most frequently altered in human cancer. It was first identified as a transforming gene activated in chemically induced rat neuroectodermal tumors. Early critical studies linked changes in erbB-2 expression and gene copy number to several human cancer, notably breast, ovarian and gastric cancer. Owing to its accessible location at the cell surface, erbB-2 is now under intensive scrutiny as a therapeutic target. In this review we will summarize the involvement of the c-erbB-2 gene in tumorigenesis. (author)

Environmental Science Education at Sinte Gleska University

Science.gov (United States)

Burns, D.

2004-12-01

At Sinte Gleska University, basically we face two problems 1. The lack of natural resources/environmental education instructors and students. 2. High turnover in the drinking water (and waste water / environmental monitoring) jobs. As soon as people are trained, they typically leave for better paying jobs elsewhere. To overcome these In addition to regular teaching we conduct several workshops year around on environmental issues ranging from tree plantation, preserving water resources, sustainable agriculture and natural therapy (ayurvedic treatment- the Lakota way of treating illness) etc. We offer workshops about the negative impacts brought about by the development and use of hydropower, fossil fuel and nuclear energy (but include topics like reclamation of land after mining). Not only does the harvest and consumption of these energy forms devastate the land and its plants, animals, water and air, but the mental, spiritual, and physical health and culture of Native peoples suffer as well. In contrast, wind power offers an environmentally friendly source of energy that also can provide a source of income to reservations.

The oncogenic action of ionizing radiation on rat skin: Progress report, February 1, 1988-January 31, 1989

International Nuclear Information System (INIS)

Burns, F.J.; Garte, S.J.

1988-01-01

Progress is described in 3 general areas corresponding to the specific aims of the proposal, including DNA strand breaks in the epidermis as a function of radiation penetration; oncogene activation in radiation-induced rat skin cancers; and carcinogenesis in rat skin induced by the neon ion beam. Numerous experiments have established that DNA strand breaks per unit dose in the rat epidermis are reduced by about 60% when the radiation penetration is reduced from 1.0 mm to 0.2 mm. The activation of oncogenes in the radiation-induced rat skin cancers followed a pattern. Four highly malignant cancers exhibited activation of K-ras and c-myc oncogenes, while the remaining 8 cancers exhibited only one or the other of these 2 oncogenes. Of 5 squamous carcinomas, 4 showed K-ras activation and 1 showed c-myc activation. Approximately 200 rats were exposed to the neon ion beam at the Bevalac in Berkeley, CA. The carcinogenicity of energetic electrons (2.0 MeV) was determined in conjunction with the neon ion experiment. It is too early to evaluate tumor incidence in the neon ion experiment, but for electrons an unusually large excess of connective tissue tumors, fibromas and sarcomas, have been observed so far. 59 refs., 2 tabs

Maak het Verschil met Je Merk : Het Identiteitsmanagementdashboard (IDM) voor Zorggroep Sint Maarten

NARCIS (Netherlands)

Bouten, L.M. (Lisanne); Morel, K.P.N. (Kaj)

2012-01-01

Om medewerkers en cliënten van Zorggroep Sint Maarten (ZSM) te helpen bijdragen aan goede zorg en deel je leven, wil ZSM inzichtelijk maken hoe goed zij presteert op beide aspecten. Het lectoraat Identiteitsmarketing heeft hiertoe een identiteitsmanagementdashboard voor ZSM ontwikkeld dat niet

Deletion mutants of region E1 a of AD12 E1 plasmids: Effect on oncogenic transformation

NARCIS (Netherlands)

Bos, J.L.; Jochemsen, A.G.; Bernards, R.A.; Schrier, P.I.; Ormondt, H. van; Eb, A.J. van der

1983-01-01

Plasmids containing the El region of Ad12 DNA can transform certain rodent cells into oncogenic cells. To study the role of the Ela subregion in the process of oncogenic transformation, Ad12 region El mutants carrying deletions in the Ela region were constructed. Deletion mutants pR7 and pR8 affect

Characterization of sur-2, a Novel Ras-Mediated Signal Transduction Component in C. elegans

National Research Council Canada - National Science Library

DesJardins, Edward

1999-01-01

... (oncogenes). A subset of proto-oncogenes comprise the RAS signal transduction pathway. Vulval development in the nematode worm Caenorhabditis elegans is controlled by a RAS signal transduction pathway. C...

Materias sintéticas como auxiliares en la construcción con hormigón

Directory of Open Access Journals (Sweden)

Editorial, Equipo

1963-03-01

Full Text Available Not availableEl desarrollo técnico de los materiales sintéticos abre hoy día, en la construcción de hormigón, muchas nuevas posibilidades de aplicación. Este hecho quedó demostrado por la empresa química Hüls AG, quien dio ocasión, a la prensa especializada, de visitar una exposición bajo el tema «Materias sintéticas de Hüls en la construcción» y a la cual siguió una conferencia. Para demostrar las amplias posibilidades de este material y para reunir nuevos conocimientos, fue erigida, en Hüls, una vivienda experimental sin tomar en consideración el aspecto de la rentabilidad.

Spitzer Imaging of Planck-Herschel Dusty Proto-Clusters at z=2-3

Science.gov (United States)

Cooray, Asantha; Ma, Jingzhe; Greenslade, Joshua; Kubo, Mariko; Nayyeri, Hooshang; Clements, David; Cheng, Tai-An

2018-05-01

We have recently introduced a new proto-cluster selection technique by combing Herschel/SPIRE imaging data and Planck/HFIk all-sky survey point source catalog. These sources are identified as Planck point sources with clumps of Herschel source over-densities with far-IR colors comparable to z=0 ULIRGS redshifted to z=2 to 3. The selection is sensitive to dusty starbursts and obscured QSOs and we have recovered couple of the known proto-clusters and close to 30 new proto-clusters. The candidate proto-clusters selected from this technique have far-IR flux densities several times higher than those that are optically selected, such as using LBG selection, implying that the member galaxies are in a special phase of heightened dusty starburst and dusty QSO activity. This far-IR luminous phase may be short but likely to be necessary piece to understand the whole stellar mass assembly history of clusters. Moreover, our photo-clusters are missed in optical selections, suggesting that optically selected proto-clusters alone do not provide adequate statistics and a comparison of the far-IR and optical selected clusters may reveal the importance of the dusty stellar mass assembly. Here, we propose IRAC observations of six of the highest priority new proto-clusters, to establish the validity of the technique and to determine the total stellar mass through SED models. For a modest observing time the science program will have a substantial impact on an upcoming science topic in cosmology with implications for observations with JWST and WFIRST to understand the mass assembly in the universe.

Aragonite precipitation by "proto-polyps" in coral cell cultures.

Directory of Open Access Journals (Sweden)

Tali Mass

Full Text Available The mechanisms of coral calcification at the molecular, cellular and tissue levels are poorly understood. In this study, we examine calcium carbonate precipitation using novel coral tissue cultures that aggregate to form "proto-polyps". Our goal is to establish an experimental system in which calcification is facilitated at the cellular level, while simultaneously allowing in vitro manipulations of the calcifying fluid. This novel coral culturing technique enables us to study the mechanisms of biomineralization and their implications for geochemical proxies. Viable cell cultures of the hermatypic, zooxanthellate coral, Stylophora pistillata, have been maintained for 6 to 8 weeks. Using an enriched seawater medium with aragonite saturation state similar to open ocean surface waters (Ω(arag~4, the primary cell cultures assemble into "proto-polyps" which form an extracellular organic matrix (ECM and precipitate aragonite crystals. These extracellular aragonite crystals, about 10 µm in length, are formed on the external face of the proto-polyps and are identified by their distinctive elongated crystallography and X-ray diffraction pattern. The precipitation of aragonite is independent of photosynthesis by the zooxanthellae, and does not occur in control experiments lacking coral cells or when the coral cells are poisoned with sodium azide. Our results demonstrate that proto-polyps, aggregated from primary coral tissue culture, function (from a biomineralization perspective similarly to whole corals. This approach provides a novel tool for investigating the biophysical mechanism of calcification in these organisms.

THE PHOTOECCENTRIC EFFECT AND PROTO-HOT JUPITERS. III. A PAUCITY OF PROTO-HOT JUPITERS ON SUPER-ECCENTRIC ORBITS

International Nuclear Information System (INIS)

Dawson, Rebekah I.; Murray-Clay, Ruth A.; Johnson, John Asher

2015-01-01

Gas giant planets orbiting within 0.1 AU of their host stars are unlikely to have formed in situ and are evidence for planetary migration. It is debated whether the typical hot Jupiter smoothly migrated inward from its formation location through the proto-planetary disk, or was perturbed by another body onto a highly eccentric orbit, which tidal dissipation subsequently shrank and circularized during close stellar passages. Socrates and collaborators predicted that the latter model should produce a population of super-eccentric proto-hot Jupiters readily observable by Kepler. We find a paucity of such planets in the Kepler sample, which is inconsistent with the theoretical prediction with 96.9% confidence. Observational effects are unlikely to explain this discrepancy. We find that the fraction of hot Jupiters with an orbital period P > 3 days produced by the star-planet Kozai mechanism does not exceed (at two-sigma) 44%. Our results may indicate that disk migration is the dominant channel for producing hot Jupiters with P > 3 days. Alternatively, the typical hot Jupiter may have been perturbed to a high eccentricity by interactions with a planetary rather than stellar companion, and began tidal circularization much interior to 1 AU after multiple scatterings. A final alternative is that early in the tidal circularization process at high eccentricities tidal circularization occurs much more rapidly than later in the process at low eccentricities, although this is contrary to current tidal theories

A Network-Based Model of Oncogenic Collaboration for Prediction of Drug Sensitivity

Directory of Open Access Journals (Sweden)

Ted G Laderas

2015-12-01

Full Text Available Tumorigenesis is a multi-step process, involving the acquisition of multiple oncogenic mutations that transform cells, resulting in systemic dysregulation that enables proliferation, among other cancer hallmarks. High throughput omics techniques are used in precision medicine, allowing identification of these mutations with the goal of identifying treatments that target them. However, the multiplicity of oncogenes required for transformation, known as oncogenic collaboration, makes assigning effective treatments difficult. Motivated by this observation, we propose a new type of oncogenic collaboration where mutations in genes that interact with an oncogene may contribute to its dysregulation, a new genomic feature that we term surrogate oncogenes. By mapping mutations to a protein/protein interaction network, we can determine significance of the observed distribution using permutation-based methods. For a panel of 38 breast cancer cell lines, we identified significant surrogate oncogenes in oncogenes such as BRCA1 and ESR1. In addition, using Random Forest Classifiers, we show that these significant surrogate oncogenes predict drug sensitivity for 74 drugs in the breast cancer cell lines with a mean error rate of 30.9%. Additionally, we show that surrogate oncogenes are predictive of survival in patients. The surrogate oncogene framework incorporates unique or rare mutations on an individual level. Our model has the potential for integrating patient-unique mutations in predicting drug-sensitivity, suggesting a potential new direction in precision medicine, as well as a new approach for drug development. Additionally, we show the prevalence of significant surrogate oncogenes in multiple cancers within the Cancer Genome Atlas, suggesting that surrogate oncogenes may be a useful genomic feature for guiding pancancer analyses and assigning therapies across many tissue types.

The Earliest Chinese Proto-Porcelain Excavated from Kiln Sites: An Elemental Analysis.

Science.gov (United States)

Li, Yu; Zhang, Bin; Cheng, Huansheng; Zheng, Jianming

2015-01-01

In June 2012, the Piaoshan kiln site was excavated in Huzhou, Zhejiang Province, which hitherto proved to be the earliest known Chinese proto-porcelain kiln. Judging from the decorative patterns of unearthed impressed stoneware and proto-porcelain sherds, the site was determined to date to the late Xia (c. 2070-c. 1600 BC), the first dynasty of China. Here, we report on proton-induced X-ray emission analyses of 118 proto-porcelain and 35 impressed stoneware sherds from Piaoshan and five subsequent kiln sites in the vicinity. Using principal components analysis on the major chemical compositions, we reveal the relationships between impressed stoneware and proto-porcelain samples from the six kiln sites. The sherds from different sites have distinctive chemical profiles. The results indicate that the raw materials were procured locally. We find a developmental tendency for early glazes towards mature calcium-based glaze. It is most likely that woody plant ashes with increased calcia-potash ratios were applied to the formula.

The Earliest Chinese Proto-Porcelain Excavated from Kiln Sites: An Elemental Analysis.

Directory of Open Access Journals (Sweden)

Yu Li

Full Text Available In June 2012, the Piaoshan kiln site was excavated in Huzhou, Zhejiang Province, which hitherto proved to be the earliest known Chinese proto-porcelain kiln. Judging from the decorative patterns of unearthed impressed stoneware and proto-porcelain sherds, the site was determined to date to the late Xia (c. 2070-c. 1600 BC, the first dynasty of China. Here, we report on proton-induced X-ray emission analyses of 118 proto-porcelain and 35 impressed stoneware sherds from Piaoshan and five subsequent kiln sites in the vicinity. Using principal components analysis on the major chemical compositions, we reveal the relationships between impressed stoneware and proto-porcelain samples from the six kiln sites. The sherds from different sites have distinctive chemical profiles. The results indicate that the raw materials were procured locally. We find a developmental tendency for early glazes towards mature calcium-based glaze. It is most likely that woody plant ashes with increased calcia-potash ratios were applied to the formula.

Equipotential surfaces in the Proto-Cleo Torsatron

International Nuclear Information System (INIS)

Trost, P.K.; Shohet, J.L.

1986-01-01

Plasma potential measurements are made in electron cyclotron resonance plasmas in the Proto-Cleo Torsatron with an emissive probe. Plots of equipotential surfaces are presented and compared with the numerical calculated vacuum magnetic surfaces

A new species of Thecadactylus from Sint Maarten, Lesser Antilles (Reptilia, Squamata, Gekkonidae

Directory of Open Access Journals (Sweden)

Gunther Koehler

2011-07-01

Full Text Available We describe a new species of Thecadactylus from the Caribbean island of Sint Maarten. The new species differs from all other species in the genus bya distinct dorsal pattern of numerous irregular but sharply deliminated black spots and blotches on an otherwise almost patternless background.

Utwory wczesnokredowego basenu protoślaskiego w polsko - czeskich Karpatach fliszowych

Czech Academy of Sciences Publication Activity Database

Waśkowska, A.; Golonka, J.; Strzeboński, P.; Krobicki, M.; Vašíček, Zdeněk; Skupien, P.

2009-01-01

Roč. 35, 2/1 (2009), s. 39-47 ISSN 0138-0974 Grant - others:GA ČR(CZ) GA205/07/1365 Program:GA Institutional research plan: CEZ:AV0Z30860518 Keywords : Flysch Carpathians * Proto - Silesian Basin * basin deposits Subject RIV: DB - Geology ; Mineralogy

Melanoma Suppressor Functions of the Carcinoma Oncogene FOXQ1

Directory of Open Access Journals (Sweden)

Archis Bagati

2017-09-01

Full Text Available Lineage-specific regulation of tumor progression by the same transcription factor is understudied. We find that levels of the FOXQ1 transcription factor, an oncogene in carcinomas, are decreased during melanoma progression. Moreover, in contrast to carcinomas, FOXQ1 suppresses epithelial-to-mesenchymal transition, invasion, and metastasis in melanoma cells. We find that these lineage-specific functions of FOXQ1 largely depend on its ability to activate (in carcinomas or repress (in melanoma transcription of the N-cadherin gene (CDH2. We demonstrate that FOXQ1 interacts with nuclear β-catenin and TLE proteins, and the β-catenin/TLE ratio, which is higher in carcinoma than melanoma cells, determines the effect of FOXQ1 on CDH2 transcription. Accordingly, other FOXQ1-dependent phenotypes can be manipulated by altering nuclear β-catenin or TLE proteins levels. Our data identify FOXQ1 as a melanoma suppressor and establish a mechanism underlying its inverse lineage-specific transcriptional regulation of transformed phenotypes.

The inhibitory NKR-P1B:Clr-b recognition axis facilitates detection of oncogenic transformation and cancer immunosurveillance

DEFF Research Database (Denmark)

Tanaka, M; Fine, Jason; Kirkham, Christina

2018-01-01

Natural killer (NK) cells express receptors specific for MHC class I (MHC-I) molecules involved in "missing-self" recognition of cancer and virus-infected cells. Here we elucidate the role of MHC-I-independent NKR-P1B:Clr-b interactions in the detection of oncogenic transformation by NK cells. Ras......-b protein, in turn promoting missing-self recognition via the NKR-P1B inhibitory receptor. Both Ras- and c-Myc-mediated Clr-b loss selectively augmented cytotoxicity of oncogene-transformed leukemia cells by NKR-P1B+ NK cells in vitro and enhanced rejection by WT mice in vivo. Interestingly, genetic...

UniProt search blastx result: AK287970 [KOME

Lifescience Database Archive (English)

Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Neofelis nebulosa (Clouded leopard) 3.00E-20 ...

UniProt search blastx result: AK288287 [KOME

Lifescience Database Archive (English)

Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Neofelis nebulosa (Clouded leopard) 3.00E-18 ...

UniProt search blastx result: AK287484 [KOME

Lifescience Database Archive (English)

Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Neofelis nebulosa (Clouded leopard) 3.00E-16 ...

UniProt search blastx result: AK288291 [KOME

Lifescience Database Archive (English)

Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Neofelis nebulosa (Clouded leopard) 6.00E-14 ...

UniProt search blastx result: AK288206 [KOME

Lifescience Database Archive (English)

Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Neofelis nebulosa (Clouded leopard) 4.00E-21 ...

PIXE analysis of proto-porcelain excavated from the Huoshaoshan kiln site in Deqing County, Zhejiang Province

International Nuclear Information System (INIS)

Zhang Bin; Cheng Huansheng; Zheng Jianming

2014-01-01

Background: Zhejiang Province is an important producing area of proto-porcelain. Huoshaoshan kiln site in Deqing County is the only kiln known currently for firing proto-porcelain from the late Western Zhou Dynasty to the late Spring and Autumn Period. Also it is the earliest kiln site unearthed for only firing proto-porcelain so far. It is of great significance for the exploration of Chinese early celadon firing technology. Purpose: The aim is to disclose the elemental characteristics of these proto-porcelains and study the sources of the raw materials and relationship between these proto-porcelains. Methods: We selected 18 samples made at the early period (from the late Western Zhou Dynasty to the early Spring and Autumn Period), 15 samples made at the middle and last period (the last period of the middle Spring and Autumn Period), and 17 samples made at the last period (the last period of the late Spring and Autumn Period). Proton Induced X-ray Emission (PIXE) was used to analyze these samples and measure the chemical compositions of these proto-porcelains. The factor analysis is used to study the sources of the raw materials and relationship between these proto-porcelains made in the different periods. Results: The results show that for the raw materials of body and glaze, the proto-porcelains at the last period are different from those at the early period, while the same as those at the middle and last period. Conclusion: PIXE combining with factor analysis can be used to study effectively the sources of the raw materials and relationship between these proto-porcelains. (authors)

Magnetic diagnostics for the proto-eta Tokamak

International Nuclear Information System (INIS)

Ferreira, J.L.; Aso, Y.; Ueda, M.; Ferreira, J.G.

1991-04-01

This work gives a general view of the magnetic diagnostics rat will be used in the Proto-Eta Tokamak. These diagnostics will be useful tools to measure currents, electric and magnetic fields involved in the plasma magnetic confinement. (author)

Proto-Acting as a New Concept: Personal Mimicry and the Origins of Role Playing

Directory of Open Access Journals (Sweden)

Steven Brown

2017-06-01

Full Text Available Proto-acting is introduced here as a new concept that refers to a set of processes that are intermediate between everyday role playing (in the Erving Goffman sense and dramatic acting. Its most characteristic process is the voluntary act of personal mimicry, which can occur in everyday contexts, such as quoting someone during conversation, or in performance contexts, such as impressionism. Proto-acting involves character portrayal, but on a much simpler and more transient scale than in dramatic acting, where a person may portray a character for an extended period of time during a stage performance. For example, this might involve impersonating the characters while reading a bedtime story to a child, or children themselves portraying characters while engaging in pretend play. Other key features of proto-acting are that it tends to be driven by gesture, have minimal scripting, and involve short bouts of alternation between the self and characters. Proto-acting, as based on personal mimicry, might provide a cognitive foundation for dramatic acting in human development. Moreover, proto-acting itself might be underlain evolutionarily by the process of pantomime, which often involves intentional mimicry of the actions of other people. Hence, the proto-acting concept is able to shed light on processes relevant to cognition, development, the performing arts, and human evolution.

Observational Corollaries of Proto-AGN: Understanding Formation of Supermassive Black Hole Seeds

Science.gov (United States)

Shlosman, Isaac

2016-10-01

Formation of supermassive black holes (SMBHs) is still an enigma. Recent detections of high-z quasars which harbor massive SMBHs provide a challenge to models of structure buildup in the universe. Main alternatives for the formation of SMBH seeds are (1) remnants of Population III stars, and (2) a direct baryonic collapse within dark matter (DM) halos of 10^8 Mo -- first halos whose virial temperature exceeds 10^4 K, and which can lead to the formation of proto-AGN -- luminous pre-SMBH objects. Potentially, this can involve both high-z objects as well as low-z dwarf galaxies in voids. We focus on the direct collapse in 10^8 Mo halos which circumvents the pitfalls of Pop III remnants. The collapse can proceed via a radiation pressure-supported quasistar -- with a modified blackbody continuum. Such a configuration requires a very efficient angular momentum transfer. Or, it can form a thick, differentially rotating, self-gravitating disk, which is associated with an X-ray-infrared continuum and Seyfert-level luminosity, anisotropic emission, massive bi-conical outflows, and will be a powerful source of the Ly-alpha emission. We propose to perform radiative transfer in the continuum and hydrogen lines (e.g., Lyman and Balmer), using our models of proto-AGN, and do it on-the-fly -- concurrently with the collapse. We shall test the path to quasistellar and disky proto-AGN, produce first synthetic spectra of proto-AGN, and address the issue of feasibility of their detection by the JWST. Finally, we shall develop the strategy of searching for these objects at high- and low-z, based on the specific features in the spectra and associated variability.

EQA-17: propuesta de un indicador sintético del producto de la atención primaria en mayores de 14 años

Directory of Open Access Journals (Sweden)

Ángel Vila Córcoles

2006-01-01

Full Text Available Múltiples indicadores miden diferentes aspectos del amplio aba-nico de actividades que desarrollan los equipos de atención primaria(EAP. Sin embargo, su amplio número dificulta su interpretaciónpuesto que la mayoría aportan información parcial y no proporcio-nan una visión global de los resultados. Este trabajo propone unmodelo teórico para el cálculo estandarizado de un indicador «sinté-tico» que permita medir y comparar el producto clínico-asistencialgenerado por los EAPs. Para la construcción del indicador sintéticose realizó una metodología de trabajo en seis fases: 1 identificacióny selección de componentes para el indicador; 2 determinación deprevalencias y coberturas teóricas esperadas; 3 ponderación de loscomponentes; 4 establecimiento de estándares; 5 formulación delos subindicadores; 6 operativización del indicador sintético final.Se seleccionó un total de 10 problemas de salud propios de la AP, quese desglosaron finalmente en una escala estandarizada de calidadasistencial (EQA con 17 ítems. Los problemas de salud que compo-nen este indicador sintético contemplan tanto la realización de acti-vidades de promoción de la salud (lucha antitabáquica como activi-dades de prevención primaria (vacunaciones antitetánica y antigri-pal, atención a patologías agudas (prescripción de antibióticos, yatención de patologías crónicas (enfermedad pulmonar obstructivacrónica, hipertensión, dislipemia, diabetes, insuficiencia cardiaca yfibrilación auricular. El concepto de un indicador "sintético" delproducto clínico-asistencial generado por los EAP puede aportar unmensaje dinamizante y motivador para muchos profesionales asis-tenciales, y su introducción podría ser útil para la mejora de losactuales modelos de gestión en atención primaria.

Prox1-Heterozygosis Sensitizes the Pancreas to Oncogenic Kras-Induced Neoplastic Transformation

Directory of Open Access Journals (Sweden)

Yiannis Drosos

2016-03-01

Full Text Available The current paradigm of pancreatic neoplastic transformation proposes an initial step whereby acinar cells convert into acinar-to-ductal metaplasias, followed by progression of these lesions into neoplasias under sustained oncogenic activity and inflammation. Understanding the molecular mechanisms driving these processes is crucial to the early diagnostic and prevention of pancreatic cancer. Emerging evidence indicates that transcription factors that control exocrine pancreatic development could have either, protective or facilitating roles in the formation of preneoplasias and neoplasias in the pancreas. We previously identified that the homeodomain transcription factor Prox1 is a novel regulator of mouse exocrine pancreas development. Here we investigated whether Prox1 function participates in early neoplastic transformation using in vivo, in vitro and in silico approaches. We found that Prox1 expression is transiently re-activated in acinar cells undergoing dedifferentiation and acinar-to-ductal metaplastic conversion. In contrast, Prox1 expression is largely absent in neoplasias and tumors in the pancreas of mice and humans. We also uncovered that Prox1-heterozygosis markedly increases the formation of acinar-to-ductal-metaplasias and early neoplasias, and enhances features associated with inflammation, in mouse pancreatic tissues expressing oncogenic Kras. Furthermore, we discovered that Prox1-heterozygosis increases tissue damage and delays recovery from inflammation in pancreata of mice injected with caerulein. These results are the first demonstration that Prox1 activity protects pancreatic cells from acute tissue damage and early neoplastic transformation. Additional data in our study indicate that this novel role of Prox1 involves suppression of pathways associated with inflammatory responses and cell invasiveness.

Power accounting of plasma discharges in the linear device Proto-MPEX

Science.gov (United States)

Showers, M.; Piotrowicz, P. A.; Beers, C. J.; Biewer, T. M.; Caneses, J.; Canik, J.; Caughman, J. B. O.; Donovan, D. C.; Goulding, R. H.; Lumsdaine, A.; Kafle, N.; Owen, L. W.; Rapp, J.; Ray, H.

2018-06-01

Plasma material interaction (PMI) studies are crucial to the successful development of future fusion reactors. Prototype Material Plasma Exposure eXperiment (Proto-MPEX) is a prototype design for the MPEX, a steady-state linear device being developed to study PMI. The primary purpose of Proto-MPEX is developing the plasma heating source concepts for MPEX. A power accounting study of Proto-MPEX works to identify machine operating parameters that could improve its performance, thereby increasing its PMI research capabilities, potentially impacting the MPEX design concept. To build a comprehensive power balance, an analysis of the helicon region has been performed implementing a diagnostic suite and software modeling to identify mechanisms and locations of heat loss from the main plasma. Of the 106.3 kW of input power, up to 90.5% of the power has been accounted for in the helicon region. When the analysis was extended to encompass the device to its end plates, 49.2% of the input power was accounted for and verified diagnostically. Areas requiring further diagnostic analysis are identified. The required improvements will be implemented in future work. The data acquisition and analysis processes will be streamlined to form a working model for future power balance studies of Proto-MPEX. ).

PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling.

Science.gov (United States)

Shrestha, Y; Schafer, E J; Boehm, J S; Thomas, S R; He, F; Du, J; Wang, S; Barretina, J; Weir, B A; Zhao, J J; Polyak, K; Golub, T R; Beroukhim, R; Hahn, W C

2012-07-19

Activating mutations in the RAS family or BRAF frequently occur in many types of human cancers but are rarely detected in breast tumors. However, activation of the RAS-RAF-MEK-ERK MAPK pathway is commonly observed in human breast cancers, suggesting that other genetic alterations lead to activation of this signaling pathway. To identify breast cancer oncogenes that activate the MAPK pathway, we screened a library of human kinases for their ability to induce anchorage-independent growth in a derivative of immortalized human mammary epithelial cells (HMLE). We identified p21-activated kinase 1 (PAK1) as a kinase that permitted HMLE cells to form anchorage-independent colonies. PAK1 is amplified in several human cancer types, including 30--33% of breast tumor samples and cancer cell lines. The kinase activity of PAK1 is necessary for PAK1-induced transformation. Moreover, we show that PAK1 simultaneously activates MAPK and MET signaling; the latter via inhibition of merlin. Disruption of these activities inhibits PAK1-driven anchorage-independent growth. These observations establish PAK1 amplification as an alternative mechanism for MAPK activation in human breast cancer and credential PAK1 as a breast cancer oncogene that coordinately regulates multiple signaling pathways, the cooperation of which leads to malignant transformation.

ProtoDESI: First On-Sky Technology Demonstration for the Dark Energy Spectroscopic Instrument

Science.gov (United States)

Fagrelius, Parker; Abareshi, Behzad; Allen, Lori; Ballester, Otger; Baltay, Charles; Besuner, Robert; Buckley-Geer, Elizabeth; Butler, Karen; Cardiel, Laia; Dey, Arjun; Duan, Yutong; Elliott, Ann; Emmet, William; Gershkovich, Irena; Honscheid, Klaus; Illa, Jose M.; Jimenez, Jorge; Joyce, Richard; Karcher, Armin; Kent, Stephen; Lambert, Andrew; Lampton, Michael; Levi, Michael; Manser, Christopher; Marshall, Robert; Martini, Paul; Paat, Anthony; Probst, Ronald; Rabinowitz, David; Reil, Kevin; Robertson, Amy; Rockosi, Connie; Schlegel, David; Schubnell, Michael; Serrano, Santiago; Silber, Joseph; Soto, Christian; Sprayberry, David; Summers, David; Tarlé, Greg; Weaver, Benjamin A.

2018-02-01

The Dark Energy Spectroscopic Instrument (DESI) is under construction to measure the expansion history of the universe using the baryon acoustic oscillations technique. The spectra of 35 million galaxies and quasars over 14,000 square degrees will be measured during a 5-year survey. A new prime focus corrector for the Mayall telescope at Kitt Peak National Observatory will deliver light to 5,000 individually targeted fiber-fed robotic positioners. The fibers in turn feed ten broadband multi-object spectrographs. We describe the ProtoDESI experiment, that was installed and commissioned on the 4-m Mayall telescope from 2016 August 14 to September 30. ProtoDESI was an on-sky technology demonstration with the goal to reduce technical risks associated with aligning optical fibers with targets using robotic fiber positioners and maintaining the stability required to operate DESI. The ProtoDESI prime focus instrument, consisting of three fiber positioners, illuminated fiducials, and a guide camera, was installed behind the existing Mosaic corrector on the Mayall telescope. A fiber view camera was mounted in the Cassegrain cage of the telescope and provided feedback metrology for positioning the fibers. ProtoDESI also provided a platform for early integration of hardware with the DESI Instrument Control System that controls the subsystems, provides communication with the Telescope Control System, and collects instrument telemetry data. Lacking a spectrograph, ProtoDESI monitored the output of the fibers using a fiber photometry camera mounted on the prime focus instrument. ProtoDESI was successful in acquiring targets with the robotically positioned fibers and demonstrated that the DESI guiding requirements can be met.

Oncogenes and radiation resistance - a review

International Nuclear Information System (INIS)

Dritschilo, A.

1992-01-01

Oncogenes exert their effects on the genetic programs of cells by regulating signal transduction pathways, resulting in multi-factorial genetic responses. By such actions, the genetic elements responsible for the cellular responses to ionizing radiation may be affected. Reports implicating the association of oncogene expression with modulation of the radiation response include the ras, raf, and myc genes. Experiments overexpressing H-ras and c-raf-1 using genetically engineered constructs result in enhanced post-radiation cellular survival. Conversely, inhibition of raf gene expression has resulted in relative radiation sensitization and delay of human squamous cell carcinoma tumor growth in nude mice. There appears to be a potential strategy for therapeutic intervention. The identification of genes that confer survival advantage following radiation exposure, and understanding their mechanisms of action, may permit a genetically based intervention for radiation sensitization. One such approach employs oligo-deoxynucleotides complementary to oncogene-encoded in RNA's (antisense DNA). (author)

Oncogenic cancer/testis antigens

DEFF Research Database (Denmark)

Gjerstorff, Morten F; Andersen, Mads H; Ditzel, Henrik J

2015-01-01

Recent developments have set the stage for immunotherapy as a supplement to conventional cancer treatment. Consequently, a significant effort is required to further improve efficacy and specificity, particularly the identification of optimal therapeutic targets for clinical testing. Cancer....../testis antigens are immunogenic, highly cancer-specific, and frequently expressed in various types of cancer, which make them promising candidate targets for cancer immunotherapy, including cancer vaccination and adoptive T-cell transfer with chimeric T-cell receptors. Our current understanding of tumor...... immunology and immune escape suggests that targeting oncogenic antigens may be beneficial, meaning that identification of cancer/testis antigens with oncogenic properties is of high priority. Recent work from our lab and others provide evidence that many cancer/testis antigens, in fact, have oncogenic...

Molecular cloning and analysis of Myc modulator 1 (Mm-1 from Bufo gargarizans (Amphibia: Anura

Directory of Open Access Journals (Sweden)

Ning Wang

2010-02-01

Full Text Available The protein of Myc modulator 1 (Mm-1 has been reported to repress the transcriptional activity of the proto-oncogene c-Myc in humans. Moreover, it was shown to be the subunit 5 of human prefoldin (PFD. So far, this gene and its homologs have been isolated and sequenced in many organisms, such as mammals and fish, but has not been sequenced for any amphibian or reptile. In order to better understand the function and evolution of Mm-1, we isolated a full-length Mm-1 cDNA (BgMm-1, GenBank accession no. EF211947 from Bufo gargarizans (Cantor, 1842 using RACE (rapid amplification of cDNA ends methods. Mm-1 in B. gargarizans is 755 bp long, comprising an open reading frame (ORF of 459 bp encoding 152 amino acids. The amino acid sequence had a prefoldin α-like domain, partially including a typical putative leucine zipper motif. BgMm-1 showed high similarity to its homolog of Mus musculus Linnaeus, 1758 (82% and Homo sapiens Linnaeus, 1758 MM-1 isoform a (81% at the amino acid level. The protein secondary structure modeled with the SWISS MODEL server revealed that there were two α-helices and four b-strands in BgMm-1 as its human orthologue, and both proteins belonged to the a class of PFD family. The phylogenetic relationships of Mm-1s from lower archaea to high mammals was consistent with the evolution of species, meanwhile the cluster result was consistent with the multiple alignment and the sequence identity analysis. RT-PCR (reverse transcriptase-polymerase chain reaction analysis demonstrated that BgMm-1 expressed widely in ten tissues of adult toad. These results can be helpful for the further investigation on the evolution of Mm-1.

Proyecto de mejora de la durabilidad de los pavimentos usados en aeropuertos empleando materiales alternativos y geo-sintéticos

OpenAIRE

Cabezuelo Moreno, Juan José

2015-01-01

Contribuir a la mejora de la durabilidad de los pavimentos usados en las pistas de aeropuertos, en particular pavimentos de tipo flexible, empleando combinaciones de capas de diferentes materiales y geo-sintéticos. En particular, plantear el uso de materiales novedosos como alternativa a las típicas capas de pavimento a base de hormigón y mejora de la durabilidad de las mismas empleando combinaciones de sendos materiales y geo-sintéticos. El mundo de la aviación y en concreto el del diseño...

Cooverexpression of EpCAM and c-myc genes in malignant breast

Indian Academy of Sciences (India)

oncogene, affects progression, treatment, and diagnosis of many adenocarcinomas. C-myc has been shown to be a downstream target of EpCAM and is also one of the most important proto-oncogenes routinely overexpressed in breast cancer.

A proto-code of ethics and conduct for European nurse directors.

Science.gov (United States)

Stievano, Alessandro; De Marinis, Maria Grazia; Kelly, Denise; Filkins, Jacqueline; Meyenburg-Altwarg, Iris; Petrangeli, Mauro; Tschudin, Verena

2012-03-01

The proto-code of ethics and conduct for European nurse directors was developed as a strategic and dynamic document for nurse managers in Europe. It invites critical dialogue, reflective thinking about different situations, and the development of specific codes of ethics and conduct by nursing associations in different countries. The term proto-code is used for this document so that specifically country-orientated or organization-based and practical codes can be developed from it to guide professionals in more particular or situation-explicit reflection and values. The proto-code of ethics and conduct for European nurse directors was designed and developed by the European Nurse Directors Association's (ENDA) advisory team. This article gives short explanations of the code' s preamble and two main parts: Nurse directors' ethical basis, and Principles of professional practice, which is divided into six specific points: competence, care, safety, staff, life-long learning and multi-sectorial working.

Characterisation of a Proto-historic bronze collection by micro-EDXRF

International Nuclear Information System (INIS)

Figueiredo, Elin; Araújo, M. Fátima; Silva, Rui J.C.; Vilaça, Raquel

2013-01-01

Highlights: ► A collection of Proto-historic metal artefacts was analysed by micro-EDXRF. ► Composition of major and minor elements has been determined. ► Artefacts were manufactured in a bronze alloy with a low impurity pattern. ► The alloy shows parallels with indigenous Late Bronze Age Iberian productions. -- Abstract: Studies concerning European Proto-historic metallic artefacts can provide important clues about technological transfers during a period of time characterised by diverse cultural interactions. A collection of Proto-historic metallic artefacts from Medronhal (western Iberian Peninsula) composed by rings, bracelets and a fibula related to different cultural affiliations were investigated by micro-EDXRF to provide a major and a minor elemental characterisation. Results show that the Medronhal collection was manufactured in a Cu–Sn alloy (binary bronze) with similar Sn contents among the various types of artefacts and a low impurity pattern. Results of the type and quality of metal were compared to other artefact collections to infer about metallurgical parallels. Strong parallels with indigenous Late Bronze Age Iberian metallurgical productions were found

Characterisation of a Proto-historic bronze collection by micro-EDXRF

Energy Technology Data Exchange (ETDEWEB)

Figueiredo, Elin, E-mail: elin@itn.pt [IST/ITN, Instituto Superior Técnico, Universidade Técnica de Lisboa, Estrada Nacional 10, 2686-953 Sacavém (Portugal); CENIMAT/I3N, Departamento de Ciência dos Materiais, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica (Portugal); Araújo, M. Fátima [IST/ITN, Instituto Superior Técnico, Universidade Técnica de Lisboa, Estrada Nacional 10, 2686-953 Sacavém (Portugal); Silva, Rui J.C. [CENIMAT/I3N, Departamento de Ciência dos Materiais, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica (Portugal); Vilaça, Raquel [CEAUCP-FCT, Instituto de Arqueologia, Departamento de História, Arqueologia e Artes, Faculdade de Letras, Universidade de Coimbra, Palácio de Sub-Ripas, 3000-395 Coimbra (Portugal)

2013-02-01

Highlights: ► A collection of Proto-historic metal artefacts was analysed by micro-EDXRF. ► Composition of major and minor elements has been determined. ► Artefacts were manufactured in a bronze alloy with a low impurity pattern. ► The alloy shows parallels with indigenous Late Bronze Age Iberian productions. -- Abstract: Studies concerning European Proto-historic metallic artefacts can provide important clues about technological transfers during a period of time characterised by diverse cultural interactions. A collection of Proto-historic metallic artefacts from Medronhal (western Iberian Peninsula) composed by rings, bracelets and a fibula related to different cultural affiliations were investigated by micro-EDXRF to provide a major and a minor elemental characterisation. Results show that the Medronhal collection was manufactured in a Cu–Sn alloy (binary bronze) with similar Sn contents among the various types of artefacts and a low impurity pattern. Results of the type and quality of metal were compared to other artefact collections to infer about metallurgical parallels. Strong parallels with indigenous Late Bronze Age Iberian metallurgical productions were found.

Oncogenic osteomalacia associated with soft tissue chondromyxoid fibroma

International Nuclear Information System (INIS)

Park, Jeong Mi; Woo, Young Kyun; Kang, Moo Il; Kang, Chang Suk; Hahn, Seong Tae

2001-01-01

Oncogenic osteomalacia is a rarely described clinical entity characterized by hypophosphatemia, phosphaturia, and a low concentration of 1,25-dihydroxyvitamin D 3 . It is most often associated with benign mesenchymal tumor and can be cured with surgical removal of the tumor. In this paper, we present a case of oncogenic osteomalacia caused by chondromyxoid fibroma in the soft tissue of the sole of the foot in a 56-year-old woman

Nicotine-mediated suppression of the retinoic acid metabolizing enzyme CYP26A1 limits the oncogenic potential of breast cancer.

Science.gov (United States)

Osanai, Makoto; Lee, Gang-Hong

2011-06-01

Tobacco smoke influences cancer development in tissues that are not directly exposed, and epidemiological studies have indicated that smoking women might experience decreased risk of breast cancer as a result of antiestrogenic effects. However, it remains to be clarified whether nicotine, one of the major addictive and best-investigated constituents of tobacco smoke, has any effect on breast cancer. Our recent work demonstrated that the retinoic acid metabolizing enzyme CYP26A1 enhances oncogenic and cell survival properties of breast carcinoma cells, implying a role as an oncogene. Here, we present evidence that nicotine significantly suppresses constitutive expression of CYP26A1, and that cells treated with nicotine exhibit enhanced sensitivity to apoptosis. In addition, nicotine may inhibit anchorage independent growth, cellular invasiveness and motility. These data show that nicotine can limit CYP26A1-mediated oncogenic characteristics, and suggest mechanisms by which nicotine might inhibit breast cancer development. © 2011 Japanese Cancer Association.

Oncogene expression in primary lung tumors in dogs that inhaled 239PuO2

International Nuclear Information System (INIS)

Kelly, G.; Kerkof, P.R.; Haley, P.J.

1988-01-01

Ten radiation-induced and three spontaneous lung tumors were analyzed for aberrant expression of known oncogenes. In 12 of 13 tumors tested, sequences hybridizing to the c-myc oncogene were expressed at levels 1.5 times higher than sequences hybridizing to β-actin. This level of oncogene expression was also observed in 9 of 13 tumors for 1 or more members of the ras family of oncogenes. Seven of thirteen tumors examined express sequences that hybridize with clones of v-ros or c-met. The ros and met clones both code for oncogenes whose normal homologues are transmembrane proteins related to the insulin receptor. (author)

Genetic variations and alternative splicing. The Glioma associated oncogene 1, GLI1.

Directory of Open Access Journals (Sweden)

Peter eZaphiropoulos

2012-07-01

Full Text Available Alternative splicing is a post-transcriptional regulatory process that is attaining stronger recognition as a modulator of gene expression. Alternative splicing occurs when the primary RNA transcript is differentially processed into more than one mature RNAs. This is the result of a variable definition/inclusion of the exons, the sequences that are excised from the primary RNA to form the mature RNAs. Consequently, RNA expression can generate a collection of differentially spliced RNAs, which may distinctly influence subsequent biological events, such as protein synthesis or other biomolecular interactions. Still the mechanisms that control exon definition and exon inclusion are not fully clarified. This mini-review highlights advances in this field as well as the impact of single nucleotide polymorphisms in affecting splicing decisions. The Glioma associated oncogene 1, GLI1, is taken as an example in addressing the role of nucleotide substitutions for splicing regulation.

mTORC1 is a critical mediator of oncogenic Semaphorin3A signaling

Energy Technology Data Exchange (ETDEWEB)

Yamada, Daisuke; Kawahara, Kohichi; Maeda, Takehiko, E-mail: maeda@nupals.ac.jp

2016-08-05

Aberration of signaling pathways by genetic mutations or alterations in the surrounding tissue environments can result in tumor development or metastasis. However, signaling molecules responsible for these processes have not been completely elucidated. Here, we used mouse Lewis lung carcinoma cells (LLC) to explore the mechanism by which the oncogenic activity of Semaphorin3A (Sema3A) signaling is regulated. Sema3A knockdown by shRNA did not affect apoptosis, but decreased cell proliferation in LLCs; both the mammalian target of rapamycin complex 1 (mTORC1) level and glycolytic activity were also decreased. In addition, Sema3A knockdown sensitized cells to inhibition of oxidative phosphorylation by oligomycin, but conferred resistance to decreased cell viability induced by glucose starvation. Furthermore, recombinant SEMA3A rescued the attenuation of cell proliferation and glycolytic activity in LLCs after Sema3A knockdown, whereas mTORC1 inhibition by rapamycin completely counteracted this effect. These results demonstrate that Sema3A signaling exerts its oncogenic effect by promoting an mTORC1-mediated metabolic shift from oxidative phosphorylation to aerobic glycolysis. -- Highlights: •Sema3A knockdown decreased proliferation of Lewis lung carcinoma cells (LLCs). •Sema3A knockdown decreased mTORC1 levels and glycolytic activity in LLCs. •Sema3A knockdown sensitized cells to inhibition of oxidative phosphorylation. •Sema3A promotes shift from oxidative phosphorylation to aerobic glycolysis via mTORC1.

FIRST DETECTION OF THERMAL RADIOJETS IN A SAMPLE OF PROTO-BROWN DWARF CANDIDATES

Energy Technology Data Exchange (ETDEWEB)

Morata, Oscar [Institute of Astronomy and Astrophysics, Academia Sinica, P.O. Box 23-141, Taipei 106, Taiwan (China); Palau, Aina; González, Ricardo F. [Centro de Radioastronomía y Astrofísica, Universidad Nacional Autónoma de México, P.O. Box 3-72, 58090 Morelia, Michoacán, México (Mexico); Gregorio-Monsalvo, Itziar de [Joint ALMA Observatory (JAO), Alonso de Córdova 3107, Vitacura, Santiago (Chile); Ribas, Álvaro [European Space Astronomy Centre (ESA), P.O. Box 78, E-28691 Villanueva de la Cañada, Madrid (Spain); Perger, Manuel [Institut de Ciències de l’Espai (CSIC-IEEC), Campus UAB—Facultat de Ciències, Torre C5—parell 2, E-08193 Bellaterra, Catalunya (Spain); Bouy, Hervé; Barrado, David; Huélamo, Nuria; Morales-Calderón, María [Centro de Astrobiología, INTA-CSIC, Dpto.Astrofísica, ESAC Campus, P.O. Box 78, E-28691 Villanueva de la Cañada, Madrid (Spain); Eiroa, Carlos [Departamento de Física Teórica, Facultad de Ciencias, Universidad Autónoma de Madrid, Cantoblanco, E-28049 Madrid (Spain); Bayo, Amelia, E-mail: omorata@asiaa.sinica.edu.tw [Max Planck Institut für Astronomie, Königstuhl 17, D-69117, Heidelberg (Germany); and others

2015-07-01

We observed with the Jansky Very Large Array at 3.6 and 1.3 cm a sample of 11 proto-brown dwarf (BD) candidates in Taurus in a search for thermal radio jets driven by the most embedded BDs. We detected for the first time four thermal radio jets in proto-BD candidates. We compiled data from UKIDSS, 2MASS, Spitzer, WISE, and Herschel to build the spectral energy distribution (SED) of the objects in our sample, which are similar to typical Class I SEDs of young stellar objects (YSOs). The four proto-BD candidates driving thermal radio jets also roughly follow the well-known trend of centimeter luminosity against bolometric luminosity determined for YSOs, assuming they belong to Taurus, although they present some excess of radio emission compared to the known relation for YSOs. Nonetheless, we are able to reproduce the flux densities of the radio jets modeling the centimeter emission of the thermal radio jets using the same type of models applied to YSOs, but with corresponding smaller stellar wind velocities and mass-loss rates, and exploring different possible geometries of the wind or outflow from the star. Moreover, we also find that the modeled mass outflow rates for the bolometric luminosities of our objects agree reasonably well with the trends found between the mass outflow rates and bolometric luminosities of YSOs, which indicates that, despite the “excess” centimeter emission, the intrinsic properties of proto-BDs are consistent with a continuation of those of very low-mass stars to a lower mass range. Overall, our study favors the formation of BDs as a scaled-down version of low-mass stars.

Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma.

Science.gov (United States)

McFadden, David G; Politi, Katerina; Bhutkar, Arjun; Chen, Frances K; Song, Xiaoling; Pirun, Mono; Santiago, Philip M; Kim-Kiselak, Caroline; Platt, James T; Lee, Emily; Hodges, Emily; Rosebrock, Adam P; Bronson, Roderick T; Socci, Nicholas D; Hannon, Gregory J; Jacks, Tyler; Varmus, Harold

2016-10-18

Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.

Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma

Science.gov (United States)

McFadden, David G.; Politi, Katerina; Bhutkar, Arjun; Chen, Frances K.; Song, Xiaoling; Pirun, Mono; Santiago, Philip M.; Kim-Kiselak, Caroline; Platt, James T.; Lee, Emily; Hodges, Emily; Rosebrock, Adam P.; Bronson, Roderick T.; Socci, Nicholas D.; Hannon, Gregory J.; Jacks, Tyler; Varmus, Harold

2016-01-01

Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity. PMID:27702896

Orphan nuclear receptor TLX functions as a potent suppressor of oncogene-induced senescence in prostate cancer via its transcriptional co-regulation of the CDKN1A (p21(WAF1) (/) (CIP1) ) and SIRT1 genes.

Science.gov (United States)

Wu, Dinglan; Yu, Shan; Jia, Lin; Zou, Chang; Xu, Zhenyu; Xiao, Lijia; Wong, Kam-Bo; Ng, Chi-Fai; Chan, Franky L

2015-05-01

Oncogene-induced senescence is an important tumour-suppressing mechanism to prevent both premalignant transformation and cancer progression. Overcoming this process is a critical step in early cancer development. The druggable orphan nuclear receptor TLX (NR2E1) is characterized as an important regulator of neural stem cells and is also implicated in the development of some brain tumours. However, its exact functional roles in cancer growth regulation still remain unclear. Here we report that TLX can act as a promoter of tumourigenesis in prostate cancer by suppressing oncogene-induced senescence. We determined that TLX exhibited an increased expression in high-grade prostate cancer tissues and many prostate cancer cell lines. Functional studies revealed that TLX could perform an oncogenic function in prostate cancer cells, as its knockdown triggered cellular senescence and cell growth arrest in vitro and in vivo, whereas its over-expression promoted the malignant growth of prostate cancer cells. Furthermore, enhancement of TLX activity, by either ectopic expression or ligand stimulation, could potently prevent doxorubicin-induced senescence in prostate cancer cells and also allow prostatic epithelial cells to escape oncogene-induced senescence induced either by activated oncogene H-Ras(G12V) or knockdown of tumour suppressor PTEN, via a mechanism of direct but differential transcriptional regulation of two senescence-associated genes, repression of CDKN1A and transactivation of SIRT1. Together, our present study shows, for the first time, that TLX may play an important role in prostate carcinogenesis through its suppression of oncogene-induced senescence, and also suggests that targeting the senescence-regulatory TLX is of potential therapeutic significance in prostate cancer. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

EphrinB1 expression is dysregulated and promotes oncogenic signaling in medulloblastoma.

Science.gov (United States)

McKinney, Nicole; Yuan, Liangping; Zhang, Hongying; Liu, Jingbo; Cho, Yoon-Jae; Rushing, Elisabeth; Schniederjan, Matthew; MacDonald, Tobey J

2015-01-01

Eph receptors and ephrin ligands are master regulators of oncogenic signaling required for proliferation, migration, and metastasis. Yet, Eph/ephrin expression and activity in medulloblastoma (MB), the most common malignant brain tumor of childhood, remains poorly defined. We hypothesized that Eph/ephrins are differentially expressed by sonic hedgehog (SHH) and non-SHH MB and that specific members contribute to the aggressive phenotype. Affymetrix gene expression profiling of 29 childhood MB, separated into SHH (N = 11) and non-SHH (N = 18), was performed followed by protein validation of selected Eph/ephrins in another 60 MB and two MB cell lines (DAOY, D556). Functional assays were performed using MB cells overexpressing or deleted for selected ephrins. We found EPHB4 and EFNA4 almost exclusively expressed by SHH MB, whereas EPHA2, EPHA8, EFNA1 and EFNA3 are predominantly expressed by non-SHH MB. The remaining family members, except EFNB1, are ubiquitously expressed by over 70-90 % MB, irrespective of subgroup. EFNB1 is the only member differentially expressed by 28 % of SHH and non-SHH MB. Corresponding protein expression for EphB/ephrinB1 and B2 was validated in MB. Only ephrinB2 was also detected in fetal cerebellum, indicating that EphB/ephrinB1 expression is MB-specific. EphrinB1 immunopositivity localizes to tumor cells within MB with the highest proliferative index. EphrinB1 overexpression promotes EphB activation, alters F-actin distribution and morphology, decreases adhesion, and significantly promotes proliferation. Either silencing or overexpression of ephrinB1 impairs migration. These results indicate that EphrinB1 is uniquely dysregulated in MB and promotes oncogenic responses in MB cells, implicating ephrinB1 as a potential target.

Oncogenic osteomalacia associated with soft tissue chondromyxoid fibroma

Energy Technology Data Exchange (ETDEWEB)

Park, Jeong Mi E-mail: jmpark@cmc.cuk.ac.kr; Woo, Young Kyun; Kang, Moo Il; Kang, Chang Suk; Hahn, Seong Tae

2001-08-01

Oncogenic osteomalacia is a rarely described clinical entity characterized by hypophosphatemia, phosphaturia, and a low concentration of 1,25-dihydroxyvitamin D{sub 3}. It is most often associated with benign mesenchymal tumor and can be cured with surgical removal of the tumor. In this paper, we present a case of oncogenic osteomalacia caused by chondromyxoid fibroma in the soft tissue of the sole of the foot in a 56-year-old woman.

The oncogenic action of ionizing radiation on rat skin

International Nuclear Information System (INIS)

Burns, F.J.

1991-01-01

Progress has occurred in several areas corresponding to the specific aims of the proposal: (1) Progression and multiple events in radiation carcinogenesis of rat skin as a function of LET; (2) cell cycle kinetics of irradiated rat epidermis as determined by double labeling and double emulsion autoradiography; (3) oncogene activation detected by in situ hybridization in radiation-induced rat skin tumors; (4) amplification of the c-myc oncogene in radiation-induced rat skin tumors as a function of LET; and (5) transformation of rat skin keratinocytes by ionizing radiation in combination with c-Ki-ras and c-myc oncogenes. 111 refs., 13 figs., 12 tabs

Utilization of circular dichroism and electrospray ionization mass spectrometry to understand the formation and conversion of G-quadruplex DNA at the human c-myb proto-oncogene.

Science.gov (United States)

Fu, Hengqing; Yang, Pengfei; Hai, Jinhui; Li, Huihui

2018-10-05

G-quadruplex DNAs are involved in a number of key biological processes, including gene expression, transcription, and apoptosis. The c-myb oncogene contains a number of GGA repeats in its promoter which forms G-quadruplex, thus it could be used as a target in cancer therapeutics. Several in-vitro studies have used Circular Dichroism (CD) spectroscopy or electrospray ionization mass spectrometry (ESI-MS) to demonstrate formation and stability of G-quadruplex DNA structure in the promoter region of human c-myb oncogene. The factors affecting the c-myb G-quadruplex structures were investigated, such as cations (i.e. K + , NH 4 + and Na + ) and co-solutes (methanol and polyethylene glycol). The results indicated that the presence of cations and co-solutes could change the G-quadruplex structural population and promote its thermodynamic stabilization as indicated by CD melting curves. It indicated that the co-solutes preferentially stabilize the c-myb G-quadruplex structure containing both homo- and hetero-stacking. In addition, protopine was demonstrated as a binder of c-myb G-quadruplex as screened from a library of natural alkaloids using ESI-MS method. CD spectra showed that it could selectively stabilize the c-myb G-quadruplex structure compared to other six G-quadruplexes from tumor-related G-rich sequences and the duplex DNAs (both long and short-chain ones). The binding of protopine could induce the change in the G-quadruplex structural populations. Therefore, protopine with its high binding specificity could be considered as a precursor for the design of drugs to target and regulate c-myb oncogene transcription. Copyright © 2018 Elsevier B.V. All rights reserved.

Clinical Implication of Elevated Human Cervical Cancer Oncogene-1 Expression in Esophageal Squamous Cell Carcinoma

OpenAIRE

Liu, Ying; Li, Ke; Ren, Zhonghai; Li, Shenglei; Zhang, Hongyan; Fan, Qingxia

2012-01-01

The human cervical cancer oncogene 1 (HCCR-1), a novel human oncoprotein, has been shown to be upregulated in various human tumors and plays a critical role in tumorigenesis and tumor progression. Here, the authors investigated HCCR-1 level in esophageal squamous cell carcinoma (ESCC) tissues and assessed the correlation between HCCR-1 level and prognosis of the patients with ESCC. HCCR-1 levels were investigated by immunohistochemistry, in situ hybridization, real-time quantit...

Oncogenic transformation in C3H10T1/2 cells by low-energy neutrons.

Science.gov (United States)

Miller, R C; Marino, S A; Napoli, J; Shah, H; Hall, E J; Geard, C R; Brenner, D J

2000-03-01

Occupational exposure to neutrons typically includes significant doses of low-energy neutrons, with energies below 100 keV. In addition, the normal-tissue dose from boron neutron capture therapy will largely be from low-energy neutrons. Microdosimetric theory predicts decreasing biological effectiveness for neutrons with energies below about 350 keV compared with that for higher-energy neutrons; based on such considerations, and limited biological data, the current radiation weighting factor (quality factor) for neutrons with energies from 10 keV to 100 keV is less than that for higher-energy neutrons. By contrast, some reports have suggested that the biological effectiveness of low-energy neutrons is similar to that of fast neutrons. The purpose of the current work is to assess the relative biological effectiveness of low-energy neutrons for an endpoint of relevance to carcinogenesis: in vitro oncogenic transformation. Oncogenic transformation induction frequencies were determined for C3H10T1/2 cells exposed to two low-energy neutron beams, respectively, with dose-averaged energies of 40 and 70 keV, and the results were compared with those for higher-energy neutrons and X-rays. These results for oncogenic transformation provide evidence for a significant decrease in biological effectiveness for 40 keV neutrons compared with 350 keV neutrons. The 70 keV neutrons were intermediate in effectiveness between the 70 and 350 keV beams. A decrease in biological effectiveness for low-energy neutrons is in agreement with most (but not all) earlier biological studies, as well as microdosimetric considerations. The results for oncogenic transformation were consistent with the currently recommended decreased values for low-energy neutron radiation weighting factors compared with fast neutrons.

Avaliação dos elásticos ortodônticos intra-orais de látex e de borracha sintética: estudo in vitro e in vivo

OpenAIRE

Daniela Ferreira de Carvalho Notaroberto

2014-01-01

Os elásticos ortodônticos intermaxilares sintéticos vem sendo cada vez mais utilizados, sendo principalmente indicados para pacientes que apresentam hiper-sensibilidade ao látex. Afim de avaliar e comparar o comportamento de elásticos de látex e sintéticos quanto a perda de força ao longo do tempo, este estudo foi realizado tanto in vitro quanto in vivo. Para o estudo in vitro foram avaliados 15 elásticos de cada material, para cada tempo: 0, 1, 3, 12 e 24 horas. No estudo in vivo, pacientes ...

Stat1 phosphorylation determines Ras oncogenicity by regulating p27 kip1.

Directory of Open Access Journals (Sweden)

Shuo Wang

Full Text Available Inactivation of p27 Kip1 is implicated in tumorigenesis and has both prognostic and treatment-predictive values for many types of human cancer. The transcription factor Stat1 is essential for innate immunity and tumor immunosurveillance through its ability to act downstream of interferons. Herein, we demonstrate that Stat1 functions as a suppressor of Ras transformation independently of an interferon response. Inhibition of Ras transformation and tumorigenesis requires the phosphorylation of Stat1 at tyrosine 701 but is independent of Stat1 phosphorylation at serine 727. Stat1 induces p27 Kip1 expression in Ras transformed cells at the transcriptional level through mechanisms that depend on Stat1 phosphorylation at tyrosine 701 and activation of Stat3. The tumor suppressor properties of Stat1 in Ras transformation are reversed by the inactivation of p27 Kip1. Our work reveals a novel functional link between Stat1 and p27 Kip1, which act in coordination to suppress the oncogenic properties of activated Ras. It also supports the notion that evaluation of Stat1 phosphorylation in human tumors may prove a reliable prognostic factor for patient outcome and a predictor of treatment response to anticancer therapies aimed at activating Stat1 and its downstream effectors.

''Normal'' tissues from humans exposed to radium contain an alteration in the c-mos locus

International Nuclear Information System (INIS)

Huberman, E.; Schlenker, R.A.; Hardwick, J.P.

1989-01-01

The structures of a number of human proto-oncogenes from persons with internal systemic exposure to radium were analyzed by restriction enzyme digestion and southern blotting of their DNA. Two extra c-mos Eco R1 restriction-fragment-length bands of 5.0 kb and 5.5 kb were found in tissue DNA from six of seven individuals. The extra c-mos bands were detected in DNA from many, but not all, of the tissues of the individuals exposed to radium. Our results suggest that the c-mos restriction-fragment-length alterations (RFLA) found in individuals exposed to radium were induced rather than inherited, are epigenetic in origin, and most likely result from changes in the methylation of bases surrounding the single exon of the c-mos proto-oncogene. 7 refs., 3 figs., 2 tabs

KLONING GEN PUTATIVE CLEAVAGE PROTEIN 1 (PCP-1 PADA UDANG VANAME (Litopenaeus vannamei YANG TERSERANG INFECTIOUS MYONECROSIS VIRUS

Directory of Open Access Journals (Sweden)

Hessy Novita

2016-12-01

Full Text Available Penanggulangan penyakit ikan dapat dilakukan dengan cara meningkatkan kekebalan tubuh ikan melalui program vaksinasi. Namun vaksinasi tidak tepat untuk udang, karena udang tidak mempunyai immunological memory seperti ikan. Oleh karena itu, perlindungan udang terhadap serangan penyakit viral dengan menggunakan RNA interference (RNAi. Teknologi RNAi digunakan untuk menghalangi (interfere proses replikasi infectious myonecrosis virus (IMNV pada udang vaname dengan cara menon-aktifkan gen putative cleavage protein 1 (PCP-1, yang berfungsi dalam pembentukan capsid dan proses transkripsi RNA IMNV. Penelitian ini bertujuan untuk melakukan kloning gen putative cleavage protein 1 dalam rangka perakitan teknologi RNAi untuk pengendalian penyakit IMNV pada udang vaname. Tahapan penelitian meliputi koleksi sampel, isolasi RNA, sintesis cDNA, amplifikasi PCR, purifikasi DNA, transformasi, isolasi plasmid, serta sekuensing dan analisis data. Hasil isolasi plasmid cDNA PCP-1 memperlihatkan semua koloni bakteri terseleksi ternyata membawa plasmid hasil insersi DNA gen PCP–1, hasil sekuen dengan nilai homologinya mencapai 100% dan 99% yang dibandingkan dengan sekuen di Genebank. Hasil penelitian menunjukkan bahwa kloning gen putative cleavage protein 1 (PCP-1 dari udang vaname yang terserang Infectious Myonecrosis Virus berhasil dikloning yang nantinya digunakan untuk perakitan RNAi. The prevention of fish diseases can be done by increasing of the fish immune through vaccination programs. However, the vaccination can not be done for the shrimp,due to the absence of  immunological memory. Therefore, the protection of shrimp against viral diseases was done by using of RNA interference (RNAi. RNAi technology is used to interfere infectious myonecrosis virus (IMNV replication process on white shrimp by disabling of putative cleavage protein 1 (PCP-1gene, which functions in capsid formation and RNA transcription process. The study was conducted to perform putative

The Putative Son's Attractiveness Alters the Perceived Attractiveness of the Putative Father.

Science.gov (United States)

Prokop, Pavol

2015-08-01

A body of literature has investigated female mate choice in the pre-mating context (pre-mating sexual selection). Humans, however, are long-living mammals forming pair-bonds which sequentially produce offspring. Post-mating evaluations of a partner's attractiveness may thus significantly influence the reproductive success of men and women. I tested herein the theory that the attractiveness of putative sons provides extra information about the genetic quality of fathers, thereby influencing fathers' attractiveness across three studies. As predicted, facially attractive boys were more frequently attributed to attractive putative fathers and vice versa (Study 1). Furthermore, priming with an attractive putative son increased the attractiveness of the putative father with the reverse being true for unattractive putative sons. When putative fathers were presented as stepfathers, the effect of the boy's attractiveness on the stepfather's attractiveness was lower and less consistent (Study 2). This suggests that the presence of an attractive boy has the strongest effect on the perceived attractiveness of putative fathers rather than on non-fathers. The generalized effect of priming with beautiful non-human objects also exists, but its effect is much weaker compared with the effects of putative biological sons (Study 3). Overall, this study highlighted the importance of post-mating sexual selection in humans and suggests that the heritable attractive traits of men are also evaluated by females after mating and/or may be used by females in mate poaching.

Amino-terminal domain of the v-fms oncogene product includes a functional signal peptide that directs synthesis of a transforming glycoprotein in the absence of feline leukemia virus gag sequences

International Nuclear Information System (INIS)

Wheeler, E.F.; Roussel, M.F.; Hampe, A.; Walker, M.H.; Fried, V.A.; Look, A.T.; Rettenmier, C.W.; Sherr, C.J.

1986-01-01

The nucleotide sequence of a 5' segment of the human genomic c-fms proto-oncogene suggested that recombination between feline leukemia virus and feline c-fms sequences might have occurred in a region encoding the 5' untranslated portion of c-fms mRNA. The polyprotein precursor gP180/sup gag-fms/ encoded by the McDonough strain of feline sarcoma virus was therefore predicted to contain 34 v-fms-coded amino acids derived from sequences of the c-fms gene that are not ordinarily translated from the proto-oncogene mRNA. The (gP180/sup gag-fms/) polyprotein was cotranslationally cleaved near the gag-fms junction to remove its gag gene-coded portion. Determination of the amino-terminal sequence of the resulting v-fms-coded glycoprotein, gp120/sup v-fms/, showed that the site of proteolysis corresponded to a predicted signal peptidase cleavage site within the c-fms gene product. Together, these analyses suggested that the linked gag sequences may not be necessary for expression of a biologically active v-fms gene product. The gag-fms sequences of feline sarcoma virus strain McDonough and the v-fms sequences alone were inserted into a murine retroviral vector containing a neomycin resistance gene. The authors conclude that a cryptic hydrophobic signal peptide sequence in v-fms was unmasked by gag deletion, thereby allowing the correct orientation and transport of the v-fms was unmasked by gag deletion, thereby allowing the correct orientation and transport of the v-fms gene product within membranous organelles. It seems likely that the proteolytic cleavage of gP180/gag-fms/ is mediated by signal peptidase and that the amino termini of gp140/sup v-fms/ and the c-fms gene product are identical

Amino-terminal domain of the v-fms oncogene product includes a functional signal peptide that directs synthesis of a transforming glycoprotein in the absence of feline leukemia virus gag sequences

Energy Technology Data Exchange (ETDEWEB)

Wheeler, E.F.; Roussel, M.F.; Hampe, A.; Walker, M.H.; Fried, V.A.; Look, A.T.; Rettenmier, C.W.; Sherr, C.J.

1986-08-01

The nucleotide sequence of a 5' segment of the human genomic c-fms proto-oncogene suggested that recombination between feline leukemia virus and feline c-fms sequences might have occurred in a region encoding the 5' untranslated portion of c-fms mRNA. The polyprotein precursor gP180/sup gag-fms/ encoded by the McDonough strain of feline sarcoma virus was therefore predicted to contain 34 v-fms-coded amino acids derived from sequences of the c-fms gene that are not ordinarily translated from the proto-oncogene mRNA. The (gP180/sup gag-fms/) polyprotein was cotranslationally cleaved near the gag-fms junction to remove its gag gene-coded portion. Determination of the amino-terminal sequence of the resulting v-fms-coded glycoprotein, gp120/sup v-fms/, showed that the site of proteolysis corresponded to a predicted signal peptidase cleavage site within the c-fms gene product. Together, these analyses suggested that the linked gag sequences may not be necessary for expression of a biologically active v-fms gene product. The gag-fms sequences of feline sarcoma virus strain McDonough and the v-fms sequences alone were inserted into a murine retroviral vector containing a neomycin resistance gene. The authors conclude that a cryptic hydrophobic signal peptide sequence in v-fms was unmasked by gag deletion, thereby allowing the correct orientation and transport of the v-fms was unmasked by gag deletion, thereby allowing the correct orientation and transport of the v-fms gene product within membranous organelles. It seems likely that the proteolytic cleavage of gP180/gag-fms/ is mediated by signal peptidase and that the amino termini of gp140/sup v-fms/ and the c-fms gene product are identical.

Consecuencias de la biología sintética en los derechos de propiedad intelectual y acceso a los recursos genéticos y distribución de los beneficios

Directory of Open Access Journals (Sweden)

Carlos Augusto Conde

2012-11-01

Full Text Available La biología sintética es una nueva tecnología, la cual representa un cambio en la explotación de recursos genéticos y corresponde a la transición de la producción natural de recursos genéticos a la producción sintética de estos en laboratorios. Como consecuencia de dicha transición, la biología sintética potencialmente podría erradicar el interés en los recursos genéticos ubicados en países en desarrollo, lo que podría llevar a las compañías farmacéuticas y biotecnológicas a no reconocer ninguna participación en los beneficios, como establece el Convenio sobre la Diversidad Biológica (CDB. El carácter disruptivo que la biología sintética podría tener es aún mayor si los derechos de propiedad intelectual (DPI, y en especial las patentes, conlleven barreras para acceder a invenciones creadas a partir de la biología sintética. Este artículo explora el impacto que la biología sintética podría llegar a tener en la regulación sobre el acceso a los recursos genéticos y la distribución de beneficios bajo el CDB y los DPI.

3D view to tumor suppression: Lkb1, polarity and the arrest of oncogenic c-Myc.

Science.gov (United States)

Partanen, Johanna I; Nieminen, Anni I; Klefstrom, Juha

2009-03-01

Machiavelli wrote, in his famous political treatise Il Principe, about disrupting organization by planting seeds of dissension or by eliminating necessary support elements. Tumor cells do exactly that by disrupting the organized architecture of epithelial cell layers during progression from contained benign tumor to full-blown invasive cancer. However, it is still unclear whether tumor cells primarily break free by activating oncogenes powerful enough to cause chaos or by eliminating tumor suppressor genes guarding the order of the epithelial organization. Studies in Drosophila have exposed genes that encode key regulators of the epithelial apicobasal polarity and which, upon inactivation, cause disorganization of the epithelial layers and promote unscheduled cell proliferation. These polarity regulator/tumor suppressor proteins, which include products of neoplastic tumor suppressor genes (nTSGs), are carefully positioned in polarized epithelial cells to maintain the order of epithelial structures and to impose a restraint on cell proliferation. In this review, we have explored the presence and prevalence of somatic mutations in the human counterparts of Drosophila polarity regulator/tumor suppressor genes across the human cancers. The screen points out LKB1, which is a causal genetic lesion in Peutz-Jeghers cancer syndrome, a gene mutated in certain sporadic cancers and a human homologue of the fly polarity gene par-4. We review the evidence linking Lkb1 protein to polarity regulation in the scope of our recent results suggesting a coupled role for Lkb1 as an architect of organized acinar structures and a suppressor of oncogenic c-Myc. We finally present models to explain how Lkb1-dependent formation of epithelial architecture is coupled to suppression of normal and oncogene-induced proliferation.

Characterization of new cell line stably expressing CHI3L1 oncogene

Directory of Open Access Journals (Sweden)

Chekhonin V. P.

2011-06-01

Full Text Available Aim. To characterize the immortalized 293 cell line after stable transfection with human oncogene (CHI3L1. Methods. 293 cells, stably transfected with pcDNA3.1_CHI3L1, and 293 cells, stably transfected with pcDNA3.1 as a negative control, were used throughout all experiments. The clones of CHI3L1-expressing 293 cells and 293 cells, transfected with pcDNA3.1, were analyzed by immunofluorescence and confocal microscopy. Cell proliferation was measured using MTT assay; analyses of ERK1/2 and AKT activation and their cellular localization were performed with anti-phospho-ERK and anti-phospho-AKT antibodies. Specific activation of MAP and PI3 kinases was measured by densitometric analysis of Western-blot signals. Results. The obtained results show quite modest ability of CHI3L1 to stimulate cell growth and reflect rather an improved cellular plating efficiency of the 293 cells stably transfected with pcDNA3.1_CHI3L1 as compared to the 293 cells transfected with an «empty» vector. ERK1/2 and AKT are activated in the 293_CHI3L1 cells. In these cells phosphorylated ERK1/2 were localized in both cell cytoplasm and nuclei while AKT only in cytoplasm. The 293_CHI3L1 cells differed from the 293 cells, transfected with an «empty» vector, in their size and ability to adhere to the culture plates. Conclusions. The overexpression of CHI3L1 is likely to have an important role in tumorigenesis via a mechanism which involves activation of PI3K and ERK1/2 pathways. The tumors which can be induced by orthotopic implantation of the transformed human cells with overexpressed human oncogene CHI3L1 into the rat brain can be used as a target for anticancer drug development.

D-type cyclins in adult human testis and testicular cancer

DEFF Research Database (Denmark)

Bartkova, J; Rajpert-de Meyts, E; Skakkebaek, N E

1999-01-01

D-type cyclins are proto-oncogenic components of the 'RB pathway', a G1/S regulatory mechanism centred around the retinoblastoma tumour suppressor (pRB) implicated in key cellular decisions that control cell proliferation, cell-cycle arrest, quiescence, and differentiation. This study focused...

Identification of Novel Ovarian Cancer Oncogenes that Function by Regulating Exosome Function

Science.gov (United States)

2017-09-01

Novel Ovarian Cancer Oncogenes that Function by Regulating Exosome Function September 2017 x 1Sep2016...31Aug2017 Email: mbirrer@partners.org 6 Identification of Novel Ovarian Cancer Oncogenes that Function by Regulating Exosome Function xx

Patandžali jogas un Kundalīni jogas sintēze Tantra jogas doktrīnā

OpenAIRE

Hvoraks, Antons

2007-01-01

Antons Hvoraks, Patandžali Jogas un Kundalīni Jogas sintēze Tantra Jogas doktrīnā, Rīga, 2007. Darba tēze: „Tantra-joga” skolas filozofija ir Patandžali jogas un Kundalīni jogas sintēze. Darbs sastāv no ievada, trim nodaļām, kuras ir sadalītas 20 apakšnodaļās, un no noslēguma daļas ar secinājumiem. Pirmajā nodaļā tiek aplūkoti klasiskās jogas uzskati par Visumu un cilvēku, par iespējām sasniegt atbrīvošanu un jogas kustības lielo izplatību. Otrajā nodaļā aprakstīti tantrisma uzs...

AKT activation drives the nuclear localization of CSE1L and a pro-oncogenic transcriptional activation in ovarian cancer cells

Energy Technology Data Exchange (ETDEWEB)

Lorenzato, Annalisa; Biolatti, Marta [Department of Oncology, University of Torino School of Medicine, Torino (Italy); Institute for Cancer Research at Candiolo, Candiolo, Torino (Italy); Delogu, Giuseppe [Department of Biomedical Sciences-Histology, University of Sassari, Sassari (Italy); Capobianco, Giampiero [Department of Surgical, Microsurgical and Medical Sciences, University of Sassari, Sassari (Italy); Farace, Cristiano [Department of Biomedical Sciences-Histology, University of Sassari, Sassari (Italy); Dessole, Salvatore; Cossu, Antonio; Tanda, Francesco [Department of Surgical, Microsurgical and Medical Sciences, University of Sassari, Sassari (Italy); Madeddu, Roberto [Department of Biomedical Sciences-Histology, University of Sassari, Sassari (Italy); National Institute of Biostructures and Biosystems, Rome (Italy); Olivero, Martina [Department of Oncology, University of Torino School of Medicine, Torino (Italy); Institute for Cancer Research at Candiolo, Candiolo, Torino (Italy); Di Renzo, Maria Flavia, E-mail: mariaflavia.direnzo@unito.it [Department of Oncology, University of Torino School of Medicine, Torino (Italy); Institute for Cancer Research at Candiolo, Candiolo, Torino (Italy)

2013-10-15

The human homolog of the yeast cse1 gene (CSE1L) is over-expressed in ovarian cancer. CSE1L forms complex with Ran and importin-α and has roles in nucleocytoplasmic traffic and gene expression. CSE1L accumulated in the nucleus of ovarian cancer cell lines, while it was localized also in the cytoplasm of other cancer cell lines. Nuclear localization depended on AKT, which was constitutively active in ovarian cancer cells, as the CSE1L protein translocated to the cytoplasm when AKT was inactivated. Moreover, the expression of a constitutively active AKT forced the translocation of CSE1L from the cytoplasm to the nucleus in other cancer cells. Nuclear accrual of CSE1L was associated to the nuclear accumulation of the phosphorylated Ran Binding protein 3 (RanBP3), which depended on AKT as well. Also in samples of human ovarian cancer, AKT activation was associated to nuclear accumulation of CSE1L and phosphorylation of RanBP3. Expression profiling of ovarian cancer cells after CSE1L silencing showed that CSE1L was required for the expression of genes promoting invasion and metastasis. In agreement, CSE1L silencing impaired motility and invasiveness of ovarian cancer cells. Altogether these data show that in ovarian cancer cells activated AKT by affecting RanBP3 phosphorylation determines the nuclear accumulation of CSE1L and likely the nuclear concentration of transcription factors conveying pro-oncogenic signals. - highlights: • CSE1L is a key player in nucleocytoplasmic traffic by forming complex with Ran. • AKT phosphorylates RanBP3 that regulates the nucleocytoplasmic gradient of Ran. • The activated oncogenic AKT drives the nuclear accumulation of CSE1L. • CSE1L in the nucleus up-regulates genes conveying pro-oncogenic signals. • CSE1L might contribute to tumor progression driven by the activated oncogenic AKT.

AKT activation drives the nuclear localization of CSE1L and a pro-oncogenic transcriptional activation in ovarian cancer cells

International Nuclear Information System (INIS)

Lorenzato, Annalisa; Biolatti, Marta; Delogu, Giuseppe; Capobianco, Giampiero; Farace, Cristiano; Dessole, Salvatore; Cossu, Antonio; Tanda, Francesco; Madeddu, Roberto; Olivero, Martina; Di Renzo, Maria Flavia

2013-01-01

The human homolog of the yeast cse1 gene (CSE1L) is over-expressed in ovarian cancer. CSE1L forms complex with Ran and importin-α and has roles in nucleocytoplasmic traffic and gene expression. CSE1L accumulated in the nucleus of ovarian cancer cell lines, while it was localized also in the cytoplasm of other cancer cell lines. Nuclear localization depended on AKT, which was constitutively active in ovarian cancer cells, as the CSE1L protein translocated to the cytoplasm when AKT was inactivated. Moreover, the expression of a constitutively active AKT forced the translocation of CSE1L from the cytoplasm to the nucleus in other cancer cells. Nuclear accrual of CSE1L was associated to the nuclear accumulation of the phosphorylated Ran Binding protein 3 (RanBP3), which depended on AKT as well. Also in samples of human ovarian cancer, AKT activation was associated to nuclear accumulation of CSE1L and phosphorylation of RanBP3. Expression profiling of ovarian cancer cells after CSE1L silencing showed that CSE1L was required for the expression of genes promoting invasion and metastasis. In agreement, CSE1L silencing impaired motility and invasiveness of ovarian cancer cells. Altogether these data show that in ovarian cancer cells activated AKT by affecting RanBP3 phosphorylation determines the nuclear accumulation of CSE1L and likely the nuclear concentration of transcription factors conveying pro-oncogenic signals. - highlights: • CSE1L is a key player in nucleocytoplasmic traffic by forming complex with Ran. • AKT phosphorylates RanBP3 that regulates the nucleocytoplasmic gradient of Ran. • The activated oncogenic AKT drives the nuclear accumulation of CSE1L. • CSE1L in the nucleus up-regulates genes conveying pro-oncogenic signals. • CSE1L might contribute to tumor progression driven by the activated oncogenic AKT

Immigration-dependent extensive growth in small island tourism economies : The cases of Aruba and Sint Maarten

NARCIS (Netherlands)

Alberts, A.

Aruba and Sint Maarten are two countries within the Kingdom of the Netherlands, situated in the Caribbean. Both have embarked on a dedicated tourism-driven and highly immigration-dependent development model starting in the 1970s and 1980s, making them typical examples of ‘Small Island Tourist

FOXM1 is an oncogenic mediator in Ewing Sarcoma.

Directory of Open Access Journals (Sweden)

Laura Christensen

Full Text Available Ewing Family Tumors (Ewing Sarcoma and peripheral Primitive Neuroectodermal Tumor are common bone and soft tissue malignancies of childhood, adolescence and young adulthood. Chromosomal translocation in these tumors produces fusion oncogenes of the EWS/ETS class, with EWS/FLI1 being by far the most common. EWS/ETS chimera are the only well established driver mutations in these tumors and they function as aberrant transcription factors. Understanding the downstream genes whose expression is modified has been a central approach to the study of these tumors. FOXM1 is a proliferation associated transcription factor which has increasingly been found to play a role in the pathogenesis of a wide range of human cancers. Here we demonstrate that FOXM1 is expressed in Ewing primary tumors and cell lines. Reduction in FOXM1 expression in Ewing cell lines results in diminished potential for anchorage independent growth. FOXM1 expression is enhanced by EWS/FLI1, though, unlike other tumor systems, it is not driven by expression of the EWS/FLI1 target GLI1. Thiostrepton is a compound known to inhibit FOXM1 by direct binding. We show that Thiostrepton diminishes FOXM1 expression in Ewing cell lines and this reduction reduces cell viability through an apoptotic mechanism. FOXM1 is involved in Ewing tumor pathogenesis and may prove to be a useful therapeutic target in Ewing tumors.

Oncogene expression in primary lung tumors in dogs that inhaled {sup 239}PuO{sub 2}

Energy Technology Data Exchange (ETDEWEB)

Kelly, G; Kerkof, P R; Haley, P J

1988-12-01

Ten radiation-induced and three spontaneous lung tumors were analyzed for aberrant expression of known oncogenes. In 12 of 13 tumors tested, sequences hybridizing to the c-myc oncogene were expressed at levels 1.5 times higher than sequences hybridizing to {beta}-actin. This level of oncogene expression was also observed in 9 of 13 tumors for 1 or more members of the ras family of oncogenes. Seven of thirteen tumors examined express sequences that hybridize with clones of v-ros or c-met. The ros and met clones both code for oncogenes whose normal homologues are transmembrane proteins related to the insulin receptor. (author)

A Novel Role for Keratin 17 in Coordinating Oncogenic Transformation and Cellular Adhesion in Ewing Sarcoma

Science.gov (United States)

Sankar, Savita; Tanner, Jason M.; Bell, Russell; Chaturvedi, Aashi; Randall, R. Lor; Beckerle, Mary C.

2013-01-01

Oncogenic transformation in Ewing sarcoma is caused by EWS/FLI, an aberrant transcription factor fusion oncogene. Glioma-associated oncogene homolog 1 (GLI1) is a critical target gene activated by EWS/FLI, but the mechanism by which GLI1 contributes to the transformed phenotype of Ewing sarcoma was unknown. In this work, we identify keratin 17 (KRT17) as a direct downstream target gene upregulated by GLI1. We demonstrate that KRT17 regulates cellular adhesion by activating AKT/PKB (protein kinase B) signaling. In addition, KRT17 is necessary for oncogenic transformation in Ewing sarcoma and accounts for much of the GLI1-mediated transformation function but via a mechanism independent of AKT signaling. Taken together, our data reveal previously unknown molecular functions for a cytoplasmic intermediate filament protein, KRT17, in coordinating EWS/FLI- and GLI1-mediated oncogenic transformation and cellular adhesion in Ewing sarcoma. PMID:24043308

Holistic flood risk assessment using agent-based modelling: the case of Sint Maarten Island

Science.gov (United States)

Abayneh Abebe, Yared; Vojinovic, Zoran; Nikolic, Igor; Hammond, Michael; Sanchez, Arlex; Pelling, Mark

2015-04-01

Floods in coastal regions are regarded as one of the most dangerous and harmful disasters. Though commonly referred to as natural disasters, coastal floods are also attributable to various social, economic, historical and political issues. Rapid urbanisation in coastal areas combined with climate change and poor governance can lead to a significant increase in the risk of pluvial flooding coinciding with fluvial and coastal flooding posing a greater risk of devastation in coastal communities. Disasters that can be triggered by hydro-meteorological events are interconnected and interrelated with both human activities and natural processes. They, therefore, require holistic approaches to help understand their complexity in order to design and develop adaptive risk management approaches that minimise social and economic losses and environmental impacts, and increase resilience to such events. Being located in the North Atlantic Ocean, Sint Maarten is frequently subjected to hurricanes. In addition, the stormwater catchments and streams on Sint Maarten have several unique characteristics that contribute to the severity of flood-related impacts. Urban environments are usually situated in low-lying areas, with little consideration for stormwater drainage, and as such are subject to flash flooding. Hence, Sint Maarten authorities drafted policies to minimise the risk of flood-related disasters on the island. In this study, an agent-based model is designed and applied to understand the implications of introduced policies and regulations, and to understand how different actors' behaviours influence the formation, propagation and accumulation of flood risk. The agent-based model built for this study is based on the MAIA meta-model, which helps to decompose, structure and conceptualize socio-technical systems with an agent-oriented perspective, and is developed using the NetLogo simulation environment. The agents described in this model are households and businesses, and

On Beam Matching and the Space-Charge Effect in protoDUNE-SP

CERN Document Server

Mandalia, Jesal Paresh

2017-01-01

In this project simulations using LArSoft have been analysed in particular looking at how the space-charge effect will affect the matching of particle tracks from the beam line monitor to the TPC and the TPC's performance measuring $\\frac{dE}{dx}$ in protoDUNE-SP. The analysis here provides some preliminary calibrations for protoDUNE-SP to account for the impact the space charge effect will have. Many areas of pion cross section analysis will be affected by the space charge effect so it is vital for a calibration to be developed.

Pasta Structures of Quark-Hadron Phase Transition in Proto-Neutron Stars

International Nuclear Information System (INIS)

Yasutake, Nobutoshi; Maruyama, Toshiki; Tatsumi, Toshitaka

2011-01-01

We study the quark-hadron mixed phase in proto-neutron stars with the finite-size effects. In the calculations of pasta structures appeared in the mixed phase, the Gibbs conditions require the pressure balance and chemical equilibrium between two phases besides the thermal equilibrium. We find that the region of the mixed phase is limited due to thermal instability. Moreover, we study the effects of neutrinos to the pasta structures. As a result, we find that the existence of neutrinos make the pasta structures unstable, too. These characteristic features of the hadron-quark mixed phase should be important for the middle stage of the evolutions of proto-neutron stars.

76 FR 54928 - Export Administration Regulations: Netherlands Antilles, Curaçao, Sint Maarten and Timor-Leste

Science.gov (United States)

2011-09-06

..., Bureau of Industry and Security, U.S. Department of Commerce at 202-482-2440 or by e-mail: Sharron.Cook... DEPARTMENT OF COMMERCE Bureau of Industry and Security 15 CFR Parts 738, 740, 745, and 748 [Docket...[ccedil]ao, Sint Maarten and Timor-Leste AGENCY: Bureau of Industry and Security, Commerce. ACTION: Final...

Photon detection system for ProtoDUNE dual phase

CERN Document Server

Cuesta, C. (on behalf of DUNE collaboration)

2017-01-01

The Deep Underground Neutrino Experiment (DUNE) is a 40-kton underground liquid argon time-projection-chamber (LAr TPC) detector, for long-baseline neutrino oscillation studies and for neutrino astrophysics and nucleon decay searches. Photon detector systems embedded within the LAr TPC add precise timing capabilities for non-beam events. The ProtoDUNE dual phase detector will consist of a 6x6x6 m3 liquid argon time-projection chamber placed at CERN and the light readout will be formed by 8-inch cryogenic photomultipliers from Hamamatsu. The characterization of the 36 photomultipliers, the base design, and the light calibration system are described. In addition, preliminary results from a 3x1x1 m3 LAr double phase detector operating at CERN are presented.

First experimental result of toroidal confinement of non-neutral plasma on Proto-RT

International Nuclear Information System (INIS)

Himura, H.; Yoshida, Z.; Morikawa, J.

1999-01-01

Recently, an internal-ring device named Proto-RT (Prototype Ring Trap) was constructed at University of Tokyo, and experiments on the device have been just initiated. The goal of Proto-RT is to explore an innovative way which has a possibility to attain a plasma equilibrium with extremely high-β (β>1) in a toroidal geometry using non-neutral condition. At the first series of the experiments, pure electron plasma (n e ∼10 12 m -3 ) is successfully confined inside a separatrix. No disruption is so far observed. The confinement time of the electron plasma is the order of 1 sec. A shear effect of magnetic fields seems to result in longer confinement. The non-neutrality of Δn e ∼10 12 m -3 is already beyond the value required to produce an enough self-electric field E in plasma, causing a strong ExB flow thoroughly all over the plasma where the hydrodynamic pressure of the flow is predicted to balance with the thermal pressure of the plasma. (author)

High power plasma heating experiments on the Proto-MPEX facility

Science.gov (United States)

Bigelow, T. S.; Beers, C. J.; Biewer, T. M.; Caneses, J. F.; Caughman, J. B. O.; Diem, S. J.; Goulding, R. H.; Green, D. L.; Kafle, N.; Rapp, J.; Showers, M. A.

2017-10-01

Work is underway to maximize the power delivered to the plasma that is available from heating sources installed on the Prototype Materials Plasma Exposure eXperiment (Proto-MPEX) at ORNL. Proto-MPEX is a linear device that has a >100 kW, 13.56 MHz helicon plasma generator available and is intended for material sample exposure to plasmas. Additional plasma heating systems include a 10 kW 18 GHz electron cyclotron heating (ECH) system, a 25 kW 8 MHz ion cyclotron heating ICH system, and a 200 kW 28 GHz electron Bernstein wave (EBW) and ECH system. Most of the heating systems have relatively good power transmission efficiency, however, the 28 GHz EBW system has a lower efficiency owing to stringent requirements on the microwave launch characteristics for EBW coupling combined with the lower output mode purity of the early-model gyrotron in use and its compact mode converter system. A goal for the Proto-MPEX is to have a combined heating power of 200 kW injected into the plasma. Infrared emission diagnostics of the target plate combined with Thomson Scattering, Langmuir probe, and energy analyzer measurements near the target are utilized to characterize the plasmas and coupling efficiency of the heating systems. ORNL is managed by UT-Battelle, LLC, for the U.S. DOE under contract DE-AC-05-00OR22725.

A MULTIWAVELENGTH CHARACTERIZATION OF PROTO-BROWN-DWARF CANDIDATES IN SERPENS

Energy Technology Data Exchange (ETDEWEB)

Riaz, B.; Caselli, P. [Max-Planck-Institut für Extraterrestrische Physik, Giessenbachstrasse 1, D-85748 Garching (Germany); Vorobyov, E. [Institute of Astrophysics, University of Vienna, Vienna 1180 (Austria); Research Institute of Physics, Southern Federal University, Rostov-on-Don 344090 (Russian Federation); Harsono, D. [Universitt Heidelberg, Zentrum fr Astronomie, Institut für Theoretische Astrophysik, Albert-Ueberle-Str. 2, D-69120, Heidelberg (Germany); Tikare, K. [IRAP, BP 44346-31028 Toulouse Cedex 4 (France); Gonzalez-Martin, O., E-mail: briaz@mpe.mpg.de [Instituto de Radioastronoma y Astrofsica (IRyA), UNAM, Antigua Carretera a Pátzcuaro # 8701, Col. Ex Hacienda San José de la Huerta, Morelia, Michoacán, C.P. 58089 (Mexico)

2016-11-10

We present results from a deep submillimeter survey in the Serpens Main and Serpens/G3–G6 clusters, conducted with the Submillimetre Common-User Bolometer Array (SCUBA-2) at the James Clerk Maxwell Telescope. We have combined near- and mid-infrared spectroscopy, Herschel PACS far-infrared photometry, submillimeter continuum, and molecular gas line observations, with the aim of conducting a detailed multiwavelength characterization of “proto-brown-dwarf” (proto-BD) candidates in Serpens. We have performed continuum and line radiative transfer modeling and have considered various classification schemes to understand the structure and the evolutionary stage of the system. We have identified four proto-BD candidates, of which the lowest-luminosity source has an L {sub bol} ∼ 0.05 L {sub ☉}. Two of these candidates show characteristics consistent with Stage 0/I systems, while the other two are Stage I-T/Class Flat systems with tenuous envelopes. Our work has also revealed a ∼20% fraction of misidentified Class 0/I/Flat sources that show characteristics consistent with Class II edge-on disk systems. We have set constraints on the mass of the central object using the measured bolometric luminosities and numerical simulations of stellar evolution. Considering the available gas+dust mass reservoir and the current mass of the central source, three of these candidates are likely to evolve into BDs.

Oncogenic LINE-1 Retroelements Sustain Prostate Tumor Cells and Promote Metastatic Progression

Science.gov (United States)

2015-10-01

limit to 20 words ). 3. ACCOMPLISHMENTS: The PI is reminded that the recipient organization is required to obtain prior written approval...activating novel oncogenic transcriptional pathways and by acting as a telomerase thereby contributing to immortalization of the metastases. We also

Lípidos sanguíneos en cerdos alimentados con pijiguao (Bactris gasipaes Kunth y lisina sintética

Directory of Open Access Journals (Sweden)

Janeth Colina R.

2011-12-01

Full Text Available Objetivo. Evaluar el efecto de la harina de pijiguao y lisina sintética sobre los lípidos sanguíneos de cerdos en crecimiento y engorde. Materiales y métodos. El estudio se realizó en dos etapas. En la primera etapa se utilizaron 72 cerdos castrados en crecimientode 30 ± 0.5 kg, en un arreglo factorial 2x3: dos niveles de lisina sintética (0 y 2.70 g/kgy tres niveles de harina de pijiguao (0, 160 y 320 g/kg. En la segunda etapa se utilizaron 16 cerdos en engorde de 67.25 ± 1.17 kg, en un arreglo factorial 2x2: dos niveles de lisinasintética (0 y 2.70 g/kg y dos niveles de pijiguao (0 y 175 g/kg. Se determinaron las concentraciones séricas de triacilgliceroles, colesterol total y ácidos grasos. Resultados. Los cerdos en crecimiento que consumieron pijiguao presentaron menores (p<0.001concentraciones de colesterol que el grupo control (2.27 y 2.23 mmol/l vs 2.56 mmol/l y triacilgliceroles (0.34 y 0.28 mmol/l vs 0.42 mmol/l. El ácido oleico incrementó (p<0.01con el mayor nivel de pijiguao (20.78% a 28.84%, y la lisina aumentó (p<0.05 el ácidolinoleico (27.83% a 31.29%. Los cerdos alimentados con pijiguao y lisina mostraron menor (p<0.001 ácido palmítico que el grupo con pijiguao sin lisina (0.23 y 0.19% vs 0.45 y 0.62%, respectivamente. En la etapa de engorde los triacilgliceroles disminuyeron (p<0.05 en los cerdos alimentados con pijiguao y lisina (0.46 a 0.36 mmol/l. Los cerdos alimentados con pijiguao mostraron menor ácido linoleico y mayor ácido oleico (p<0.001. Conclusiones. Las dietas con pijiguao y lisina sintética no causaron efectos negativos sobre los lípidos sanguíneos de cerdos.

THERE ARE NO STARLESS MASSIVE PROTO-CLUSTERS IN THE FIRST QUADRANT OF THE GALAXY

Energy Technology Data Exchange (ETDEWEB)

Ginsburg, A.; Bally, J.; Battersby, C. [Center for Astrophysics and Space Astronomy, University of Colorado, Boulder, CO 80309 (United States); Bressert, E. [European Southern Observatory, Karl Schwarzschild str. 2, D-85748 Garching bei Muenchen (Germany)

2012-10-20

We search the {lambda} = 1.1 mm Bolocam Galactic Plane Survey for clumps containing sufficient mass to form {approx}10{sup 4} M{sub Sun} star clusters. Eighteen candidate massive proto-clusters are identified in the first Galactic quadrant outside of the central kiloparsec. This sample is complete to clumps with mass M{sub clump} > 10{sup 4} M{sub Sun} and radius r {approx}< 2.5 pc. The overall Galactic massive cluster formation rate is CFR(M{sub cluster} > 10{sup 4}) {approx}<5 Myr{sup -1}, which is in agreement with the rates inferred from Galactic open clusters and M31 massive clusters. We find that all massive proto-clusters in the first quadrant are actively forming massive stars and place an upper limit of {tau}{sub starless} < 0.5 Myr on the lifetime of the starless phase of massive cluster formation. If massive clusters go through a starless phase with all of their mass in a single clump, the lifetime of this phase is very short.

Study on the pre-qin pottery and proto-porcelain from boluo county, Guangdong province with INAA

International Nuclear Information System (INIS)

Wang Jianping; Chen Tiemei

2003-01-01

Seventy-seven pottery and proto-porcelain sherds collected from Meihuadun, Yingang and Henglingshan sites of Boluo County, Guangdong Province were studied with INAA. These sherds are of Western Zhou to Warring States Period. Concentrations of 27 elements were measured, then principal component analysis and other statistical procedures were applied to the data set in order to classify these sherds. This study shows: (1) Though these 3 archaeological sites are located close to each other within an area of about 1000 km 2 , ancient potters of these sites might use raw materials of different origins for pottery production, as pottery sherds of these 3 sites show different chemical compositions. Such differentiation is also observed for the proto-porcelain samples, indicating that proto-porcelain samples found at Meihuadun and Henglingshan might be of different provenance; (2) In each site during the Western Zhou to Spring-Autumn Period the same raw material was used for both hard pottery and soft pottery manufacturing, while during the Warring States Period no similarity in chemical compositions was observed between hard pottery and soft pottery samples. It is wondered if this phenomenon means an advancement of ceramic technology

Oncogenes and radiosensitivity: in vitro studies. Potential impact in radiotherapy

International Nuclear Information System (INIS)

Alapetite, C.; Moustacchi, E.; Cosset, J.M.

1992-01-01

It is of interest to address the question of whether or not activated oncogenes can influence tumorigenic cell response to radiations. Malignant transformation through transfection of oncogenes offers a possibility for in vitro comparison of transformed cells and parental cells. Murin cellular system analysis suggests an acquisition of radioresistance through some oncogenes transfection. In human cells, only a limited number of oncogenes (ras and myc) has been studied so far. To date, no crucial influence could be demonstrated. The extension of the analysis to other oncogenes and suppressor genes could potentially be helpful for the choice and the modalities of cancer treatment

Caenorhabditis elegans histone deacetylase hda-1 is required for morphogenesis of the vulva and LIN-12/Notch-mediated specification of uterine cell fates.

Science.gov (United States)

Ranawade, Ayush Vasant; Cumbo, Philip; Gupta, Bhagwati P

2013-08-07

Chromatin modification genes play crucial roles in development and disease. In Caenorhabditis elegans, the class I histone deacetylase family member hda-1, a component of the nucleosome remodeling and deacetylation complex, has been shown to control cell proliferation. We recovered hda-1 in an RNA interference screen for genes involved in the morphogenesis of the egg-laying system. We found that hda-1 mutants have abnormal vulva morphology and vulval-uterine connections (i.e., no uterine-seam cell). We characterized the vulval defects by using cell fate-specific markers and found that hda-1 is necessary for the specification of all seven vulval cell types. The analysis of the vulval-uterine connection defect revealed that hda-1 is required for the differentiation of the gonadal anchor cell (AC), which in turn induces ventral uterine granddaughters to adopt π fates, leading to the formation of the uterine-seam cell. Consistent with these results, hda-1 is expressed in the vulva and AC. A search for hda-1 target genes revealed that fos-1 (fos proto-oncogene family) acts downstream of hda-1 in vulval cells, whereas egl-43 (evi1 proto-oncogene family) and nhr-67 (tailless homolog, NHR family) mediate hda-1 function in the AC. Furthermore, we showed that AC expression of hda-1 plays a crucial role in the regulation of the lin-12/Notch ligand lag-2 to specify π cell fates. These results demonstrate the pivotal role of hda-1 in the formation of the vulva and the vulval-uterine connection. Given that hda-1 homologs are conserved across the phyla, our findings are likely to provide a better understanding of HDAC1 function in development and disease.

scid Thymocytes with TCRbeta gene rearrangements are targets for the oncogenic effect of SCL and LMO1 transgenes.

Science.gov (United States)

Chervinsky, D S; Lam, D H; Melman, M P; Gross, K W; Aplan, P D

2001-09-01

SCL and LMO1 were both discovered by virtue of their activation by chromosomaltranslocation in patients with T-cell acute lymphoblastic leukemia (T-ALL). Overexpression of SCL and LMO1 in the thymus of transgenic mice leads to T-ALL at a young age. scid (severe combined immunodeficient) mice are unable to efficiently recombine antigen receptor genes and consequently display a developmental block at the CD4-CD8- to CD4+CD8+ transition. To test the hypothesis that this developmental block would protect SCL/LMO1 transgenic mice from developing T-ALL, we crossed the SCL and LMO1 transgenes onto a scid background. The age of onset for T-ALL in the SCL/LMO1/scid mice was significantly delayed (P < 0.001) compared with SCL/LMO1/wild-type mice. Intriguingly, all of the SCL/LMO1/scid malignancies displayed clonal, in-frame TCRbeta gene rearrangements. Taken together, these findings suggest that the "leaky" scid thymocyte that undergoes a productive TCRbeta gene rearrangement is susceptible to the oncogenic action of SCL and LMO1 and additionally suggests that TCRbeta gene rearrangements may be required for the oncogenic action of SCL and LMO1.

Uso do feromônio sexual sintético para captura de machos da traça-das-crucíferas

Directory of Open Access Journals (Sweden)

MICHEREFF MIRIAN FERNANDES FURTADO

2000-01-01

Full Text Available Este trabalho teve como objetivo estudar a atração dos machos da traça-das-crucíferas (Plutella xylostella L., Lepidoptera: Yponomeutidae por diferentes formulações do feromônio sexual sintético. Os tratamentos consistiram em: 1 formulação comercial; 2 Z11,16:Ald; 3 Z11,16:Ac; 4 mistura 7:3 de 2+3; 5 mistura 5:5 de 2+3; 6 septos de borracha com hexano (testemunha; e 7 cinco fêmeas virgens. A formulação comercial do feromônio sexual sintético propiciou maior captura de machos, não diferindo significativamente de fêmeas virgens e da mistura 5:5 utilizadas como isca. Os componentes isoladamente foram pouco atrativos aos machos. Foram testados cinco modelos de armadilhas. A armadilha Pherocon 1 CP (33,2 machos/armadilha/noite foi a mais eficiente na captura de machos, seguida pelas armadilhas Cilíndrica Aberta, Cilíndrica Fechada, Delta e Redonda Aberta. Três alturas de instalação da armadilha foram avaliadas. Ocorreu significativamente maior captura de machos na altura do ápice das plantas (30 cm do solo. As alturas de 5 e 60 cm não diferiram entre si.

PIAS1 Promotes Lymphomagenesis through MYC Upregulation

Directory of Open Access Journals (Sweden)

Andrea Rabellino

2016-06-01

Full Text Available The MYC proto-oncogene is a transcription factor implicated in a broad range of cancers. MYC is regulated by several post-translational modifications including SUMOylation, but the functional impact of this post-translational modification is still unclear. Here, we report that the SUMO E3 ligase PIAS1 SUMOylates MYC. We demonstrate that PIAS1 promotes, in a SUMOylation-dependent manner, MYC phosphorylation at serine 62 and dephosphorylation at threonine 58. These events reduce the MYC turnover, leading to increased transcriptional activity. Furthermore, we find that MYC is SUMOylated in primary B cell lymphomas and that PIAS1 is required for the viability of MYC-dependent B cell lymphoma cells as well as several cancer cell lines of epithelial origin. Finally, Pias1-null mice display endothelial defects reminiscent of Myc-null mice. Taken together, these results indicate that PIAS1 is a positive regulator of MYC.

Cellular oncogene expression following exposure of mice to γ-rays

International Nuclear Information System (INIS)

Anderson, A.; Woloschak, G.E.

1991-01-01

We examined the effects of total body exposure of BCF1 mice to γ-rays (300 cGy) in modulating expression of cellular oncogenes in both gut and liver tissues. We selected specific cellular oncogenes (c-fos, c-myc, c-src, and c-H-ras), based on their normal expression in liver and gut tissues from untreated mice. As early as 5 min. following whole body exposure of BCF1 mice to γ-rays we detected induction of mRNA specific for c-src and c-H-ras in both liver and gut tissues. c-fos RNA was slightly decreased in accumulation in gut but was unaffected in liver tissue from irradiated mice relative to untreated controls. c-myc mRNA accumulation was unaffected in all tissues examined. These experiments document that modulation of cellular oncogene expression can occur as an early event in tissues following irradiation and suggest that this modulation may play a role in radiation-induced carcinogenesis

'Cancer genes and their expression; blueprint to future improvements in radiation protection?'

International Nuclear Information System (INIS)

Paterson, M.C.

1996-01-01

The field of molecular oncology is reviewed, with some reference to the effects of ionizing radiation. There are three classes of cancer genes: oncogenes, tumor suppressor genes, and modulator genes. Proto-oncogenes control the synthesis of proteins which regulate cell division; these proto-oncogenes, of which about 100 have been identified, become oncogenes when damaged. Oncogenes are dominant. Only about a dozen tumor-suppressor genes have been identified; they are recessive. One example of a tumor suppressor gene is that producing p53 protein, which shuts down DNA replication temporarily to allow time for enzymatic repair of damage resulting from radiation or other damaging agents. Modulator genes are a heterogeneous class, including those genes that facilitate the destruction of pre-malignant cells by immune surveillance. Modulator genes also include those responsible for DNA repair. The study of DNA repair and its defects has made recent strides, and 12 participating enzymes have now been identified. It may soon be possible to monitor low-level radiation effects in individuals at the molecular level. Perhaps individuals will be monitored for their 'carcinogen exposure response' index, giving them the opportunity to adjust their lifestyles and occupations accordingly. 20 refs

Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures.

Directory of Open Access Journals (Sweden)

Alessandro Furlan

Full Text Available The development of targeted molecular therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targeting agents acting on the oncogenic path(s at multiple levels is a promising approach for molecular therapies. 2-phenylimidazo[2,1-b]benzothiazole derivatives have been highlighted for their properties of targeting oncogenic Met receptor tyrosine kinase (RTK signaling. In this study, we evaluated the mechanism of action of one of the most active imidazo[2,1-b]benzothiazol-2-ylphenyl moiety-based agents, Triflorcas, on a panel of cancer cells with distinct features. We show that Triflorcas impairs in vitro and in vivo tumorigenesis of cancer cells carrying Met mutations. Moreover, Triflorcas hampers survival and anchorage-independent growth of cancer cells characterized by "RTK swapping" by interfering with PDGFRβ phosphorylation. A restrained effect of Triflorcas on metabolic genes correlates with the absence of major side effects in vivo. Mechanistically, in addition to targeting Met, Triflorcas alters phosphorylation levels of the PI3K-Akt pathway, mediating oncogenic dependency to Met, in addition to Retinoblastoma and nucleophosmin/B23, resulting in altered cell cycle progression and mitotic failure. Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels. Moreover, the disease-oriented NCI Anticancer Drug Screen revealed that Triflorcas elicits a unique profile of growth inhibitory-responses on cancer cell lines, indicating a novel mechanism of drug action. The anti-tumor activity elicited by 2-phenylimidazo[2,1-b]benzothiazole derivatives through combined inhibition of distinct effectors in

RET/PTC1-Driven Neoplastic Transformation and Proinvasive Phenotype of Human Thyrocytes Involve Met Induction and β-Catenin Nuclear Translocation1

Science.gov (United States)

Cassinelli, Giuliana; Favini, Enrica; Degl'Innocenti, Debora; Salvi, Alessandro; De Petro, Giuseppina; Pierotti, Marco A; Zunino, Franco; Borrello, Maria Grazia; Lanzi, Cinzia

2009-01-01

Activation of the RET gene by chromosomal rearrangements generating RET/PTC oncogenes is a frequent, early, and causative event in papillary thyroid carcinoma (PTC). We have previously shown that, in human primary thyrocytes, RET/PTC1 induces a transcriptional program including the MET proto-oncogene. In PTCs, β-catenin is frequently mislocated to the cytoplasm nucleus. We investigated the interplay between Ret/ptc1 signaling and Met in regulating the proinvasive phenotype and β-catenin localization in cellular models of human PTC. Here, we show that Met protein is expressed and is constitutively active in human thyrocytes exogenously expressing RET/PTC1 as well as a mutant (Y451F) devoid of the main Ret/ptc1 multidocking site. Both in transformed thyrocytes and in the human PTC cell line TPC-1, Ret/ptc1-Y451-dependent signaling and Met cooperated to promote a proinvasive phenotype. Accordingly, gene/functional silencing of either RET/PTC1 or MET abrogated early branching morphogenesis in TPC-1 cells. The same effect was obtained by blocking the common downstream effector Akt. Y451 of Ret/ptc1 was required to promote proliferation and nuclear translocation of β-catenin, suggesting that these oncogene-driven effects are Met-independent. Pharmacologic inhibition of Ret/ptc1 and Met tyrosine kinases by the multitarget small molecule RPI-1 blocked cell proliferation and invasive ability and dislocated β-catenin from the nucleus. Altogether, these results support that Ret/ptc1 cross talks with Met at transcriptional and signaling levels and promotes β-catenin transcriptional activity to drive thyrocyte neoplastic transformation. Such molecular network, promoting disease initiation and acquisition of a proinvasive phenotype, highlights new options to design multitarget therapeutic strategies for PTCs. PMID:19107227

Formation of a hybrid-type proto-atmosphere on Mars accreting in the solar nebula

Science.gov (United States)

Saito, Hiroaki; Kuramoto, Kiyoshi

2018-03-01

Recent studies of the chronology of Martian meteorites suggest that the growth of Mars was almost complete within a few Myr after the birth of the Solar system. During such rapid accretion, proto-Mars likely gravitationally maintained both the solar nebula component and the impact degassing component, containing H2O vapour and reduced gas species, as a proto-atmosphere to be called a hybrid-type proto-atmosphere. Here we numerically analyse the mass and composition of the degassed component and the atmospheric thermal structure sustained by accretional heating. Our results predict that a growing Mars possibly acquired a massive and hot hybrid-type proto-atmosphere with surface pressure and temperature greater than several kbar and 2000 K, respectively, which is sufficient to produce a deep magma ocean. In such a high-temperature and high-pressure environment, a significant amount of H2O, CH4, CO, and H2 is expected to be partitioned into the planetary interior, although this would strongly depend on the dynamics of the magma ocean and mantle solidification. The dissolved H2O may explain the wet Martian mantle implied from basaltic Martian meteorites. Along with the remnant reduced atmosphere after the hydrodynamic atmospheric escape, dissolved reduced gas species may have maintained an earliest Martian surface environment that allowed prebiotic chemical evolution and liquid H2O activities.

Cannabis sintético: aspectos toxicológicos, usos clínicos y droga de diseño

Directory of Open Access Journals (Sweden)

Andrés Felipe Casadiego Mesa

2015-07-01

Full Text Available La planta Cannabis Sativa, tiene un largo historial de uso en el transcurso de la humanidad y desde hace varias décadas, se ha retomado el interés por ella debido a su potencial terapéutico relacionado con diversidad de patologías. Sin embargo, el acercamiento a los aspectos toxicológicos, clínicos y terapéuticos de la planta y sus derivados sintéticos se ha visto limitado, debido a las connotaciones culturales y legales que existen en la actualidad alrededor de su uso, ya que dichos derivados sintéticos están siendo utilizados con fines recreativos, exponiendo a gran cantidad de personas a riesgos en su salud. Así pues, este artículo expondrá algunas generalidades sobre la planta, el sistema endocannabinoide y sus ligandos, su uso como droga de síntesis y su uso terapéutico, principalmente en las enfermedades neurodegenerativas del Parkinson y el Alzheimer.

SCD1 Expression is dispensable for hepatocarcinogenesis induced by AKT and Ras oncogenes in mice.

Directory of Open Access Journals (Sweden)

Lei Li

Full Text Available Increased de novo lipogenesis is one of the major metabolic events in cancer. In human hepatocellular carcinoma (HCC, de novo lipogenesis has been found to be increased and associated with the activation of AKT/mTOR signaling. In mice, overexpression of an activated form of AKT results in increased lipogenesis and hepatic steatosis, ultimately leading to liver tumor development. Hepatocarcinogenesis is dramatically accelerated when AKT is co-expressed with an oncogenic form of N-Ras. SCD1, the major isoform of stearoyl-CoA desaturases, catalyzing the conversion of saturated fatty acids (SFA into monounsaturated fatty acids (MUFA, is a key enzyme involved in de novo lipogenesis. While many studies demonstrated the requirement of SCD1 for tumor cell growth in vitro, whether SCD1 is necessary for tumor development in vivo has not been previously investigated. Here, we show that genetic ablation of SCD1 neither inhibits lipogenesis and hepatic steatosis in AKT-overexpressing mice nor affects liver tumor development in mice co-expressing AKT and Ras oncogenes. Molecular analysis showed that SCD2 was strongly upregulated in liver tumors from AKT/Ras injected SCD1(-/- mice. Noticeably, concomitant silencing of SCD1 and SCD2 genes was highly detrimental for the growth of AKT/Ras cells in vitro. Altogether, our study provides the evidence, for the first time, that SCD1 expression is dispensable for AKT/mTOR-dependent hepatic steatosis and AKT/Ras-induced hepatocarcinogenesis in mice. Complete inhibition of stearoyl-CoA desaturase activity may be required to efficiently suppress liver tumor development.

MicroRNA-99 family members suppress Homeobox A1 expression in epithelial cells.

Science.gov (United States)

Chen, Dan; Chen, Zujian; Jin, Yi; Dragas, Dragan; Zhang, Leitao; Adjei, Barima S; Wang, Anxun; Dai, Yang; Zhou, Xiaofeng

2013-01-01

The miR-99 family is one of the evolutionarily most ancient microRNA families, and it plays a critical role in developmental timing and the maintenance of tissue identity. Recent studies, including reports from our group, suggested that the miR-99 family regulates various physiological processes in adult tissues, such as dermal wound healing, and a number of disease processes, including cancer. By combining 5 independent genome-wide expression profiling experiments, we identified a panel of 266 unique transcripts that were down-regulated in epithelial cells transfected with miR-99 family members. A comprehensive bioinformatics analysis using 12 different sequence-based microRNA target prediction algorithms revealed that 81 out of these 266 down-regulated transcripts are potential direct targets for the miR-99 family. Confirmation experiments and functional analyses were performed to further assess 6 selected miR-99 target genes, including mammalian Target of rapamycin (mTOR), Homeobox A1 (HOXA1), CTD small phosphatase-like (CTDSPL), N-myristoyltransferase 1 (NMT1), Transmembrane protein 30A (TMEM30A), and SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5). HOXA1 is a known proto-oncogene, and it also plays an important role in embryonic development. The direct targeting of the miR-99 family to two candidate binding sequences located in the HOXA1 mRNA was confirmed using a luciferase reporter gene assay and a ribonucleoprotein-immunoprecipitation (RIP-IP) assay. Ectopic transfection of miR-99 family reduced the expression of HOXA1, which, in consequence, down-regulated the expression of its downstream gene (i.e., Bcl-2) and led to reduced proliferation and cell migration, as well as enhanced apoptosis. In summary, we identified a number of high-confidence miR-99 family target genes, including proto-oncogene HOXA1, which may play an important role in regulating epithelial cell proliferation and migration during

MicroRNA-99 family members suppress Homeobox A1 expression in epithelial cells.

Directory of Open Access Journals (Sweden)

Dan Chen

Full Text Available The miR-99 family is one of the evolutionarily most ancient microRNA families, and it plays a critical role in developmental timing and the maintenance of tissue identity. Recent studies, including reports from our group, suggested that the miR-99 family regulates various physiological processes in adult tissues, such as dermal wound healing, and a number of disease processes, including cancer. By combining 5 independent genome-wide expression profiling experiments, we identified a panel of 266 unique transcripts that were down-regulated in epithelial cells transfected with miR-99 family members. A comprehensive bioinformatics analysis using 12 different sequence-based microRNA target prediction algorithms revealed that 81 out of these 266 down-regulated transcripts are potential direct targets for the miR-99 family. Confirmation experiments and functional analyses were performed to further assess 6 selected miR-99 target genes, including mammalian Target of rapamycin (mTOR, Homeobox A1 (HOXA1, CTD small phosphatase-like (CTDSPL, N-myristoyltransferase 1 (NMT1, Transmembrane protein 30A (TMEM30A, and SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5. HOXA1 is a known proto-oncogene, and it also plays an important role in embryonic development. The direct targeting of the miR-99 family to two candidate binding sequences located in the HOXA1 mRNA was confirmed using a luciferase reporter gene assay and a ribonucleoprotein-immunoprecipitation (RIP-IP assay. Ectopic transfection of miR-99 family reduced the expression of HOXA1, which, in consequence, down-regulated the expression of its downstream gene (i.e., Bcl-2 and led to reduced proliferation and cell migration, as well as enhanced apoptosis. In summary, we identified a number of high-confidence miR-99 family target genes, including proto-oncogene HOXA1, which may play an important role in regulating epithelial cell proliferation and

The Y-located gonadoblastoma gene TSPY amplifies its own expression through a positive feedback loop in prostate cancer cells

Energy Technology Data Exchange (ETDEWEB)

Kido, Tatsuo; Lau, Yun-Fai Chris, E-mail: Chris.Lau@UCSF.edu

2014-03-28

Highlights: • Y-encoded proto-oncoprotein TSPY amplifies its expression level via a positive feedback loop. • TSPY binds to the chromatin/DNA at exon 1 of TSPY gene. • TSPY enhances the gene expression in a TSPY exon 1 sequence dependent manner. • The conserved SET/NAP-domain is essential for TSPY transactivation. • Insights on probable mechanisms on TSPY exacerbation on cancer development in men. - Abstract: The testis-specific protein Y-encoded (TSPY) is a repetitive gene located on the gonadoblastoma region of the Y chromosome, and has been considered to be the putative gene for this oncogenic locus on the male-only chromosome. It is expressed in spermatogonial cells and spermatocytes in normal human testis, but abundantly in gonadoblastoma, testicular germ cell tumors and a variety of somatic cancers, including melanoma, hepatocellular carcinoma and prostate cancer. Various studies suggest that TSPY accelerates cell proliferation and growth, and promotes tumorigenesis. In this report, we show that TSPY could bind directly to the chromatin/DNA at exon 1 of its own gene, and greatly enhance the transcriptional activities of the endogenous gene in the LNCaP prostate cancer cells. Domain mapping analyses of TSPY have localized the critical and sufficient domain to the SET/NAP-domain. These results suggest that TSPY could efficiently amplify its expression and oncogenic functions through a positive feedback loop, and contribute to the overall tumorigenic processes when it is expressed in various human cancers.

Malignant transformation of diploid human fibroblasts by transfection of oncogenes

Energy Technology Data Exchange (ETDEWEB)

McCormick, J.J.

1992-01-01

This document consist of brief reports prepared by postdoctoral students supported by the project, each describing his accomplishments under the grant. Topics include (1) Malignant Transformation of MSU-1. 1 Cells by Gamma Radiation, (2) Correlation between Levels of ras Expression and Presence of Transformed Phenotypes Including Tumorigenicity, Using a Modulatable Promoter, (3) Relation between Specific rad Oncogene Expression, (4) Correlation of Genetic Changes in Fibroblastic Tumors with Malignancies, (5)Transformation of MSU-1.1 Cells by sis Oncogene, (6) Malignant Transformation of MSU-1.0 Cells, (7) Correlation of Urokinase Plasminogen Activation (mu-PA) with Malignant Phenotype, (8)Two Dimensional Gel Electrophoresis Studies of the Proteins of the Major Cell Strains of the MSU-1 Family of Cells, and (9) Correlation between Proteinase Activity Levels and Malignancy.

Malignant transformation of diploid human fibroblasts by transfection of oncogenes

International Nuclear Information System (INIS)

McCormick, J.J.

1992-01-01

This document consist of brief reports prepared by postdoctoral students supported by the project, each describing his accomplishments under the grant. Topics include (1) Malignant Transformation of MSU-1. 1 Cells by Gamma Radiation, (2) Correlation between Levels of ras Expression and Presence of Transformed Phenotypes Including Tumorigenicity, Using a Modulatable Promoter, (3) Relation between Specific rad Oncogene Expression, (4) Correlation of Genetic Changes in Fibroblastic Tumors with Malignancies, (5)Transformation of MSU-1.1 Cells by sis Oncogene, (6) Malignant Transformation of MSU-1.0 Cells, (7) Correlation of Urokinase Plasminogen Activation (mu-PA) with Malignant Phenotype, (8)Two Dimensional Gel Electrophoresis Studies of the Proteins of the Major Cell Strains of the MSU-1 Family of Cells, and (9) Correlation between Proteinase Activity Levels and Malignancy

From General Aberrant Alternative Splicing in Cancers and Its Therapeutic Application to the Discovery of an Oncogenic DMTF1 Isoform

Directory of Open Access Journals (Sweden)

Na Tian

2017-03-01

Full Text Available Alternative pre-mRNA splicing is a crucial process that allows the generation of diversified RNA and protein products from a multi-exon gene. In tumor cells, this mechanism can facilitate cancer development and progression through both creating oncogenic isoforms and reducing the expression of normal or controllable protein species. We recently demonstrated that an alternative cyclin D-binding myb-like transcription factor 1 (DMTF1 pre-mRNA splicing isoform, DMTF1β, is increasingly expressed in breast cancer and promotes mammary tumorigenesis in a transgenic mouse model. Aberrant pre-mRNA splicing is a typical event occurring for many cancer-related functional proteins. In this review, we introduce general aberrant pre-mRNA splicing in cancers and discuss its therapeutic application using our recent discovery of the oncogenic DMTF1 isoform as an example. We also summarize new insights in designing novel targeting strategies of cancer therapies based on the understanding of deregulated pre-mRNA splicing mechanisms.

Identification of ALV-J associated acutely transforming virus Fu-J carrying complete v-fps oncogene.

Science.gov (United States)

Wang, Yixin; Li, Jianliang; Li, Yang; Fang, Lichun; Sun, Xiaolong; Chang, Shuang; Zhao, Peng; Cui, Zhizhong

2016-06-01

Transduction of oncogenes by ALVs and generation of acute transforming viruses is common in natural viral infections. In order to understand the molecular basis for the rapid oncogenicity of Fu-J, an acutely transforming avian leukosis virus isolated from fibrosarcomas in crossbreed broilers infected with subgroup J avian leukosis virus (ALV-J) in China, complete genomic structure of Fu-J virus was determined by PCR amplification and compared with those of Fu-J1, Fu-J2, Fu-J3, Fu-J4, and Fu-J5 reported previously. The results showed that the genome of Fu-J was defective, with parts of gag gene replaced by the complete v-fps oncogene and encoded a 137 kDa Gag-fps fusion protein. Sequence analysis revealed that Fu-J and Fu-J1 to Fu-J5 were related quasi-species variants carrying different lengths of v-fps oncogenes generated from recombination between helper virus and c-fps gene. Comparison of virus carrying v-fps oncogene also gave us a glimpse of the molecular characterization and evolution process of the acutely transforming ALV.

IQGAP1 is an oncogenic target in canine melanoma.

Directory of Open Access Journals (Sweden)

Becky H Lee

Full Text Available Canine oral mucosal melanoma is an aggressive malignant neoplasm and is characterized by local infiltration and a high metastatic potential. The disease progression is similar to that of human oral melanomas. Whereas human cutaneous melanoma is primarily driven by activating mutations in Braf (60% or Nras (20%, human mucosal melanoma harbors these mutations much less frequently. This makes therapeutic targeting and research modeling of the oral form potentially different from that of the cutaneous form in humans. Similarly, research has found only rare Nras mutations and no activating Braf mutations in canine oral melanomas, but they are still reliant on MAPK signaling. IQGAP1 is a signaling scaffold that regulates oncogenic ERK1/2 MAPK signaling in human Ras- and Raf- driven cancers, including melanomas. To investigate whether IQGAP1 is a potential target in canine melanoma, we examined the expression and localization of IQGAP1 in primary canine melanomas and canine oral melanoma cell lines obtained from the University of California-Davis. Using CRISPR/Cas9 knockout of IQGAP1, we examined effects on downstream ERK1/2 pathway activity and assayed proliferation of cell lines when treated with a peptide that blocks the interaction between IQGAP1 and ERK1/2. We observed that canine IQGAP1 is expressed and localizes to a similar extent in both human and canine melanoma by qPCR, Western blot, and immunofluorescence. Deletion of IQGAP1 reduces MAPK pathway activation in cell lines, similar to effects seen in human BrafV600E cell lines. Additionally, we demonstrated reduced proliferation when these cells are treated with a blocking peptide in vitro.

Identification of Driving ALK Fusion Genes and Genomic Landscape of Medullary Thyroid Cancer.

Directory of Open Access Journals (Sweden)

Jun Ho Ji

2015-08-01

Full Text Available The genetic landscape of medullary thyroid cancer (MTC is not yet fully understood, although some oncogenic mutations have been identified. To explore genetic profiles of MTCs, formalin-fixed, paraffin-embedded tumor tissues from MTC patients were assayed on the Ion AmpliSeq Cancer Panel v2. Eighty-four sporadic MTC samples and 36 paired normal thyroid tissues were successfully sequenced. We discovered 101 hotspot mutations in 18 genes in the 84 MTC tissue samples. The most common mutation was in the ret proto-oncogene, which occurred in 47 cases followed by mutations in genes encoding Harvey rat sarcoma viral oncogene homolog (N = 14, serine/threonine kinase 11 (N = 11, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (N = 6, mutL homolog 1 (N = 4, Kiesten rat sarcoma viral oncogene homolog (N = 3 and MET proto-oncogene (N = 3. We also evaluated anaplastic lymphoma kinase (ALK rearrangement by immunohistochemistry and break-apart fluorescence in situ hybridization (FISH. Two of 98 screened cases were positive for ALK FISH. To identify the genomic breakpoint and 5' fusion partner of ALK, customized targeted cancer panel sequencing was performed using DNA from tumor samples of the two patients. Glutamine:fructose-6-phosphate transaminase 1 (GFPT1-ALK and echinoderm microtubule-associated protein-like 4 (EML4-ALK fusions were identified. Additional PCR analysis, followed by Sanger sequencing, confirmed the GFPT1-ALK fusion, indicating that the fusion is a result of intra-chromosomal translocation or deletion. Notably, a metastatic MTC case harboring the EML4-ALK fusion showed a dramatic response to an ALK inhibitor, crizotinib. In conclusion, we found several genetic mutations in MTC and are the first to identify ALK fusions in MTC. Our results suggest that the EML4-ALK fusion in MTC may be a potential driver mutation and a valid target of ALK inhibitors. Furthermore, the GFPT1-ALK fusion may be a potential candidate for molecular

Enhancers of Polycomb EPC1 and EPC2 sustain the oncogenic potential of MLL leukemia stem cells

Science.gov (United States)

Huang, Xu; Spencer, Gary J; Lynch, James T; Ciceri, Filippo; Somerville, Tim D D; Somervaille, Tim C P

2013-01-01

Through a targeted knockdown (KD) screen of chromatin regulatory genes we identified the EP400 complex components EPC1 and EPC2 as critical oncogenic co-factors in acute myeloid leukemia (AML). EPC1 and EPC2 were required for the clonogenic potential of human AML cells of multiple molecular subtypes. Focusing on MLL-mutated AML as an exemplar, Epc1 or Epc2 KD induced apoptosis of murine MLL-AF9 AML cells and abolished leukemia stem cell potential. By contrast, normal hematopoietic stem and progenitor cells (HSPC) were spared. Similar selectivity was observed for human primary AML cells versus normal CD34+ HSPC. In keeping with these distinct functional consequences, Epc1 or Epc2 KD induced divergent transcriptional consequences in murine MLL-AF9 granulocyte-macrophage progenitor-like (GMP) cells versus normal GMP, with a signature of increased MYC activity in leukemic but not normal cells. This was caused by accumulation of MYC protein and was also observed following KD of other EP400 complex genes. Pharmacological inhibition of MYC:MAX dimerization, or concomitant MYC KD, reduced apoptosis following EPC1 KD, linking the accumulation of MYC to cell death. Therefore EPC1 and EPC2 are components of a complex which directly or indirectly serves to prevent MYC accumulation and AML cell apoptosis, thus sustaining oncogenic potential. PMID:24166297

Oncogenic fusion proteins adopt the insulin-like growth factor signaling pathway.

Science.gov (United States)

Werner, Haim; Meisel-Sharon, Shilhav; Bruchim, Ilan

2018-02-19

The insulin-like growth factor-1 receptor (IGF1R) has been identified as a potent anti-apoptotic, pro-survival tyrosine kinase-containing receptor. Overexpression of the IGF1R gene constitutes a typical feature of most human cancers. Consistent with these biological roles, cells expressing high levels of IGF1R are expected not to die, a quintessential feature of cancer cells. Tumor specific chromosomal translocations that disrupt the architecture of transcription factors are a common theme in carcinogenesis. Increasing evidence gathered over the past fifteen years demonstrate that this type of genomic rearrangements is common not only among pediatric and hematological malignancies, as classically thought, but may also provide a molecular and cytogenetic foundation for an ever-increasing portion of adult epithelial tumors. In this review article we provide evidence that the mechanism of action of oncogenic fusion proteins associated with both pediatric and adult malignancies involves transactivation of the IGF1R gene, with ensuing increases in IGF1R levels and ligand-mediated receptor phosphorylation. Disrupted transcription factors adopt the IGF1R signaling pathway and elicit their oncogenic activities via activation of this critical regulatory network. Combined targeting of oncogenic fusion proteins along with the IGF1R may constitute a promising therapeutic approach.

The small FOXP1 isoform predominantly expressed in activated B cell-like diffuse large B-cell lymphoma and full-length FOXP1 exert similar oncogenic and transcriptional activity in human B cells.

Science.gov (United States)

van Keimpema, Martine; Grüneberg, Leonie J; Schilder-Tol, Esther J M; Oud, Monique E C M; Beuling, Esther A; Hensbergen, Paul J; de Jong, Johann; Pals, Steven T; Spaargaren, Marcel

2017-03-01

The forkhead transcription factor FOXP1 is generally regarded as an oncogene in activated B cell-like diffuse large B-cell lymphoma. Previous studies have suggested that a small isoform of FOXP1 rather than full-length FOXP1, may possess this oncogenic activity. Corroborating those studies, we herein show that activated B cell-like diffuse large B-cell lymphoma cell lines and primary activated B cell-like diffuse large B-cell lymphoma cells predominantly express a small FOXP1 isoform, and that the 5'-end of the Foxp1 gene is a common insertion site in murine lymphomas in leukemia virus- and transposon-mediated insertional mutagenesis screens. By combined mass spectrometry, (quantative) reverse transcription polymerase chain reaction/sequencing, and small interfering ribonucleic acid-mediated gene silencing, we determined that the small FOXP1 isoform predominantly expressed in activated B cell-like diffuse large B-cell lymphoma lacks the N-terminal 100 amino acids of full-length FOXP1. Aberrant overexpression of this FOXP1 isoform (ΔN100) in primary human B cells revealed its oncogenic capacity; it repressed apoptosis and plasma cell differentiation. However, no difference in potency was found between this small FOXP1 isoform and full-length FOXP1. Furthermore, overexpression of full-length FOXP1 or this small FOXP1 isoform in primary B cells and diffuse large B-cell lymphoma cell lines resulted in similar gene regulation. Taken together, our data indicate that this small FOXP1 isoform and full-length FOXP1 have comparable oncogenic and transcriptional activity in human B cells, suggesting that aberrant expression or overexpression of FOXP1, irrespective of the specific isoform, contributes to lymphomagenesis. These novel insights further enhance the value of FOXP1 for the diagnostics, prognostics, and treatment of diffuse large B-cell lymphoma patients. Copyright© Ferrata Storti Foundation.

Functional Analysis of the Proto-oncogenes Septin9 and Nras

DEFF Research Database (Denmark)

Lassen, Louise Berkhoudt

filaments. Both SEPT7 and SEPT9 containing filaments were intensified under hypoxia in wild type cells compared to non-hypoxic cells despite their transcriptional downregulation. Due to earlier finding of Sept9 as a frequent integration site in T-cell lymphomas induced by retrovirus, the function of Sept9...... the murine leukemia virus Akv 1-99 in either sense or antisense direction. In addition a floxed PGK/Tn5 neomycin cassette was inserted. Expression analysis of Nras within knock in was used to study the effect of the LTR. If inserted before the endogenous promoter, the LTR in the antisense direction was found...... of Nras caused early postnatal lethality of the homozygous mice. A thorough analysis revealed that the homozygous mice suffered from granulocytosis and T-cell expansion within the spleen. The increased population of granulocytes was mainly immature, and subsequently a decrease of monocytes was found...

THE OFFICE OF THE PROTOS ARCHON IN BITHYNIA AND THRACE

Directory of Open Access Journals (Sweden)

Ligia Ruscu

2015-12-01

Full Text Available The paper examines the occurrence of the office of the protos archon and of the synarchia in Greek cities of the provinces of Pontus et Bithynia and of Thrace, particularly as it concerns its relevance for the relations and reciprocal influences of the two provinces.

Problem-Solving Test: The Role of a Micro-RNA in the Regulation of "fos" Gene Expression

Science.gov (United States)

Szeberenyi, Jozsef

2009-01-01

The "fos" proto-oncogene codes for a component of the AP1 transcription factor, an important regulator of gene expression and cell proliferation. Dysregulation of AP1 function may lead to the malignant transformation of the cell. The present test describes an experiment in which the role of a micro-RNA (miR-7b) in the regulation of "fos" gene…

Verdad y apertura de mundo. El problema de los juicios sintéticos a priori tras el giro lingüístico

Directory of Open Access Journals (Sweden)

Cristina LAFONT

2009-11-01

Full Text Available RESUMEN: Este artículo analiza el impacto del giro lingüístico en la transformación de la concepción kantiana de los juicios sintéticos a priori. Se centra para ello en dos concepciones contemporáneas de los mismos, a saber, el a priori hermenéutico de Heidegger y el a priori contextual de Putnam, y saca a relucir expresamente tanto sus rasgos similares como sus importantes diferencias: mientras que la concepción heideggeriana mantiene el idealismo transcendental de Kant a través de la suposición hermenéutica de que el significado determina la referencia, la concepción de Putnam rompe por completo con la teoría kantiana de los juicios sintéticos a priori, según la cual éstos no pueden ser modificados por la sola experiencia, al tiempo que rechaza la suposición kantiana de que los juicios sintéticos a priori y aposteriori son dos clases permanentes de juicios. En contraste con Heidegger, Putnam es por eso capaz de mostrar que los juicios sintéticos apriori son modificables bajo condiciones especiales.ABSTRACT: This paper analyzes the impact of the linguistic turn in the transformation of the Kantian conception of the synthetic a priori. It focuses on two contemporary conceptions of the synthetic apriori, namely, Heidegger's hermeneutic apriori and Putnam's contextual apriori and shows their strikingly similar features as well as their important differences: whereas Heidegger's conception retains Kant's transcendental idealism via the hermeneutic assumption that meaning determines reference, Putnam's conception breaks entirely of Kant's conception fo synthetic a priori judgments, namely, that they cannot be revised by experience alone, while rejecting the Kantian assumption that synthetic apriori and aposteriori are permanent statuses of judgments. In contradistinction to Heidegger, Putnam is thus able to show that synthetic apriori judgments are revisable under special conditions.

Induction of human microsomal prostaglandin E synthase 1 by activated oncogene RhoA GTPase in A549 human epithelial cancer cells

Energy Technology Data Exchange (ETDEWEB)

Choi, Hye Jin [Laboratory of Systems Mucosal Biomodulation, Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Lee, Dong-Hyung [Department of Obstetrics and Gynecology, Medical Research Institute, Pusan National University, Busan (Korea, Republic of); Park, Seong-Hwan; Kim, Juil; Do, Kee Hun [Laboratory of Systems Mucosal Biomodulation, Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan (Korea, Republic of); An, Tae Jin; Ahn, Young Sup; Park, Chung Berm [Department of Herbal Crop Research, NIHHS, RDA, Eumseong (Korea, Republic of); Moon, Yuseok, E-mail: moon@pnu.edu [Laboratory of Systems Mucosal Biomodulation, Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Medical Research Institute and Research Institute for Basic Sciences, Pusan National University, Busan (Korea, Republic of)

2011-09-30

Highlights: {yields} As a target of oncogene RhoA-linked signal, a prostaglandin metabolism is assessed. {yields} RhoA activation increases PGE{sub 2} levels and its metabolic enzyme mPGES-1. {yields} RhoA-activated NF-{kappa}B and EGR-1 are positively involved in mPGES-1 induction. -- Abstract: Oncogenic RhoA GTPase has been investigated as a mediator of pro-inflammatory responses and aggressive carcinogenesis. Among the various targets of RhoA-linked signals, pro-inflammatory prostaglandin E{sub 2} (PGE{sub 2}), a major prostaglandin metabolite, was assessed in epithelial cancer cells. RhoA activation increased PGE{sub 2} levels and gene expression of the rate-limiting PGE{sub 2} producing enzymes, cyclooxygenase-2 and microsomal prostaglandin E synthase 1 (mPGES-1). In particular, human mPGES-1 was induced by RhoA via transcriptional activation in control and interleukin (IL)-1{beta}-activated cancer cells. To address the involvement of potent signaling pathways in RhoA-activated mPGES-1 induction, various signaling inhibitors were screened for their effects on mPGES-1 promoter activity. RhoA activation enhanced basal and IL-1{beta}-mediated phosphorylated nuclear factor-{kappa}B and extracellular signal-regulated kinase1/2 proteins, all of which were positively involved in RhoA-induced gene expression of mPGES-1. As one potent down-stream transcription factor of ERK1/2 signals, early growth response gene 1 product also mediated RhoA-induced gene expression of mPGES-1 by enhancing transcriptional activity. Since oncogene-triggered PGE{sub 2} production is a critical modulator of epithelial tumor cells, RhoA-associated mPGES-1 represents a promising chemo-preventive or therapeutic target for epithelial inflammation and its associated cancers.

TUG1: a pivotal oncogenic long non-coding RNA of human cancers.

Science.gov (United States)

Li, Zheng; Shen, Jianxiong; Chan, Matthew T V; Wu, William Ka Kei

2016-08-01

Long non-coding RNAs (lncRNAs) are a group greater than 200 nucleotides in length. An increasing number of studies has shown that lncRNAs play important roles in diverse cellular processes, including proliferation, differentiation, apoptosis, invasion and chromatin remodelling. In this regard, deregulation of lncRNAs has been documented in human cancers. TUG1 is a recently identified oncogenic lncRNA whose aberrant upregulation has been detected in different types of cancer, including B-cell malignancies, oesophageal squamous cell carcinoma, bladder cancer, hepatocellular carcinoma and osteosarcoma. In these malignancies, knock-down of TUG1 has been shown to suppress cell proliferation, invasion and/or colony formation. Interestingly, TUG1 has been found to be downregulated in non-small cell lung carcinoma, indicative of its tissue-specific function in tumourigenesis. Pertinent to clinical practice, TUG1 may act as a prognostic biomarker for tumours. In this review, we summarize current knowledge concerning the role of TUG1 in tumour progression and discuss mechanisms associated with it. © 2016 John Wiley & Sons Ltd.

The Oncogenic Roles of DICER1 RNase IIIb Domain Mutations in Ovarian Sertoli-Leydig Cell Tumors

Directory of Open Access Journals (Sweden)

Yemin Wang

2015-08-01

Full Text Available DICER1, an endoribonuclease required for microRNA (miRNA biogenesis, is essential for embryogenesis and the development of many organs including ovaries. We have recently identified somatic hotspot mutations in RNase IIIb domain of DICER1 in half of ovarian Sertoli-Leydig cell tumors, a rare class of sex-cord stromal cell tumors in young women. These hotspot mutations lost IIIb cleavage activity of DICER1 in vitro and failed to produce 5p-derived miRNAs in mouse Dicer1-null ES cells. However, the oncogenic potential of these hotspot DICER1 mutations has not been studied. Here, we further revealed that the global expression of 5p-derived miRNAs was dramatically reduced in ovarian Sertoli-Leydig cell tumors carrying DICER1 hotspot mutations compared with those without DICER1 hotspot mutation. The miRNA production defect was associated with the deregulation of genes controlling cell proliferation and the cell fate. Using an immortalized human granulosa cell line, SVOG3e, we determined that the D1709N-DICER1 hotspot mutation failed to produce 5p-derived miRNAs, deregulated the expression of several genes that control gonadal differentiation and cell proliferation, and promoted cell growth. Re-expression of let-7 significantly inhibited the growth of D1709N-DICER1 SVOG3e cells, accompanied by the suppression of key regulators of cell cycle control and ovarian gonad differentiation. Taken together, our data revealed that DICER1 hotspot mutations cause systemic loss of 5p-miRNAs that can both drive pseudodifferentiation of testicular elements and cause oncogenic transformation in the ovary.

Comportamiento mecánico de yeso reforzado con polímeros sintéticos

OpenAIRE

García Santos, Alfonso

1988-01-01

Se presenta un estudio de la resistencia mecánica del yeso, basado en su refuerzo mediante la adición de polímeros sintéticos, en forma de fibras y dispersiones acuosas. Se pretende mejorar las características mecánicas del yeso, entre cuyas cualidades se pueden enumerar las siguientes: abundancia en España, bajo coste energético, manejabilidad y propiedades de habitabilidad (acústicas, higrotérmicas, etc.). El aumento de las características mecánicas del yeso permite su utilización como elem...

A Screen Identifies the Oncogenic Micro-RNA miR-378a-5p as a Negative Regulator of Oncogene-Induced Senescence

DEFF Research Database (Denmark)

Kooistra, Susanne Marije; Rudkjær, Lise Christine; Lees, Michael James

2014-01-01

Oncogene-induced senescence (OIS) can occur in response to hyperactive oncogenic signals and is believed to be a fail-safe mechanism protecting against tumorigenesis. To identify new factors involved in OIS, we performed a screen for microRNAs that can overcome or inhibit OIS in human diploid fib...

Complete coding sequence of the human raf oncogene and the corresponding structure of the c-raf-1 gene

Energy Technology Data Exchange (ETDEWEB)

Bonner, T I; Oppermann, H; Seeburg, P; Kerby, S B; Gunnell, M A; Young, A C; Rapp, U R

1986-01-24

The complete 648 amino acid sequence of the human raf oncogene was deduced from the 2977 nucleotide sequence of a fetal liver cDNA. The cDNA has been used to obtain clones which extend the human c-raf-1 locus by an additional 18.9 kb at the 5' end and contain all the remaining coding exons.

Thermal History and Volatile Partitioning between Proto-Atmosphere and Interior of Mars Accreted in a Solar Nebula

Science.gov (United States)

Saito, Hiroaki; Kuramoto, Kiyoshi

2015-11-01

Recent precise Hf-W chronometry of Martian meteorites reveals that Mars had likely reached the half of its present mass within 3 Myr from the birth of the solar system (Dauphas and Pourmand, 2011). Hence, the accretion is considered to almost proceed within the solar nebula associated with the capture of nebula gas components. At the same time, the impact degassing may inevitably occur because impact velocity increases high enough for such degassing when a proto-planet gets larger than around lunar size. Thus, we can expect the formation of a hybrid-type proto-atmosphere that consists of nebula gas and degassed one.This study analyzes the thermal structure of this proto-atmosphere sustained by accretional heating by building a 1D radiative-convective equilibrium model. Raw materials of Mars are supposed to be volatile-rich on the basis of the geochemical systematics of Mars meteorites (Dreibus and Wanke, 1988). The composition of degassed component comprised of H2, H2O, CH4, and CO is determined by chemical equilibrium with silicate and metal under the physical condition of locally heated region generated by each impact (Kuramoto, 1997). Degassed component lies beneath the nebula gas atmosphere at altitudes below the compositional boundary height that would change depending on the amount of degassed component. The accretion time is taken to be from 1 to 6 Myr.Our model predicts that the surface temperature exceeds the liquidus temperature of rock when a proto Mars grows larger than 0.7 times of its present mass for the longest accretion time case. In this case, the magma ocean mass just after the end of accretion is 0.2 times of its present mass if heat transfer and heat sources such as short-lived radionuclides are neglected in the interior. The corresponding amount of water dissolved into the magma ocean would be around 1.8 times the present Earth ocean mass. These results suggest that the earliest Mars would be hot enough to form deep magma oceans, which

The Oncogenic Risks of Diagnostic CT Scam Studies in Children

International Nuclear Information System (INIS)

Brent, R.

2004-01-01

Brenner et al (2001) reported that estimates of the exposure to children from CT scans indicates that the exposures are both higher than from conventional radiographic studies and higher than is necessary to obtain quality examinations. utilizing the oncogenic risk data from the RERF study in Japan, Brenner et al estimated that the oncogenic risk in this population of CT exposed children exposed each year would result in an additional 500 cases of cancer. This risk estimate is supported by the RERF epidemiological data obtained from the populations exposed in Hiroshima and Nagasaki. the increased risks associated with the increased exposure from CT scans have raised concern and stimulated discussion. Although there is little doubt about the benefits of CT scans in improving the health care of children, there is concern about the estimated oncogenic risk, especially since the frequency of CT studies has been increasing. Applying the oncogenic risks of ionizing radiation from the RERF data may not be appropriate for all types of radiation exposure for accurately predicting the incidence of cancer in exposed children because of the impact of 1) partial versus whole-body irradiation, and 2) the protraction of the exposure. Other population of children who have been exposed to radiation and whose incidence of cancer has been studied will be presented and those studies indicate that the risk of cancer is much lower or not increased at all with exposures in the diagnostic range. finally, the dramatic impact of the use of CT scans in clinical pediatric practice saves lives and improves diagnostic accuracy. Therefore, it is crucial that a scholarly evaluation of the risks and benefits should be initiated. The radiology community and the manufacturers have already initiated programs to decrease the exposure significantly. But it is essential that well-planned, retrospective and prospective epidemiology studies should be initiated to study the oncogenic risks. If you want to

Inhibitor of CDK interacting with cyclin A1 (INCA1) regulates proliferation and is repressed by oncogenic signaling

DEFF Research Database (Denmark)

Baumer, Nicole; Tickenbrock, Lara; Tschanter, Petra

2011-01-01

The cell cycle is driven by the kinase activity of cyclin/CDK complexes which is negatively regulated by CDK inhibitor proteins. Recently, we identified INCA1 as interaction partner and substrate of cyclin A1 in complex with CDK2. On a functional level, we identified a novel cyclin binding site...... in the INCA1 protein. INCA1 inhibited CDK2 activity and cell proliferation. The inihibitory effects depended on the cyclin-interacting domain. Mitogenic and oncogenic signals suppressed INCA1 expression, while it was induced by cell cycle arrest. We established a deletional mouse model that showed increased...... CDK2 activity in spleen with altered spleen architecture in Inca1-/- mice. Inca1-/- embryonic fibroblasts showed an increase in the fraction of S-phase cells. Furthermore, blasts from ALL and AML patients expressed significantly reduced INCA1 levels highlighting its relevance for growth control...

A germline RET proto-oncogene mutation in multiple members of an ...

African Journals Online (AJOL)

Makia Marafie

2016-09-17

Sep 17, 2016 ... The Egyptian Journal of Medical Human Genetics (2017) 18, 193–197. HOSTED BY ... been reported in 85% of tested individuals, nearly 50% of them are amino acid .... [1] Krampitz GW, Norton JA. RET gene mutations ...

An oncogenic axis of STAT-mediated BATF3 upregulation causing MYC activity in classical Hodgkin lymphoma and anaplastic large cell lymphoma.

Science.gov (United States)

Lollies, A; Hartmann, S; Schneider, M; Bracht, T; Weiß, A L; Arnolds, J; Klein-Hitpass, L; Sitek, B; Hansmann, M-L; Küppers, R; Weniger, M A

2018-01-01

Classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) feature high expression of activator protein-1 (AP-1) transcription factors, which regulate various physiological processes but also promote lymphomagenesis. The AP-1 factor basic leucine zipper transcription factor, ATF-like 3 (BATF3), is highly transcribed in cHL and ALCL; however, its functional importance in lymphomagenesis is unknown. Here we show that proto-typical CD30 + lymphomas, namely cHL (21/30) and primary mediastinal B-cell lymphoma (8/9), but also CD30 + diffuse large B-cell lymphoma (15/20) frequently express BATF3 protein. Mass spectrometry and co-immunoprecipitation established interactions of BATF3 with JUN and JUNB in cHL and ALCL lines. BATF3 knockdown using short hairpin RNAs was toxic for cHL and ALCL lines, reducing their proliferation and survival. We identified MYC as a critical BATF3 target and confirmed binding of BATF3 to the MYC promoter. JAK/STAT signaling regulated BATF3 expression, as chemical JAK2 inhibition reduced and interleukin 13 stimulation induced BATF3 expression in cHL lines. Chromatin immunoprecipitation substantiated a direct regulation of BATF3 by STAT proteins in cHL and ALCL lines. In conclusion, we identified STAT-mediated BATF3 expression that is essential for lymphoma cell survival and promoted MYC activity in cHL and ALCL, hence we recognized a new oncogenic axis in these lymphomas.

DNA damage and repair in oncogenic transformation by heavy ion radiation

Science.gov (United States)

Yang, T. C.; Mei, M.; George, K. A.; Craise, L. M.

1996-01-01

Energetic heavy ions are present in galactic cosmic rays and solar particle events. One of the most important late effects in risk assessment is carcinogenesis. We have studied the carcinogenic effects of heavy ions at the cellular and molecular levels and have obtained quantitative data on dose-response curves and on the repair of oncogenic lesions for heavy particles with various charges and energies. Studies with repair inhibitors and restriction endonucleases indicated that for oncogenic transformation DNA is the primary target. Results from heavy ion experiments showed that the cross section increased with LET and reached a maximum value of about 0.02 micrometer2 at about 500 keV/micrometer. This limited size of cross section suggests that only a fraction of cellular genomic DNA is important in radiogenic transformation. Free radical scavengers, such as DMSO, do not give any effect on induction of oncogenic transformation by 600 MeV/u iron particles, suggesting most oncogenic damage induced by high-LET heavy ions is through direct action. Repair studies with stationary phase cells showed that the amount of reparable oncogenic lesions decreased with an increase of LET and that heavy ions with LET greater than 200 keV/micrometer produced only irreparable oncogenic damage. An enhancement effect for oncogenic transformation was observed in cells irradiated by low-dose-rate argon ions (400 MeV/u; 120 keV/micrometer). Chromosomal aberrations, such as translocation and deletion, but not sister chromatid exchange, are essential for heavy-ion-induced oncogenic transformation. The basic mechanism(s) of misrepair of DNA damage, which form oncogenic lesions, is unknown.

Rapid internalization of the oncogenic K+ channel K(V10.1.

Directory of Open Access Journals (Sweden)

Tobias Kohl

Full Text Available K(V10.1 is a mammalian brain voltage-gated potassium channel whose ectopic expression outside of the brain has been proven relevant for tumor biology. Promotion of cancer cell proliferation by K(V10.1 depends largely on ion flow, but some oncogenic properties remain in the absence of ion permeation. Additionally, K(V10.1 surface populations are small compared to large intracellular pools. Control of protein turnover within cells is key to both cellular plasticity and homeostasis, and therefore we set out to analyze how endocytic trafficking participates in controlling K(V10.1 intracellular distribution and life cycle. To follow plasma membrane K(V10.1 selectively, we generated a modified channel of displaying an extracellular affinity tag for surface labeling by α-bungarotoxin. This modification only minimally affected K(V10.1 electrophysiological properties. Using a combination of microscopy and biochemistry techniques, we show that K(V10.1 is constitutively internalized involving at least two distinct pathways of endocytosis and mainly sorted to lysosomes. This occurs at a relatively fast rate. Simultaneously, recycling seems to contribute to maintain basal K(V10.1 surface levels. Brief K(V10.1 surface half-life and rapid lysosomal targeting is a relevant factor to be taken into account for potential drug delivery and targeting strategies directed against K(V10.1 on tumor cells.

The oncogenic potential of three different 7, 12-dimethylbenz (a)anthracene transformed C3H/10T1/2 cell clones at various passages and the importance of the mode of immunosuppression

International Nuclear Information System (INIS)

Saxholm, H.J.K.

1979-01-01

The oncogenic potential of C3H/10T1/2 cells which were transformed in vitro with 7,12-dimethylbenz(a)anthracene is reported. The ability of the cells to grow as malignant tumors in syngeneic immunosuppressed mice was used as parameter for oncogenic potential. Cells of types I, II and III were assayed at several dosage levels, i.e., 10 4 , 10 5 or 10 6 cells per inoculum, with or without immunosuppression by antithymocyte serum globulin fraction. The studies were performed in several strains of host animals, i.e., male and female syngeneic C3H mice supplied by the National Cancer Institute, C3H mice supplied by Charles River and nude, athymic female mice. Morphological transformation preceded oncological transformation, and type I cells could not be established as tumors. Type II and type III cells developed oncogenic potential only after several passages in culture. Oncogenic potential was pronounced in the type III cells, and less strongly expressed in type II cells. Also tested were different methods of immunosuppression of the animal against the expression of the oncogenic potential of DMBA transformed C3H/10T1/2 cells from type II and III clones. Immunosuppression by antithymocyte serum globulin fraction was an effective method of preparing the syngeneic host so that cells with a low oncogenic potential would grow as tumors, whereas total body irradiation was not effective. For cells with a high oncogenic potential both ways of immunosuppression were sufficient. Admixing lethally irradiated cells in the cell inoculum slightly enhanced the tumor development from cells with low oncogenic potential and such addition was clearly effective for cells with a higher oncogenic potential, both for the antibody-treated and for the irradiated series. The findings were reproducible. The study stresses the importance of immunosuppression by antithymocyte globulins for detecting in vitro transformed weakly oncogenic cells. (author)

MicroRNA-193b-3p acts as a tumor suppressor by targeting the MYB oncogene in T-cell acute lymphoblastic leukemia.

Science.gov (United States)

Mets, E; Van der Meulen, J; Van Peer, G; Boice, M; Mestdagh, P; Van de Walle, I; Lammens, T; Goossens, S; De Moerloose, B; Benoit, Y; Van Roy, N; Clappier, E; Poppe, B; Vandesompele, J; Wendel, H-G; Taghon, T; Rondou, P; Soulier, J; Van Vlierberghe, P; Speleman, F

2015-04-01

The MYB oncogene is a leucine zipper transcription factor essential for normal and malignant hematopoiesis. In T-cell acute lymphoblastic leukemia (T-ALL), elevated MYB levels can arise directly through T-cell receptor-mediated MYB translocations, genomic MYB duplications or enhanced TAL1 complex binding at the MYB locus or indirectly through the TAL1/miR-223/FBXW7 regulatory axis. In this study, we used an unbiased MYB 3'untranslated region-microRNA (miRNA) library screen and identified 33 putative MYB-targeting miRNAs. Subsequently, transcriptome data from two independent T-ALL cohorts and different subsets of normal T-cells were used to select miRNAs with relevance in the context of normal and malignant T-cell transformation. Hereby, miR-193b-3p was identified as a novel bona fide tumor-suppressor miRNA that targets MYB during malignant T-cell transformation thereby offering an entry point for efficient MYB targeting-oriented therapies for human T-ALL.

The human T-cell leukemia virus type-1 p30II protein activates p53 and induces the TIGAR and suppresses oncogene-induced oxidative stress during viral carcinogenesis.

Science.gov (United States)

Romeo, Megan; Hutchison, Tetiana; Malu, Aditi; White, Averi; Kim, Janice; Gardner, Rachel; Smith, Katie; Nelson, Katherine; Bergeson, Rachel; McKee, Ryan; Harrod, Carolyn; Ratner, Lee; Lüscher, Bernhard; Martinez, Ernest; Harrod, Robert

2018-05-01

In normal cells, aberrant oncogene expression leads to the accumulation of cytotoxic metabolites, including reactive oxygen species (ROS), which can cause oxidative DNA-damage and apoptosis as an intrinsic barrier against neoplastic disease. The c-Myc oncoprotein is overexpressed in many lymphoid cancers due to c-myc gene amplification and/or 8q24 chromosomal translocations. Intriguingly, p53 is a downstream target of c-Myc and hematological malignancies, such as adult T-cell leukemia/lymphoma (ATL), frequently contain wildtype p53 and c-Myc overexpression. We therefore hypothesized that p53-regulated pro-survival signals may thwart the cell's metabolic anticancer defenses to support oncogene-activation in lymphoid cancers. Here we show that the Tp53-induced glycolysis and apoptosis regulator (TIGAR) promotes c-myc oncogene-activation by the human T-cell leukemia virus type-1 (HTLV-1) latency-maintenance factor p30 II , associated with c-Myc deregulation in ATL clinical isolates. TIGAR prevents the intracellular accumulation of c-Myc-induced ROS and inhibits oncogene-induced cellular senescence in ATL, acute lymphoblastic leukemia, and multiple myeloma cells with elevated c-Myc expression. Our results allude to a pivotal role for p53-regulated antioxidant signals as mediators of c-Myc oncogenic functions in viral and non-viral lymphoid tumors. Copyright © 2018 Elsevier Inc. All rights reserved.

An Interaction with Ewing's Sarcoma Breakpoint Protein EWS Defines a Specific Oncogenic Mechanism of ETS Factors Rearranged in Prostate Cancer.

Science.gov (United States)

Kedage, Vivekananda; Selvaraj, Nagarathinam; Nicholas, Taylor R; Budka, Justin A; Plotnik, Joshua P; Jerde, Travis J; Hollenhorst, Peter C

2016-10-25

More than 50% of prostate tumors have a chromosomal rearrangement resulting in aberrant expression of an oncogenic ETS family transcription factor. However, mechanisms that differentiate the function of oncogenic ETS factors expressed in prostate tumors from non-oncogenic ETS factors expressed in normal prostate are unknown. Here, we find that four oncogenic ETS (ERG, ETV1, ETV4, and ETV5), and no other ETS, interact with the Ewing's sarcoma breakpoint protein, EWS. This EWS interaction was necessary and sufficient for oncogenic ETS functions including gene activation, cell migration, clonogenic survival, and transformation. Significantly, the EWS interacting region of ERG has no homology with that of ETV1, ETV4, and ETV5. Therefore, this finding may explain how divergent ETS factors have a common oncogenic function. Strikingly, EWS is fused to various ETS factors by the chromosome translocations that cause Ewing's sarcoma. Therefore, these findings link oncogenic ETS function in both prostate cancer and Ewing's sarcoma. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

A pesquisa com a fosfoetanolamina sintética como inibidor da progressão de tumores

Directory of Open Access Journals (Sweden)

Natália Aparecida Oliveira Caetano

2017-11-01

Full Text Available Introdução: A fosfoetanolamina sintética (FS, conhecida como pílula do câncer, foi apresentada como promissora do tratamento de tumores. Essa substância tem seu mecanismo de ação voltado para as membranas celulares pela transdução de sinais e metabolismo de lipídeos que resultam na indução da apoptose. Objetivo: O presente trabalho avaliou os artigos da literatura que relacionam o uso da substância fosfoetanolamina sintética (FS como inibidor da progressão e disseminação de células tumorais no Brasil. Buscou-se também descrever os possíveis mecanismos associados com a ação da molécula para tratamento de tumores. Método: O trabalho é uma revisão bibliográfica, narrativa, exploratória e integrativa, nas bases de dados Biblioteca Virtual de Saúde, Google acadêmico, Pubmed e Scientific Electronic Library Online (SciELO. Critérios de inclusão: artigos completos disponíveis na literatura nacional e internacional, com palavras FS e tumores. Resultados: A partir de resultados de busca com 65 artigos, foram selecionados 19 artigos. Após análises das fontes de informações acima, foram selecionados os artigos que descreveram os efeitos da fosfoetanolamina sintética e os possíveis mecanismos associados com a ação da FS para tratamento de tumores. Conclusão: A fosfoetanolamina é um composto lipídico em elevada concentração em tumores, associada com elevada taxa de apoptose. Pesquisas préclínicas buscam validar a utilização da FS para tratamento tumoral. Até o presente não há dados que comprovem a eficácia da FS em neoplasias. Estudos clínicos relacionados ao uso da FS em tumores são essenciais para validação do uso da FS. Em abril de 2017, A FS não mostrou eficácia clínica em ensaios preliminares e os testes clínicos foram suspensos pela ANVISA.

CNVs affecting cancer predisposing genes (CPGs) detected as incidental findings in routine germline diagnostic chromosomal microarray (CMA) testing.

Science.gov (United States)

Innes, Josie; Reali, Lisa; Clayton-Smith, Jill; Hall, Georgina; Lim, Derek Hk; Burghel, George J; French, Kim; Khan, Unzela; Walker, Daniel; Lalloo, Fiona; Evans, D Gareth R; McMullan, Dominic; Maher, Eamonn R; Woodward, Emma R

2018-02-01

Identification of CNVs through chromosomal microarray (CMA) testing is the first-line investigation in individuals with learning difficulties/congenital abnormalities. Although recognised that CMA testing may identify CNVs encompassing a cancer predisposition gene (CPG), limited information is available on the frequency and nature of such results. We investigated CNV gains and losses affecting 39 CPGs in 3366 pilot index case individuals undergoing CMA testing, and then studied an extended cohort (n=10 454) for CNV losses at 105 CPGs and CNV gains at 9 proto-oncogenes implicated in inherited cancer susceptibility. In the pilot cohort, 31/3366 (0.92%) individuals had a CNV involving one or more of 16/39 CPGs. 30/31 CNVs involved a tumour suppressor gene (TSG), and 1/30 a proto-oncogene (gain of MET ). BMPR1A , TSC2 and TMEM127 were affected in multiple cases. In the second stage analysis, 49/10 454 (0.47%) individuals in the extended cohort had 50 CNVs involving 24/105 CPGs. 43/50 CNVs involved a TSG and 7/50 a proto-oncogene (4 gains, 3 deletions). The most frequently involved genes, FLCN (n=10) and SDHA (n=7), map to the Smith-Magenis and cri-du-chat regions, respectively. Incidental identification of a CNV involving a CPG is not rare and poses challenges for future cancer risk estimation. Prospective data collection from CPG-CNV cohorts ascertained incidentally and through syndromic presentations is required to determine the risks posed by specific CNVs. In particular, ascertainment and investigation of adults with CPG-CNVs and adults with learning disability and cancer, could provide important information to guide clinical management and surveillance. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

The Melanocyte Fate in Neural Crest is Triggered by Myb Proteins through Activation of c-kit

Czech Academy of Sciences Publication Activity Database

Karafiát, Vít; Dvořáková, Marta; Pajer, Petr; Čermák, Vladimír; Dvořák, Michal

2007-01-01

Roč. 64, č. 21 (2007), s. 2975-2984 ISSN 1420-682X R&D Projects: GA MŠk(CZ) LC06061; GA ČR GA204/06/1728 Institutional research plan: CEZ:AV0Z50520514 Keywords : c-myb proto-oncogene * v-mybAMV oncogene * neural crest * cell fate determination * melanocytes * c-kit signal Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.239, year: 2007

Vidrios sintéticos homogéneos para lodos cementantes = Homogenous synthetic mud-to-cement cementing glasses

NARCIS (Netherlands)

2008-01-01

Una familia de vidrios sintéticos en el campo de la fase cuaternaria de CaO-SiO2-Al2O3-MgO (CSAM) con propiedades hidráulicas y puzolánicas para usar en diferentes aplicaciones en el área cementante de pozos de gas y petróleo. Un método para fabricar una pasta de lodo cementante (MTC) y un método

Trisomy of the Dscr1 gene suppresses early progression of pancreatic intraepithelial neoplasia driven by oncogenic Kras

International Nuclear Information System (INIS)

Lee, Jang Choon; Shin, Jimin; Baek, Kwan-Hyuck

2013-01-01

Highlights: •A single extra copy of Dscr1 restrains progression of PanIN-1A to PanIN-1B lesions. •Dscr1 trisomy attenuates calcineurin–NFAT pathway in neoplastic ductal epithelium. •Dscr1 trisomy leads to upregulation of p15 INK4b in neoplastic ductal epithelium. •A single extra copy of Dscr1 reduces epithelial proliferation in early PanIN lesions. •Dscr1 trisomy may protect Down syndrome individuals from pancreatic cancer. -- Abstract: Individuals with Down syndrome exhibit remarkably reduced incidence of most solid tumors including pancreatic cancer. Multiple mechanisms arising from the genetic complexity underlying Down syndrome has been suggested to contribute to such a broad cancer protection. In this study, utilizing a genetically engineered mouse model of pancreatic cancer, we demonstrate that trisomy of the Down syndrome critical region-1 (Dscr1), an endogenous calcineurin inhibitor localized on chromosome 21, suppresses the progression of pancreatic intraepithelial neoplasia-1A (PanIN-1A) to PanIN-1B lesions without affecting the initiation of PanIN lesions mediated by oncogenic Kras G12D . In addition, we show that Dscr1 trisomy attenuates nuclear localization of nuclear factor of activated T-cells (NFAT) accompanied by upregulation of the p15 Ink4b tumor suppressor and reduction of cell proliferation in early PanIN lesions. Our data suggest that attenuation of calcineurin–NFAT signaling in neoplastic pancreatic ductal epithelium by a single extra copy of Dscr1 is sufficient to inhibit the progression of early PanIN lesions driven by oncogenic Kras, and thus may be a potential mechanism underlying reduced incidence of pancreatic cancer in Down syndrome individuals

Understanding personal risk of oropharyngeal cancer: risk-groups for oncogenic oral HPV infection and oropharyngeal cancer.

Science.gov (United States)

D'Souza, G; McNeel, T S; Fakhry, C

2017-12-01

Incidence of human papillomavirus (HPV)-related oropharyngeal cancer is increasing. There is interest in identifying healthy individuals most at risk for development of oropharyngeal cancer to inform screening strategies. All data are from 2009 to 2014, including 13 089 people ages 20-69 in the National Health and Nutrition Examination Survey (NHANES), oropharyngeal cancer cases from the Surveillance, Epidemiology, and End Results (SEER 18) registries (representing ∼28% of the US population), and oropharyngeal cancer mortality from National Center for Health Statistics (NCHS). Primary study outcomes are (i) prevalence of oncogenic HPV DNA in an oral rinse and gargle sample, and (ii) incident oropharyngeal squamous cell cancer. Oncogenic oral HPV DNA is detected in 3.5% of all adults age 20-69 years; however, the lifetime risk of oropharyngeal cancer is low (37 per 10 000). Among men 50-59 years old, 8.1% have an oncogenic oral HPV infection, 2.1% have an oral HPV16 infection, yet only 0.7% will 'ever' develop oropharyngeal cancer in their lifetime. Oncogenic oral HPV prevalence was higher in men than women, and increased with number of lifetime oral sexual partners and tobacco use. Men who currently smoked and had ≥5 lifetime oral sexual partners had 'elevated risk' (prevalence = 14.9%). Men with only one of these risk factors (i.e. either smoked and had 2-4 partners or did not smoke and had ≥5 partners) had 'medium risk' (7.3%). Regardless of what other risk factors participants had, oncogenic oral HPV prevalence was 'low' among those with only ≤1 lifetime oral sexual partner (women = 0.7% and men = 1.7%). Screening based upon oncogenic oral HPV detection would be challenging. Most groups have low oncogenic oral HPV prevalence. In addition to the large numbers of individuals who would need to be screened to identify prevalent oncogenic oral HPV, the lifetime risk of developing oropharyngeal caner among those with infection remains

Cell Cycle Regulation by Alternative Polyadenylation of CCND1.

Science.gov (United States)

Wang, Qiong; He, Guopei; Hou, Mengmeng; Chen, Liutao; Chen, Shangwu; Xu, Anlong; Fu, Yonggui

2018-05-01

Global shortening of 3'UTRs by alternative polyadenylation (APA) has been observed in cancer cells. However, the role of APA in cancer remains unknown. CCND1 is a proto-oncogene that regulates progression through the G1-S phase of the cell cycle; moreover, it has been observed to be switching to proximal APA sites in cancer cells. To investigate the biological function of the APA of CCND1, we edited the weak poly(A) signal (PAS) of the proximal APA site to a canonical PAS using the CRISPR/Cas9 method, which can force the cells to use a proximal APA site. Cell cycle profiling and proliferation assays revealed that the proximal APA sites of CCND1 accelerated the cell cycle and promoted cell proliferation, but UTR-APA and CR-APA act via different molecular mechanisms. These results indicate that PAS editing with CRISPR/Cas9 provides a good method by which to study the biological function of APA.

Diseño de nuevos ligantes sintéticos a partir de materiales reciclados

OpenAIRE

Fuentes Audén, Cristina

2011-01-01

La mayor parte de los pavimentos actuales están fabricados con una mezcla de áridos minerales ligados con betún de petróleo llamado asfalto. La tecnología del betún ha tenido que adecuarse a un sistema de transporte que demanda cada vez mejor resistencia y durabilidad. De esta forma, el betún está siendo modificado mediante la adición de polímeros. Por otra parte, existen una serie de aplicaciones especiales en las que el betún es sustituido por nuevos materiales llamados ligantes sintéticos....

Un estudio de los indicadores sintéticos de sostenibilidad como instrumentos de planificación

Directory of Open Access Journals (Sweden)

Molina Luque, Julián

2007-01-01

Full Text Available Desde finales de los ochenta el desarrollo sostenible se ha constituido como el objetivo a alcanzar en todos los ámbitos. La gestión de este nuevo objetivo lleva implícita la consideración simultánea de numerosa información de naturaleza económica, social y medioambiental. En los últimos años viene siendo práctica común la definición de un sistema de indicadores de sostenibilidad como principal instrumento de planificación. No obstante, la toma de decisiones de los agentes implicados en la planificación basada en la información proporcionada por dicho sistema no es una tarea sencilla. Para facilitar la utilización de la información contenida en este sistema por parte de los planificadores, los indicadores sintéticos constituyen un importante instrumento. En este contexto, en el presente trabajo se elaboran indicadores sintéticos de sostenibilidad para el caso del sector turístico español, centrando nuestro análisis en el caso de los destinos costeros. Para la obtención de estas medidas se aplican procedimientos de agregación alternativos basados en el Análisis de Componentes Principales y el indicador de distancia DP2.

The Leukemic Stem Cell Niche: Adaptation to “Hypoxia” versus Oncogene Addiction

Directory of Open Access Journals (Sweden)

Giulia Cheloni

2017-01-01

Full Text Available Previous studies based on low oxygen concentrations in the incubation atmosphere revealed that metabolic factors govern the maintenance of normal hematopoietic or leukemic stem cells (HSC and LSC. The physiological oxygen concentration in tissues ranges between 0.1 and 5.0%. Stem cell niches (SCN are placed in tissue areas at the lower end of this range (“hypoxic” SCN, to which stem cells are metabolically adapted and where they are selectively hosted. The data reported here indicated that driver oncogenic proteins of several leukemias are suppressed following cell incubation at oxygen concentration compatible with SCN physiology. This suppression is likely to represent a key positive regulator of LSC survival and maintenance (self-renewal within the SCN. On the other hand, LSC committed to differentiation, unable to stand suppression because of addiction to oncogenic signalling, would be unfit to home in SCN. The loss of oncogene addiction in SCN-adapted LSC has a consequence of crucial practical relevance: the refractoriness to inhibitors of the biological activity of oncogenic protein due to the lack of their molecular target. Thus, LSC hosted in SCN are suited to sustain the long-term maintenance of therapy-resistant minimal residual disease.

Detección de una mutación no estándar en el Proto-oncogen RET por mutagénesis dirigida Detection of a non-standard mutation in the ret protoncogene by site directed mutagenesis

Directory of Open Access Journals (Sweden)

Sebastián Real

2005-03-01

Full Text Available El síndrome de MEN2A es una enfermedad autosómica dominante que se caracteriza por el desarrollo de cáncer medular de tiroides, feocromocitoma e hiperplasia de paratiroides. Mutaciones en el ret proto-oncogén se asocian con MEN2A, con una penetrancia cercana al 100%. El gen se encuentra en el cromosoma 10q11.2 y codifica para una proteína transmembrana con función de receptor del tipo tirosina quinasa. Mutaciones que afectan el dominio extracelular de la proteína estimulan la dimerización espontánea del receptor y un aumento de la actividad de tirosina quinasa basal. El codón 634 codifica para una cisteína, y es considerado un sitio hot-spot por encontrarse mutado en el 85% de las familias con MEN2A. Para este sitio, nuestro grupo desarrolló en 2002 una metodología de detección indirecta y económica. Ante una familia sospechada de MEN2A, se aplicó esta estrategia, que reveló un codón 634 sano. Por posterior secuenciación se confirmó que el paciente índice portaba una mutación en el codón 611. Se desarrolló una nueva estrategia familia-específica por PCR mutagénica, que permitió diagnosticar en nuestro país a todos los integrantes de la familia con costos accesibles. Un niño en el cual se halló la mutación, fue tiroidectomizado preventivamente, y a la fecha goza de buena salud. De esta manera, combinando la estrategia de detección de mutaciones en el sitio hot-spot y un posterior diseño de otra metodología familia-específica se pudo diagnosticar e intervenir preventivamente a la familia, sin enviar todas las muestras al extranjero.MEN2A is an autosomic dominant disease, characterized by medullary thyroid cancer, pheochromocytoma and parathyroid hyperplasia. Mutations in the ret proto-oncogene are associated with this disease, with almost 100% of pennetrance. The gene, situated on chromosome 10q11.2, codes for a transmembrane protein with a tirosinkinase-like receptor function. Mutations that affect its

Effects of cellular non-protein sulfhydryl depletion in radiation induced oncogenic transformation and genotoxicity in mouse C3H 10T1/2 cells

International Nuclear Information System (INIS)

Hei, T.K.; Geard, C.R.; Hall, E.J.

1984-01-01

A study was made of the effects of cellular non-protein sulfhydryl (NPSH) depletion on cytotoxicity, cell cycle kinetics, oncogenic transformation and sister chromatid exchange (SCE) in C 3 H 10T1/2 cells. Using DL-Buthionine S-R-Sulfoximine (BSO) to deplete thiols, it was found spectrophotometrically that less than 5% of control NPSH level remained in the cells after 24-hour treatment under aerated conditions. Such NPSH depleted cells, when subject to a 3 Gy γ-ray treatment, were found to have no radiosensitizing response either in terms of cell survival or oncogenic transformation. In addition, decreased levels of NPSH had no effect on spontaneous or radiation-induced SCE nor were cell cycle kinetics additionally altered. Therefore, the inability of NPSH depletion to alter γ-ray induced cellular transformation was unrelated to any possible effect of BSO on the cell cycle. These results suggest that such depletion may result in little or no additional oncogenic or genotoxic effects on aerated normal tissues

Oncogenic HPV among HIV infected female population in West Bengal, India

Directory of Open Access Journals (Sweden)

Sengupta Sharmila

2011-03-01

Full Text Available Abstract Background Prevalence of both cervical cancer and Human Immunodeficiency Virus (HIV infection are very high in India. Natural history of Human Papilloma Virus (HPV infection is known to be altered in HIV positive women and there is an increased possibility of persistence of HPV infections in this population. Therefore, this study was conducted to understand the epidemiology and circulating genotypes of oncogenic HPV among HIV positive and negative female population in West Bengal, India. Methods In this hospital-based cross-sectional study, 93 known HIV positive females attending a pre-ART registration clinic and 1106 HIV negative females attending a Reproductive and Child Health Care Clinic were subjected to study. Cervical cell samples collected from the study population were tested for the presence of HPV 16, 18 using specific primers. Roche PCR assay was used to detect other specific HPV genotypes in the cervical cells specimens of HIV positive cases only. Results Prevalence of HPV 16, 18 among HIV positive females (32.2%; n = 30 was higher than HIV negative females (9.1%; n = 101. About 53% (23/43 of cases with oncogenic HPV were infected with genotypes other than 16, 18 either as single/multiple infections. HPV 18 and HPV 16 were the predominant genotypes among HIV positive and HIV negative subjects respectively. Oncogenic HPV was not found to be associated with age and duration of sexual exposure. But the presence of HIV was found to a statistically significant predictor oncogenic HPV. Conclusion The currently available HPV vaccines offer protection only against HPV 16 and 18 and some cross- protection to few associated genotypes. These vaccines are therefore less likely to offer protection against cervical cancer in HIV positive women a high percentage of who were infected with non-16 and non-18 oncogenic HPV genotypes. Additionally, there is a lack of sufficient evidence of immunogenicity in HIV infected individuals. Therefore

A Miocene hyperdiverse crocodylian community reveals peculiar trophic dynamics in proto-Amazonian mega-wetlands

Science.gov (United States)

Salas-Gismondi, Rodolfo; Flynn, John J.; Baby, Patrice; Tejada-Lara, Julia V.; Wesselingh, Frank P.; Antoine, Pierre-Olivier

2015-01-01

Amazonia contains one of the world's richest biotas, but origins of this diversity remain obscure. Onset of the Amazon River drainage at approximately 10.5 Ma represented a major shift in Neotropical ecosystems, and proto-Amazonian biotas just prior to this pivotal episode are integral to understanding origins of Amazonian biodiversity, yet vertebrate fossil evidence is extraordinarily rare. Two new species-rich bonebeds from late Middle Miocene proto-Amazonian deposits of northeastern Peru document the same hyperdiverse assemblage of seven co-occurring crocodylian species. Besides the large-bodied Purussaurus and Mourasuchus, all other crocodylians are new taxa, including a stem caiman—Gnatusuchus pebasensis—bearing a massive shovel-shaped mandible, procumbent anterior and globular posterior teeth, and a mammal-like diastema. This unusual species is an extreme exemplar of a radiation of small caimans with crushing dentitions recording peculiar feeding strategies correlated with a peak in proto-Amazonian molluscan diversity and abundance. These faunas evolved within dysoxic marshes and swamps of the long-lived Pebas Mega-Wetland System and declined with inception of the transcontinental Amazon drainage, favouring diversification of longirostrine crocodylians and more modern generalist-feeding caimans. The rise and demise of distinctive, highly productive aquatic ecosystems substantially influenced evolution of Amazonian biodiversity hotspots of crocodylians and other organisms throughout the Neogene. PMID:25716785

Trisomy of the Dscr1 gene suppresses early progression of pancreatic intraepithelial neoplasia driven by oncogenic Kras

Energy Technology Data Exchange (ETDEWEB)

Lee, Jang Choon; Shin, Jimin; Baek, Kwan-Hyuck, E-mail: khbaek@skku.edu

2013-10-11

Highlights: •A single extra copy of Dscr1 restrains progression of PanIN-1A to PanIN-1B lesions. •Dscr1 trisomy attenuates calcineurin–NFAT pathway in neoplastic ductal epithelium. •Dscr1 trisomy leads to upregulation of p15{sup INK4b} in neoplastic ductal epithelium. •A single extra copy of Dscr1 reduces epithelial proliferation in early PanIN lesions. •Dscr1 trisomy may protect Down syndrome individuals from pancreatic cancer. -- Abstract: Individuals with Down syndrome exhibit remarkably reduced incidence of most solid tumors including pancreatic cancer. Multiple mechanisms arising from the genetic complexity underlying Down syndrome has been suggested to contribute to such a broad cancer protection. In this study, utilizing a genetically engineered mouse model of pancreatic cancer, we demonstrate that trisomy of the Down syndrome critical region-1 (Dscr1), an endogenous calcineurin inhibitor localized on chromosome 21, suppresses the progression of pancreatic intraepithelial neoplasia-1A (PanIN-1A) to PanIN-1B lesions without affecting the initiation of PanIN lesions mediated by oncogenic Kras{sup G12D}. In addition, we show that Dscr1 trisomy attenuates nuclear localization of nuclear factor of activated T-cells (NFAT) accompanied by upregulation of the p15{sup Ink4b} tumor suppressor and reduction of cell proliferation in early PanIN lesions. Our data suggest that attenuation of calcineurin–NFAT signaling in neoplastic pancreatic ductal epithelium by a single extra copy of Dscr1 is sufficient to inhibit the progression of early PanIN lesions driven by oncogenic Kras, and thus may be a potential mechanism underlying reduced incidence of pancreatic cancer in Down syndrome individuals.

Evolución de la expresión del grado superlativo absoluto en el adjetivo: las perífrasis sustitutivas del superlativo sintético en español antiguo

OpenAIRE

Serradilla Castaño, Ana María

2005-01-01

El objetivo de este estudio es explicar la evolución sintáctica y semántica del superlativo absoluto perifrástico en español. Al analizar estas perífrasis en español medieval y clásico, se observan ciertas peculiaridades sintácticas: se dan casos de doble intensificación, debidos a un debilitamiento del valor superlativo; hay elementos intercalados entre el adverbio y el adjetivo, y existen casos de adverbio pospuesto; hechos ambos que tienen que ver con la existencia de un ...

FoxA1 as a lineage-specific oncogene in luminal type breast cancer

International Nuclear Information System (INIS)

Yamaguchi, Noritaka; Ito, Emi; Azuma, Sakura; Honma, Reiko; Yanagisawa, Yuka; Nishikawa, Akira; Kawamura, Mika; Imai, Jun-ichi

2008-01-01

The forkhead transcription factor FoxA1 is thought to be involved in mammary tumorigenesis. However, the precise role of FoxA1 in breast cancer development is controversial. We examined expression of FoxA1 in 35 human breast cancer cell lines and compared it with that of ErbB2, a marker of poor prognosis in breast cancer. We found that FoxA1 is expressed at high levels in all ErbB2-positive cell lines and a subset of ErbB2-negative cell lines. Down-regulation of FoxA1 by RNA interference significantly suppressed proliferation of ErbB2-negative and FoxA1-positive breast cancer cell lines. Down-regulation of FoxA1 also enhanced the toxic effect of Herceptin on ErbB2-positive cell lines through induction of apoptosis. Taken together with previous data that FoxA1 is a marker of luminal cells in mammary gland, our present results suggest that FoxA1 plays an important role as a lineage-specific oncogene in proliferation of cancer cells derived from mammary luminal cells

Systematic validation of predicted microRNAs for cyclin D1

International Nuclear Information System (INIS)

Jiang, Qiong; Feng, Ming-Guang; Mo, Yin-Yuan

2009-01-01

MicroRNAs are the endogenous small non-coding RNA molecules capable of silencing protein coding genes at the posttranscriptional level. Based on computer-aided predictions, a single microRNA could have over a hundred of targets. On the other hand, a single protein-coding gene could be targeted by many potential microRNAs. However, only a relatively small number of these predicted microRNA/mRNA interactions are experimentally validated, and no systematic validation has been carried out using a reporter system. In this study, we used luciferease reporter assays to validate microRNAs that can silence cyclin D1 (CCND1) because CCND1 is a well known proto-oncogene implicated in a variety of types of cancers. We chose miRanda (http://www.microRNA.org) as a primary prediction method. We then cloned 51 of 58 predicted microRNA precursors into pCDH-CMV-MCS-EF1-copGFP and tested for their effect on the luciferase reporter carrying the 3'-untranslated region (UTR) of CCND1 gene. Real-time PCR revealed the 45 of 51 cloned microRNA precursors expressed a relatively high level of the exogenous microRNAs which were used in our validation experiments. By an arbitrary cutoff of 35% reduction, we identified 7 microRNAs that were able to suppress Luc-CCND1-UTR activity. Among them, 4 of them were previously validated targets and the rest 3 microRNAs were validated to be positive in this study. Of interest, we found that miR-503 not only suppressed the luciferase activity, but also suppressed the endogenous CCND1 both at protein and mRNA levels. Furthermore, we showed that miR-503 was able to reduce S phase cell populations and caused cell growth inhibition, suggesting that miR-503 may be a putative tumor suppressor. This study provides a more comprehensive picture of microRNA/CCND1 interactions and it further demonstrates the importance of experimental target validation

Sequence variation of functional HTLV-II tax alleles among isolates from an endemic population: lack of evidence for oncogenic determinant in tax.

Science.gov (United States)

Hjelle, B; Chaney, R

1992-02-01

Human T-cell leukemia-lymphoma virus type II (HTLV-II) has been isolated from patients with hairy cell leukemia (HCL). We previously described a population with longstanding endemic HTLV-II infection, and showed that there is no increased risk for HCL in the affected groups. We thus have direct evidence that the endemic form(s) of HTLV-II cause HCL infrequently, if at all. By comparison, there is reason to suspect that the viruses isolated from patients with HCL had an etiologic role in the disease in those patients. One way to reconcile these conflicting observations is to consider that isolates of HTLV-II might differ in oncogenic potential. To determine whether the structure of the putative oncogenic determinant of HTLV-II, tax2, might differ in the new isolates compared to the tax of the prototype HCL isolate, MO, four new functional tax cDNAs were cloned from new isolates. Sequence analysis showed only minor (0.9-2.0%) amino acid variation compared to the published sequence of MO tax2. Some codons were consistently different from published sequences of the MO virus, but in most cases, such variations were also found in each of two tax2 clones we isolated from the MO T-cell line. These variations rendered the new clones more similar to the tax1 of the pathogenic virus HTLV-I. Thus we find no evidence that pathologic determinants of HTLV-II can be assigned to the tax gene.

Adenovirus-Mediated Delivery of Decoy Hyper Binding Sites Targeting Oncogenic HMGA1 Reduces Pancreatic and Liver Cancer Cell Viability.

Science.gov (United States)

Hassan, Faizule; Ni, Shuisong; Arnett, Tyler C; McKell, Melanie C; Kennedy, Michael A

2018-03-30

High mobility group AT-hook 1 (HMGA1) protein is an oncogenic architectural transcription factor that plays an essential role in early development, but it is also implicated in many human cancers. Elevated levels of HMGA1 in cancer cells cause misregulation of gene expression and are associated with increased cancer cell proliferation and increased chemotherapy resistance. We have devised a strategy of using engineered viruses to deliver decoy hyper binding sites for HMGA1 to the nucleus of cancer cells with the goal of sequestering excess HMGA1 at the decoy hyper binding sites due to binding competition. Sequestration of excess HMGA1 at the decoy binding sites is intended to reduce HMGA1 binding at the naturally occurring genomic HMGA1 binding sites, which should result in normalized gene expression and restored sensitivity to chemotherapy. As proof of principle, we engineered the replication defective adenovirus serotype 5 genome to contain hyper binding sites for HMGA1 composed of six copies of an individual HMGA1 binding site, referred to as HMGA-6. A 70%-80% reduction in cell viability and increased sensitivity to gemcitabine was observed in five different pancreatic and liver cancer cell lines 72 hr after infection with replication defective engineered adenovirus serotype 5 virus containing the HMGA-6 decoy hyper binding sites. The decoy hyper binding site strategy should be general for targeting overexpression of any double-stranded DNA-binding oncogenic transcription factor responsible for cancer cell proliferation.

Ejercitar arquitecturas sintácticas / Drilling syntactic structure

Directory of Open Access Journals (Sweden)

Cassany, Daniel

2016-04-01

Full Text Available El artículo rescata la importancia de los conocimientos sintácticos y ofrece sugerencias prácticas de ejercicios que rompen con la gramática prescriptiva tradicional y favorecen el dominio de la sintaxis del español. El objetivo es adecuar los procedimientos de enseñanza y aprendizaje al contexto del enfoque comunicativo. El estudio realizado combina la búsqueda bibliográfica con la sistematización de la práctica escolar a partir de la contextualización de la experiencia adquirida a las potencialidades del mundo digital. El resultado esencial es la caracterización y propuestas de ejercicios que armonizan la perspectiva lingüista y la comunicativa. The paper gives arguments on the importance of syntactic knowledge offering hints of drills that break with the prescriptive traditional grammar and at the same time favor the command of Spanish syntactic structures. The aim is to tailor teaching and learning procedures to the context of the communicative approach. The study combines bibliographic search with the systematization of school practice by contextualizing prior experiences to the potentials of the digital world. The findings offer a characterization of drilling and a proposal of exercises that give harmony to linguistic and communicative perspective.

The oncogenic action of ionizing radiation on rat skin: Progress report, February 1, 1987-January 31, 1988

International Nuclear Information System (INIS)

Burns, F.J.

1987-01-01

The work outlined in this report includes: epidermal DNA strand breaks and radiation penetration; activation of oncogenes in radiation induced rat skin tumors; and rat skin carcinogenesis by neon ions. The effect of radiation penetration on DNA single strand breaks has been studied extensively in rat and mouse epidermis. The results show clearly that the number of strand breaks per unit dose in the epidermal DNA is reduced by 50% to 65% when the radiation penetration is reduced from 1.0 mm to 0.2 mm. This penetration effect on DNA strand breaks was not seen in mouse epidermal cell lines growing in plastic dishes. The results imply that DNA strand breakage in superficial cells is partially dependent on the radiation dose to underlying tissue. The phenomenon is not mediated by systemic interactions as it was observed in irradiated explanted skin. The oncogene activation pattern in the radiation-induced skin tumors was found to be tumor dependent. Either K-ras activation or c-myc amplification or both was observed in each tumor analyzed so far. Even benign fibromas exhibited c-myc amplification. The carcinogenicity of high penetration electrons (2.0 MeV) was determined in preparation for similar studies with a neon ion beam at the Berkeley Bevelac. The principal finding so far is a large excess of connective tissue tumors, fibromas (benign) and sarcomas (malignant). 59 refs., 1 tab

[Oncogenic action of ionizing radiation

International Nuclear Information System (INIS)

1990-01-01

An extensive experiment involving approximately 400 rats exposed to the neon ion beam at the Bevalac in Berkeley, CA and to electrons is nearing completion. The carcinogenicity of energetic electrons was determined for comparison with the neon ion results. As in past reports we will describe progress in three areas corresponding to the specific aims of the proposal: (1) carcinogenesis and DNA strand breaks in rat skin following exposure by the neon ions or electrons; (2) DNA strand breaks in the epidermis as a function of radiation penetration; (3) oncogene activation in radiation-induced rat skin cancers. 72 refs., 6 tabs

Helicon wave field measurements in Proto-MPEX

Science.gov (United States)

Caneses, Juan Francisco; Piotrowicz, Pawel; Goulding, Richard; Caughman, John; Showers, Missy; Kafle, Nischal; Rapp, Juergen; Campbell, Ian; Proto-MPEX Team

2016-10-01

A high density Deuterium discharge (ne 5e19 m-3, Te 4 eV) has been recently observed in ProtoMPEX (Prototype Material Plasma Exposure eXperiment). The discharge (100 kW, 13.56 MHz, D2, 700 G at the source, 1e4 G at the Target) begins with a low density plasma with hollow Te profile and transitions in about 100 ms to a high density mode with flat Te profile. It is believed that the transition to the high density mode is produced by a ``helicon resonance'' as evidenced by the centrally-peaked power deposition profile observed with IR imaging on a 2 mm thick metallic target plate. In this work, we present b-dot probe measurements of the radial helicon wavefields 30 cm downstream of the antenna during both the low and high density modes. In addition, we compare the experimental results with full wave simulations. This manuscript has been authored by UT-Battelle, LLC, under Contract No. DE-AC05-00OR22725 with the U.S. Department of Energy.

Epigenetic Pathways of Oncogenic Viruses: Therapeutic Promises.

Science.gov (United States)

El-Araby, Amr M; Fouad, Abdelrahman A; Hanbal, Amr M; Abdelwahab, Sara M; Qassem, Omar M; El-Araby, Moustafa E

2016-02-01

Cancerous transformation comprises different events that are both genetic and epigenetic. The ultimate goal for such events is to maintain cell survival and proliferation. This transformation occurs as a consequence of different features such as environmental and genetic factors, as well as some types of infection. Many viral infections are considered to be causative agents of a number of different malignancies. To convert normal cells into cancerous cells, oncogenic viruses must function at the epigenetic level to communicate with their host cells. Oncogenic viruses encode certain epigenetic factors that lead to the immortality and proliferation of infected cells. The epigenetic effectors produced by oncogenic viruses constitute appealing targets to prevent and treat malignant diseases caused by these viruses. In this review, we highlight the importance of epigenetic reprogramming for virus-induced oncogenesis, with special emphasis on viral epigenetic oncoproteins as therapeutic targets. The discovery of molecular components that target epigenetic pathways, especially viral factors, is also discussed. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Assessment of differential expression of oncogenes in adenocarcinoma of stomach with fluorescent labeling and simultaneous amplification of gene transcripts

International Nuclear Information System (INIS)

Rajcevic, U.; Hudler, P.; Komel, R.; Mijovski, G.; Gorjanc, G.; Kovac, M.; Hoelzl, G.; Repse, S.; Juvan, R.; Huber, C.G.

2007-01-01

Background. Gastric cancer is one of the leading malignancies with a poor prognosis and low survival rates. Although the mechanisms underlying its development are still unknown, there is a consensus that genetic instability, inactivation of tumor suppressor genes and over-expression of oncogenes are involved in the early and late stages of gastric carcinogenesis. In the present study we wanted to display differential expression of seven oncogenes, namely CCNE1, EGF, ERBB3, FGF4, HRG1, HGFR and TDGF1. Patients and methods. We employed a method based on the multiplex reverse transcription polymerase chain (RT-PCR) method with a fluorescence detection. Results. More than half of patients (74.3%) out of total 74 with gastric adenocarcinoma had over-expressed at least one oncogene, with the exception of FGF4, which was expressed in tumor tissue of less than one third of patients. 56.8% of the patients patients showed over-expression of two or more oncogenes. Conclusions. Patients with precancerous lesions had elevated levels of TDGF1 or cripto-1 (64.9%) and CCNE1 (57.1%), suggesting that they could be used as markers for an early detection of malignant changes in stomach. Finally, the fluorescent multiplex RT-PCR method could be of value for rapid assessment of oncogene mRNA levels in small samples of tumor or precancerous biopsies. (author)

Oncogenes Activate an Autonomous Transcriptional Regulatory Circuit That Drives Glioblastoma

Directory of Open Access Journals (Sweden)

Dinesh K. Singh

2017-01-01

Full Text Available Efforts to identify and target glioblastoma (GBM drivers have primarily focused on receptor tyrosine kinases (RTKs. Clinical benefits, however, have been elusive. Here, we identify an SRY-related box 2 (SOX2 transcriptional regulatory network that is independent of upstream RTKs and capable of driving glioma-initiating cells. We identified oligodendrocyte lineage transcription factor 2 (OLIG2 and zinc-finger E-box binding homeobox 1 (ZEB1, which are frequently co-expressed irrespective of driver mutations, as potential SOX2 targets. In murine glioma models, we show that different combinations of tumor suppressor and oncogene mutations can activate Sox2, Olig2, and Zeb1 expression. We demonstrate that ectopic co-expression of the three transcription factors can transform tumor-suppressor-deficient astrocytes into glioma-initiating cells in the absence of an upstream RTK oncogene. Finally, we demonstrate that the transcriptional inhibitor mithramycin downregulates SOX2 and its target genes, resulting in markedly reduced proliferation of GBM cells in vivo.

Reconstructing the Prostate Cancer Transcriptional Regulatory Network

Science.gov (United States)

2010-09-01

and disease prognosis. J Clin Oncol 2006;24:3763–70. 13. Klein CA, Schmidt- Kittler O, Schardt JA, Pantel K, Speicher MR, Riethmuller G. Comparative...Cancer Gene Discovery Jessica Kao1., Keyan Salari1,2., Melanie Bocanegra1, Yoon-La Choi1,3, Luc Girard4, Jeet Gandhi4, Kevin A. Kwei1, Tina Hernandez...JM, Klein RC, Oka M, Cowan KH (1995) Posttranscriptional regulation of the c-myb proto-oncogene in estrogen receptor-positive breast cancer cells

V-cbl, an oncogene from a dual-recombinant murine retrovirus that induces early B-lineage lymphomas

International Nuclear Information System (INIS)

Langdon, W.Y.; Klinken, S.P.; Hartley, J.W.; Morse, H.C. III; Ruscetti, S.K.

1989-01-01

Cas NS-1 is an acutely transforming murine retrovirus that induces pre-B and pro-B cell lymphomas. Molecular cloning showed it was generated from the ecotropic Cas-Br-M virus by sequential recombinations with endogenous retroviral sequences and a cellular oncogene. The oncogene sequence shows no homology with known oncogenes but some similarity to the yeast transcriptional activator GCN4. A 100-kDa gag-cbl fusion protein, with no detectable kinase activity, is responsible for the cellular transformation. The cellular homologue of v-cbl, present in mouse and human DNA, is expressed in a range of hemopoietic lineages

B lymphoma Moloney murine leukemia virus insertion region 1: An oncogenic mediator in prostate cancer.

Science.gov (United States)

Liu, Qipeng; Li, Qiaqia; Zhu, Sen; Yi, Yang; Cao, Qi

2018-06-01

B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1), a core member of polycomb repressive complex 1 (PRC1), has been intensely investigated in the field of cancer epigenetics for decades. Widely known as a critical regulator in cellular physiology, BMI1 is essential in self-renewal and differentiation in different lineages of stem cells. BMI1 also plays a significant role in cancer etiology for its involvement in pathological progress such as epithelial-mesenchymal transition (EMT) and cancer stem cell maintenance, propagation, and differentiation. Importantly, overexpression of BMI1 is predictive for drug resistance, tumor recurrence, and eventual therapy failure of various cancer subtypes, which renders the pharmacological targeting at BMI1 as a novel and promising therapeutic approach. The study on prostate cancer, a prevalent hormone-related cancer among men, has promoted enormous research advancements in cancer genetics and epigenetics. This review summarizes the role of BMI1 as an oncogenic and epigenetic regulator in tumor initiation, progression, and relapse of prostate cancer.

Identification of an intracellular protein that specifically interacts with photoaffinity-labeled oncogenic p21 protein

International Nuclear Information System (INIS)

Lee, G.; Ronai, Z.A.; Pincus, M.R.; Brandt-Rauf, P.W.; Weinstein, I.B.; Murphy, R.B.; Delohery, T.M.; Nishimura, S.; Yamaizumi, Z.

1989-01-01

An oncogenic 21-kDa (p21) protein (Harvey RAS protein with Val-12) has been covalently modified with a functional reagent that contains a photoactivatable aromatic azide group. This modified p21 protein has been introduced quantitatively into NIH 3T3 cells using an erythrocyte-mediated fusion technique. The introduced p21 protein was capable of inducing enhanced pinocytosis and DNA synthesis in the recipient cells. To identify the putative intracellular protein(s) that specifically interact with modified p21 protein, the cells were pulsed with [ 35 S]methionine at selected times after fusion and then UV-irradiated to activate the azide group. The resulting nitrene covalently binds to amino acid residues in adjacent proteins, thus linking the p21 protein to these proteins. The cells were then lysed, and the lysate was immunoprecipitated with the anti-p21 monoclonal antibody Y13-259. The immunoprecipitate was analyzed by SDS/PAGE to identify p21 - protein complexes. By using this technique, the authors found that three protein complexes of 51, 64, and 82 kDa were labeled specifically and reproducibly. The most prominent band is the 64-kDa protein complex that shows a time-dependent rise and fall, peaking within a 5-hr period after introduction of the p21 protein the cells. These studies provide evidence that in vitro the p21 protein becomes associated with a protein whose mass is about 43 kDa. They suggest that the formation of this complex may play a role in mediating early events involved with cell transformation induced by RAS oncogenes

Functional Characterization of PaLAX1, a Putative Auxin Permease, in Heterologous Plant Systems1[W][OA

Science.gov (United States)

Hoyerová, Klára; Perry, Lucie; Hand, Paul; Laňková, Martina; Kocábek, Tomáš; May, Sean; Kottová, Jana; Pačes, Jan; Napier, Richard; Zažímalová, Eva

2008-01-01

We have isolated the cDNA of the gene PaLAX1 from a wild cherry tree (Prunus avium). The gene and its product are highly similar in sequences to both the cDNAs and the corresponding protein products of AUX/LAX-type genes, coding for putative auxin influx carriers. We have prepared and characterized transformed Nicotiana tabacum and Arabidopsis thaliana plants carrying the gene PaLAX1. We have proved that constitutive overexpression of PaLAX1 is accompanied by changes in the content and distribution of free indole-3-acetic acid, the major endogenous auxin. The increase in free indole-3-acetic acid content in transgenic plants resulted in various phenotype changes, typical for the auxin-overproducing plants. The uptake of synthetic auxin, 2,4-dichlorophenoxyacetic acid, was 3 times higher in transgenic lines compared to the wild-type lines and the treatment with the auxin uptake inhibitor 1-naphthoxyacetic acid reverted the changes caused by the expression of PaLAX1. Moreover, the agravitropic response could be restored by expression of PaLAX1 in the mutant aux1 plants, which are deficient in auxin influx carrier activity. Based on our data, we have concluded that the product of the gene PaLAX1 promotes the uptake of auxin into cells, and, as a putative auxin influx carrier, it affects the content and distribution of free endogenous auxin in transgenic plants. PMID:18184737

Determination of the transforming activities of adenovirus oncogenes.

Science.gov (United States)

Speiseder, Thomas; Nevels, Michael; Dobner, Thomas

2014-01-01

The last 50 years of molecular biological investigations into human adenoviruses (Ads) have contributed enormously to our understanding of the basic principles of normal and malignant cell growth. Much of this knowledge stems from analyses of the Ad productive infection cycle in permissive host cells. Also, initial observations concerning the transforming potential of human Ads subsequently revealed decisive insights into the molecular mechanisms of the origins of cancer and established Ads as a model system for explaining virus-mediated transformation processes. Today it is well established that cell transformation by human Ads is a multistep process involving several gene products encoded in early transcription units 1A (E1A) and 1B (E1B). Moreover, a large body of evidence now indicates that alternative or additional mechanisms are engaged in Ad-mediated oncogenic transformation involving gene products encoded in early region 4 (E4) as well as epigenetic changes resulting from viral DNA integration. In particular, studies on the transforming potential of several E4 gene products have now revealed new pathways that point to novel general mechanisms of virus-mediated oncogenesis. In this chapter we describe in vitro and in vivo assays to determine the transforming and oncogenic activities of the E1A, E1B, and E4 oncoproteins in primary baby rat kidney cells, human amniotic fluid cells and athymic nude mice.

A Miocene hyperdiverse crocodylian community reveals peculiar trophic dynamics in proto-Amazonian mega-wetlands.

Science.gov (United States)

Salas-Gismondi, Rodolfo; Flynn, John J; Baby, Patrice; Tejada-Lara, Julia V; Wesselingh, Frank P; Antoine, Pierre-Olivier

2015-04-07

Amazonia contains one of the world's richest biotas, but origins of this diversity remain obscure. Onset of the Amazon River drainage at approximately 10.5 Ma represented a major shift in Neotropical ecosystems, and proto-Amazonian biotas just prior to this pivotal episode are integral to understanding origins of Amazonian biodiversity, yet vertebrate fossil evidence is extraordinarily rare. Two new species-rich bonebeds from late Middle Miocene proto-Amazonian deposits of northeastern Peru document the same hyperdiverse assemblage of seven co-occurring crocodylian species. Besides the large-bodied Purussaurus and Mourasuchus, all other crocodylians are new taxa, including a stem caiman-Gnatusuchus pebasensis-bearing a massive shovel-shaped mandible, procumbent anterior and globular posterior teeth, and a mammal-like diastema. This unusual species is an extreme exemplar of a radiation of small caimans with crushing dentitions recording peculiar feeding strategies correlated with a peak in proto-Amazonian molluscan diversity and abundance. These faunas evolved within dysoxic marshes and swamps of the long-lived Pebas Mega-Wetland System and declined with inception of the transcontinental Amazon drainage, favouring diversification of longirostrine crocodylians and more modern generalist-feeding caimans. The rise and demise of distinctive, highly productive aquatic ecosystems substantially influenced evolution of Amazonian biodiversity hotspots of crocodylians and other organisms throughout the Neogene. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Influencia de acondicionadores sintéticos y orgánicos en cuatro suelos del Valle del Cauca

Directory of Open Access Journals (Sweden)

Madriñan Molina Raúl

1990-06-01

Full Text Available A cuatro tipos de suelos con problemas de compactación – Fluventic haplustoll (1, Pachic haplustoll (2, Typic pellustert (3 y Petrocalcic natrustalf (4 - se les aplicaron Potasium propenoate, dos dosis del producto en seco y dos dosis en líquido, cachaza y gallinaza. La planta indicadora fue la soya P-32. El experimento se diseñó completamente al azar, con nueve tratamientos y tres replicaciones. En área foliar y producción de materia seca total, mostraron diferencias significativas los tratamientos con acondicionador sin rético en forma líquida en el suelo 1; las 2 dosis del acondicionador sintético en forma sólida lo mismo que la gallinaza mostraron diferencias significativas en los suelos 2 y 3. Se encontraron diferencias significativas para los tratamientos con acondicionador sintético en espacio aéreo para los suelos 1,2 Y 3; en densidad aparente en seco yen húmedo yen resistencia al penetrómetro para el suelo 2. Los análisis químicos del suelo realizados al finalizar el experimento mostraron niveles inadecuados en elementos mayores y menores, excepto boro, en los suelos 1, 2 y 3.The purpose of this work was to investigate the effect of one synthetic soil conditioner (potassium propenoate and two kinds of organic products (sugar Mill factory residue and poultry manure in the physical properties of soils with compactación problems of the Cauca Valley. Four types of soils were utilized: fluventic haplustoll (1, Pachic haplustoll (2, Typic pellustert (3, and Petrocalcic natrustalf (4. Soybean P-32 was indicator plant, utilizing a completely randomized block design with nine treatments and three replications. The leaf area and yield of total dry matter were significatively better with syntetic conditioner in liquid form for soil L; the soil conditioner applied in solid form and the poultry manure were of significant levels for soils 2 and 3. Significant differences were found in favor of the synthetic conditioner for the air

Proto pectin degradation of raw material by the acid hydrolysis

International Nuclear Information System (INIS)

Khalikov, D.Kh.; Gorshkova, R.M.; Khalikova, S.; Avloev, Kh.Kh.; Mukhiddinov, Z.K.

2007-01-01

The article presents results of hydrolysis proto pectin apples, an orange and a basket of sunflower depending on ph a solution. The reaction products are divided into three fractions conditionally named as micro gel, pectin substances and oligosaccharide. It was shown that the high-quality pectin extracted from orange, but high percentage of carboxylic group in the sunflower pectin allow it to by used as a drug delivery materials

Proto-2, an ALICE detector prototype, went to the United States (during transport)

CERN Multimedia

2002-01-01

Proto-2, an ALICE detector prototype, overcame its prototype status to become a real part of the STAR experiment at the US Brookhaven National Laboratory.After more than two years across the ocean, it has just arrived back at CERN

Somatic RET mutation in a patient with pigmented adrenal pheochromocytoma

NARCIS (Netherlands)

Maison, Nicole; Korpershoek, Esther; Eisenhofer, Graeme; Robledo, Mercedes; de Krijger, Ronald; Beuschlein, Felix

UNLABELLED: Pheochromocytomas (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors arising from chromaffin cells of the neural crest. Mutations in the RET-proto-oncogene are associated with sporadic pheochromocytoma, familial or sporadic medullary thyroid carcinoma (MTC) and multiple

El desafío de los datos sintácticos en los diccionarios para aprendices extranjeros del español

DEFF Research Database (Denmark)

Tarp, Sven

2018-01-01

Esta contribución trata de los datos sintácticos en los diccionarios para aprendices extranjeros del español. Empezará con una discusión sobre la dialéctica entre gramáticas y diccionarios a la luz de las nuevas posibilidades que ofrecen las tecnologías de computación e información. A continuació...

Utwory formacji wierzowskej na tle wcesnokredowych warunków sedymentacji w zachodnej cześci basenu protoślaskiego (Morawy, Republika Czeska)

Czech Academy of Sciences Publication Activity Database

Waśkowska, A.; Golonka, J.; Strzeboński, P.; Krobicki, M.; Vašíček, Zdeněk; Skupien, P.

2009-01-01

Roč. 35, 2/1 (2009), s. 31-38 ISSN 0138-0974 Institutional research plan: CEZ:AV0Z30860518 Keywords : Outer Western Carpathians * Veřovice Formation * proto - Silesian Basin Subject RIV: DB - Geology ; Mineralogy

A influência da calcitonina sintética de salmão na cicatrização cutânea de ratos

Directory of Open Access Journals (Sweden)

José Neiva Eulálio

Full Text Available OBJETIVO: O presente trabalho tem como objetivo investigar a influência da calcitonina sintética do salmão no processo cicatricial da pele da região dorsal em ratos, analisando parâmetros bioquímicos, biomecânicos e histológicos, e suas possíveis interrelações. MÉTODO: Setenta e dois (72 ratos machos adultos foram submetidos, sob anestesia geral inalatória a uma incisão linear na pele que foi, subseqüentemente, suturada. Metade dos ratos (grupo teste foi tratada no pós-operatório com calcitonina sintética do salmão, e a outra metade, sem tratamento, constituiu o grupo controle. Os animais, em pares de nove ratos cada (teste e controle, foram sacrificados no 5º, 10º, 15º e 20º dias pós-operatório para a remoção dos fragmentos de pele com cicatriz para as análises bioquímicas, biomecânicas e histológicas. Utilizou-se o teste "t" de Student para a comparação de médias de amostras independentes e o teste de correlação de Pearson para verificar o grau de associação entre as médias das variáveis. RESULTADOS: A calcitonina sintética de salmão acelerou o processo cicatricial da pele, mas não de maneira linear e constante. Em comparação com os animais não-tratados, houve aumento significativo tanto do conteúdo de hidroxiprolina nas fases de proliferação inicial e tardia da cicatrização, quanto da carga máxima de ruptura na fase de proliferação tardia. Os resultados histológicos corroboram os resultados bioquímicos e biomecânicos, sugerindo uma correlação entre conteúdo de colágeno, resistência à tração e histologia da cicatriz. CONCLUSÃO: A calcitonina sintética de salmão acelerou o processo cicatricial da pele, modificando significativamente o conteúdo de colágeno e a carga máxima de ruptura, mas não de maneira linear e constante.

Imaging manifestations and its clinical significance in patients with oncogenic osteomalacia

International Nuclear Information System (INIS)

Yu Wei; Lin Qiang; Zhang Yunqing; Jiang Bo; Jin Jin; Jiang Yan; Li Mei; Li Fang

2006-01-01

Objective: To compare images from different modality for detecting lesions in patients with oncogenic osteomalacia. Methods: Eight patients with oncogenic osteomalacia were recruited in this study. The age ranged from 28 to 69 years (mean age 44.1, 5 men and 3 women). All patients were diagnosed as osteomalacia according to their clinical and radiographic manifestations. Main laboratory tests included serum calcium, phosphorus, alkaline phosphatase activity, parathyroid hormone, urinary phosphorus as well as liver and renal functions. Octreotide scans were performed for all patients according to clinical request for confirming the oncogenic osteomalacia. Further examinations of MR imaging in 8 patients, spiral CT in four patients and conventional radiography in four patients were obtained after the octreotide scans respectively. All patients had operation for their tumor resections and for the pathologic diagnostic findings. Results: Abnormal laboratory findings in all patients included low serum phosphorus level (ranged from 0.29 to 0.65 mmol·L -1 ), elevated alkaline phosphatase activity (ranged from 36. 6 to 310.6 μmol·s -1 ·L -1 ) as well as urinary phosphorus level (ranged from 11.5 to 40. 9 mmol·L -1 ). Normal results included parathyroid hormone level, liver and renal functions. Pathology confirmed the diagnosis of 4 soft tissue tumors including 1 hemangiomas, 1 giant-cell tumor of tendon sheath, 1 hemangiopericytoma and 1 mesenchymal tumor, as well as 4 bone tumors including 1 malignant neurofibroma, 2 mesenchymal tumors and 1 fibroblastoma. All lesions were shown abnormal region of increasing uptake tracer on octreotide scans. However, the octreotide scans could not determine where (bone or soft tissues) the lesions located. MR imaging could differentiate the lesions within the bone or within the soft tissues in all patients. All lesions had hypo- or iso- signal intensity on T 1 WI and high signal intensity on T 2 WI with heterogeneous in 6 tumors and

The oncogenic properties of EWS/WT1 of desmoplastic small round cell tumors are unmasked by loss of p53 in murine embryonic fibroblasts

International Nuclear Information System (INIS)

Bandopadhayay, Pratiti; Thomas, David M; Algar, Elizabeth; Ekert, Paul G; Jabbour, Anissa M; Riffkin, Christopher; Salmanidis, Marika; Gordon, Lavinia; Popovski, Dean; Rigby, Lin; Ashley, David M; Watkins, David N

2013-01-01

Desmoplastic small round cell tumor (DSRCT) is characterized by the presence of a fusion protein EWS/WT1, arising from the t (11;22) (p13;q12) translocation. Here we examine the oncogenic properties of two splice variants of EWS/WT1, EWS/WT1-KTS and EWS/WT1 + KTS. We over-expressed both EWS/WT1 variants in murine embryonic fibroblasts (MEFs) of wild-type, p53 +/- and p53 -/- backgrounds and measured effects on cell-proliferation, anchorage-independent growth, clonogenicity after serum withdrawal, and sensitivity to cytotoxic drugs and gamma irradiation in comparison to control cells. We examined gene expression profiles in cells expressing EWS/WT1. Finally we validated our key findings in a small series of DSRCT. Neither isoform of EWS/WT1 was sufficient to transform wild-type MEFs however the oncogenic potential of both was unmasked by p53 loss. Expression of EWS/WT1 in MEFs lacking at least one allele of p53 enhanced cell-proliferation, clonogenic survival and anchorage-independent growth. EWS/WT1 expression in wild-type MEFs conferred resistance to cell-cycle arrest after irradiation and daunorubicin induced apoptosis. We show DSRCT commonly have nuclear localization of p53, and copy-number amplification of MDM2/MDMX. Expression of either isoform of EWS/WT1 induced characteristic mRNA expression profiles. Gene-set enrichment analysis demonstrated enrichment of WNT pathway signatures in MEFs expressing EWS/WT1 + KTS. Wnt-activation was validated in cell lines with over-expression of EWS/WT1 and in DSRCT. In conclusion, we show both isoforms of EWS/WT1 have oncogenic potential in MEFs with loss of p53. In addition we provide the first link between EWS/WT1 and Wnt-pathway signaling. These data provide novel insights into the function of the EWS/WT1 fusion protein which characterize DSRCT

Characterization of ion fluxes and heat fluxes for PMI relevant conditions on Proto-MPEX

Science.gov (United States)

Beers, Clyde; Shaw, Guinevere; Biewer, Theodore; Rapp, Juergen

2016-10-01

Plasma characterization, in particular, particle flux and electron and ion temperature distributions nearest to an exposed target, are critical to quantifying Plasma Surface Interaction (PSI). In the Proto-Material Plasma Exposure eXperiment (Proto-MPEX), the ion fluxes and heat fluxes are derived from double Langmuir Probes (DLP) and Thomson Scattering in front of the target assuming Bohm conditions at the sheath entrance. Power fluxes derived from ne and Te measurements are compared to heat fluxes measured with IR thermography. The comparison will allow conclusions on the sheath heat transmission coefficient to be made experimentally. Different experimental conditions (low and high density plasmas (0.5 - 6 x 1019 m-3) with different magnetic configuration are compared. This work was supported by the U.S. D.O.E. contract DE-AC05-00OR22725.

Transformation and oncogenicity by Adenoviruses

NARCIS (Netherlands)

Bernards, R.A.; Eb, A.J. van der

1984-01-01

Adenoviruses have attracted considerable attention since it was discovered by TRENTIN et all. and HUEBNER et al. that certain species (formerly called serotypes) are oncogenic when injected into newborn hamsters. Since then, adenoviruses have been used extensively as a model for studies on tumor

Oncogenic N-Ras Stimulates SRF-Mediated Transactivation via H3 Acetylation at Lysine 9

Directory of Open Access Journals (Sweden)

Sun-Ju Yi

2018-01-01

Full Text Available Signal transduction pathways regulate the gene expression by altering chromatin dynamics in response to mitogens. Ras proteins are key regulators linking extracellular stimuli to a diverse range of biological responses associated with gene regulation. In mammals, the three ras genes encode four Ras protein isoforms: H-Ras, K-Ras4A, K-Ras4B, and N-Ras. Although emerging evidence suggests that Ras isoforms differentially regulate gene expressions and are functionally nonredundant, the mechanisms underlying Ras specificity and Ras signaling effects on gene expression remain unclear. Here, we show that oncogenic N-Ras acts as the most potent regulator of SRF-, NF-κB-, and AP-1-dependent transcription. N-Ras-RGL2 axis is a distinct signaling pathway for SRF target gene expression such as Egr1 and JunB, as RGL2 Ras binding domain (RBD significantly impaired oncogenic N-Ras-induced SRE activation. By monitoring the effect of Ras isoforms upon the change of global histone modifications in oncogenic Ras-overexpressed cells, we discovered that oncogenic N-Ras elevates H3K9ac/H3K23ac levels globally in the chromatin context. Importantly, chromatin immunoprecipitation (ChIP assays revealed that H3K9ac is significantly enriched at the promoter and coding regions of Egr1 and JunB. Collectively, our findings define an undocumented role of N-Ras in modulating of H3 acetylation and in gene regulation.

Targeting oncogenic Myc as a strategy for cancer treatment.

Science.gov (United States)

Chen, Hui; Liu, Hudan; Qing, Guoliang

2018-01-01

The MYC family oncogene is deregulated in >50% of human cancers, and this deregulation is frequently associated with poor prognosis and unfavorable patient survival. Myc has a central role in almost every aspect of the oncogenic process, orchestrating proliferation, apoptosis, differentiation, and metabolism. Although Myc inhibition would be a powerful approach for the treatment of many types of cancers, direct targeting of Myc has been a challenge for decades owing to its "undruggable" protein structure. Hence, alternatives to Myc blockade have been widely explored to achieve desirable anti-tumor effects, including Myc/Max complex disruption, MYC transcription and/or translation inhibition, and Myc destabilization as well as the synthetic lethality associated with Myc overexpression. In this review, we summarize the latest advances in targeting oncogenic Myc, particularly for cancer therapeutic purposes.

Modulating factors in the expression of radiation-induced oncogenic transformation

International Nuclear Information System (INIS)

Hall, E.J.; Hei, T.K.

1990-01-01

Many assays for oncogenic transformation have been developed ranging from those in established rodent cell lines where morphological alteration is scored, to those in human cells growing in nude mice where tumor invasiveness is scored. In general, systems that are most quantitaive are also the least relevant in terms of human carcinogenesis and human risk estimation. The development of cell culture systems has made it possible to assess at the cellular level the oncogenic potential of a variety of chemical, physical and viral agents. Cell culture systems afford the opportunity to identify factors and conditions that may prevent or enhance cellular transformation by radiation and chemicals. Permissive and protective factors in radiation-induced transformation include thyroid hormone and the tumor promoter TPA that increase the transformation incidence for a given dose of radiation, and retinoids, selenium, vitamin E, and 5-aminobenzamide that inhibit the expression of transformation. Densely ionizing α-particles, similar to those emitted by radon daughters, are highly effective in inducing transformations and appear to interact in a supra-additive fashion with asbestos fibers. The activation of a known dominant oncogene has not yet been demonstrated in radiation-induced oncogenic transformation. The most likely mechanism for radiation activation of an oncogene would be via the production of a chromosomal translocation. Radiation also efficiently induces deletions and may thus lead to the loss of a suppressor gene

Y-box Binding Protein-1 Enhances Oncogenic Transforming Growth Factor β Signaling in Breast Cancer Cells via Triggering Phospho-Activation of Smad2.

Science.gov (United States)

Stope, Matthias B; Weiss, Martin; Koensgen, Dominique; Popp, Simone L; Joffroy, Christian; Mustea, Alexander; Buck, Miriam B; Knabbe, Cornelius

2017-12-01

Transforming growth factor β (TGFβ) plays a role in diverse oncogenic pathways including cell proliferation and cell motility and is regulated by the pleiotropic factor Y-box binding protein-1 (YB-1). In breast cancer, Sma/Mad related protein 2 (Smad2) represents the most common downstream transducer in TGFβ signaling. Here, YB-1's impact on Smad2 phospho-activation was characterized by incubation of the breast cancer cell line MCF-7 with or without TGFβ1 in the absence or presence of overexpressed YB-1 protein. The phospho-status of Smad2 was assessed via western blotting. Analysis of MCF-7 cells revealed no induction of total Smad2 neither in the presence of TGFβ1, nor during YB-1 overexpression. In contrast, incubation with TGFβ1 led to an increase of phosphorylated Smad2 forms which was significantly amplified by simultaneously overexpressed YB-1 (2.8±0.2-fold). Oncogenic YB-1 indirectly enhances TGFβ signaling cascades via Smad2 phospho-activation and may represent a promising factor for future diagnosis and therapy of breast cancer. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Comments to the plenary presentation "Reconstructing Pre-Proto-Uralic typology spanning the millennia of linguistic evolution" by Juha Janhunen / Lśzl̤ Keresztes

Index Scriptorium Estoniae

Keresztes, Lśzl̤

2001-01-01

Kommentaar: Janhunen, Juha. "Reconstructing Pre-Proto-Uralic typology spanning the millennia of linguistic evolution", Congressus nonus internationalis fenno-ugristarum. Tartu, 2000, 1, lk. 59-76. Ettekanne konverentsilt - Congressus internationalis fenno-ugristarum (9 : 2000 : Tartu)

Induction of non-apoptotic programmed cell death by oncogenic RAS in human epithelial cells and its suppression by MYC overexpression.

Science.gov (United States)

Dendo, Kasumi; Yugawa, Takashi; Nakahara, Tomomi; Ohno, Shin-Ichi; Goshima, Naoki; Arakawa, Hirofumi; Kiyono, Tohru

2018-02-09

Oncogenic mutations of RAS genes, found in about 30% of human cancers, are considered to play important roles in cancer development. However, oncogenic RAS can also induce senescence in mouse and human normal fibroblasts. In some cell lines, oncogenic RAS has been reported to induce non-apoptotic programed cell death (PCD). Here, we investigated effects of oncogenic RAS expression in several types of normal human epithelial cells. Oncogenic RAS but not wild-type RAS stimulated macropinocytosis with accumulation of large-phase lucent vacuoles in the cytoplasm, subsequently leading to cell death which was indistinguishable from a recently proposed new type of PCD, methuosis. A RAC1 inhibitor suppressed accumulation of macropinosomes and overexpression of MYC attenuated oncogenic RAS-induced such accumulation, cell cycle arrest and cell death. MYC suppression or rapamycin treatment in some cancer cell lines harbouring oncogenic mutations in RAS genes induced cell death with accumulation of macropinosomes. These results suggest that this type of non-apoptotic PCD is a tumour-suppressing mechanism acting against oncogenic RAS mutations in normal human epithelial cells, which can be overcome by MYC overexpression, raising the possibility that its induction might be a novel approach to treatment of RAS-mutated human cancers. © The Author(s) 2017. Published by Oxford University Press.

Oncogenic transformation with radiation and chemicals: review

International Nuclear Information System (INIS)

Hall, E.J.; Hei, T.K.

1985-01-01

Quantitative in vitro assay systems for oncogenic transformation are a powerful research tool. They may be based on short-term cultures of hamster embryo cells, or established cell lines of mouse origin. While X-ray-induced transformation of human cells has been demonstrated, it has proved difficult to develop quantitative assay systems based on cells of human origin. The presently available quantitative assays have two quite distinct basic uses. First, they may be useful to accumulate data which is essentially pragmatic in nature. For example, they may be used to compare and contrast the oncogenic potential of chemotherapeutic agents or hypoxic cell sensitizers used or proposed in the clinic. They may be used to identify compounds that inhibit or suppress the transformation incidence resulting from known oncogenic agents, or they may be used to demonstrate the interaction between two different agents, such as radiation and asbestos. Second, they may prove to be invaluable in the study of the basic mechanisms of carcinogenesis, inasmuch as they represent models of tumourigenesis in which the various steps can be manipulated and modified more readily and in a controlled way. (author)

Constraints on the Moment of Inertia of a Proto Neutron Star from the ...

Indian Academy of Sciences (India)

0} system. It is found that for a proto neu- tron star, the mass, the moment of inertia and their own maximum values as a function of .... Our previous work shows that such hyperon coupling constants can give the neutron star matter a better ...

Predictive value of EGFR overexpression and gene amplification on icotinib efficacy in patients with advanced esophageal squamous cell carcinoma.

NARCIS (Netherlands)

Wang, X.; Niu, H.; Fan, Q.; Lu, P.; Ma, C.; Liu, W.; Liu, Y.; Li, W.; Hu, S.; Ling, Y.; Guo, L.; Ying, J.; Huang, J.

2016-01-01

This study aimed to search for a molecular marker for targeted epithelial growth factor receptor (EGFR) inhibitor Icotinib by analyzing protein expression and amplification of EGFR proto-oncogene in esophageal squamous cell carcinoma (ESCC) patients.Immunohistochemistry and fluorescence in situ

Mouse models in leukemia

NARCIS (Netherlands)

Voncken, J.W.

1995-01-01

Human Philadelphia-positive leukemia results from a balanced chromosomal translocation, which fuses the BCR gene on chromosome 22 to the ABL proto-oncogene on chromosome 9. The understanding of Ph-positive leukemogenesis has advanced enormously over

No mutations found by RET mutation scanning in sporadic and hereditary neuroblastoma

NARCIS (Netherlands)

Hofstra, R. M.; Cheng, N. C.; Hansen, C.; Stulp, R. P.; Stelwagen, T.; Clausen, N.; Tommerup, N.; Caron, H.; Westerveld, A.; Versteeg, R.; Buys, C. H.

1996-01-01

Neuroblastoma occasionally occurs in diseases associated with abnormal neurocrest differentiation, e.g. Hirschsprung disease. Expression studies in developing mice suggest that the proto-oncogene RET plays a role in neurocrest differentiation. In humans expression of RET is limited to certain tumor

No mutations found by RET mutation scanning in sporadic and hereditary neuroblastoma

NARCIS (Netherlands)

Hofstra, RMW; Cheng, NC; Stulp, RP; Stelwagen, T; Clausen, N; Tommerup, N; Caron, H; Westerveld, A; Buys, CHCM

Neuroblastoma occasionally occurs in diseases associated with abnormal neurocrest differentiation, e.g. Hirschsprung disease. Expression studies in developing mice suggest that the proto-oncogene RET plays a role in neurocrest differentiation. In humans expression of RT is limited to certain tumor

Oncogenic osteomalacia diagnosed by blood pool scintigraphy

International Nuclear Information System (INIS)

Palaniswamy, Shanmuga Sundaram; Subramanyam, Padma; Kumar, Harish

2011-01-01

Oncogenic osteomalacia is a rare metabolic bone disease characterized by phosphaturia and hypophosphatemia. Certain tumors secrete a phosphaturic factor, which results in this metabolic abnormality; this factor called as phosphatonin, is in fact a fibroblast growth factor 23 (FGF-23) involved closely in phosphate homeostasis and skeletogenesis. Complete excision of these tumors facilitates reversal of the problem. We have reported here the case of a patient who was crippled with this disease and on thorough investigation revealed an oncogenic osteomalacia with tumor focus in the right tibia. The tumor was identified as a mesenchymal tumor, i.e., hemangiopericytoma. Tumor excision alleviated patient symptoms with rapid symptomatic and biochemical improvement

Cyclin K and cyclin D1b are oncogenic in myeloma cells

Directory of Open Access Journals (Sweden)

Renoir Jack-Michel

2010-05-01

Full Text Available Abstract Background Aberrant expression of cyclin D1 is a common feature in multiple myeloma (MM and always associated with mantle cell lymphoma (MCL. CCND1 gene is alternatively spliced to produce two cyclin D1 mRNA isoforms which are translated in two proteins: cyclin D1a and cyclin D1b. Both isoforms are present in MM cell lines and primary cells but their relative role in the tumorigenic process is still elusive. Results To test the tumorigenic potential of cyclin D1b in vivo, we generated cell clones derived from the non-CCND1 expressing MM LP-1 cell line, synthesizing either cyclin D1b or cyclin K, a structural homolog and viral oncogenic form of cyclin D1a. Immunocompromised mice injected s.c. with LP-1K or LP-1D1b cells develop tumors at the site of injection. Genome-wide analysis of LP-1-derived cells indicated that several cellular processes were altered by cyclin D1b and/or cyclin K expression such as cell metabolism, signal transduction, regulation of transcription and translation. Importantly, cyclin K and cyclin D1b have no major action on cell cycle or apoptosis regulatory genes. Moreover, they impact differently cell functions. Cyclin K-expressing cells have lost their migration properties and display enhanced clonogenic capacities. Cyclin D1b promotes tumorigenesis through the stimulation of angiogenesis. Conclusions Our study indicates that cyclin D1b participates into MM pathogenesis via previously unrevealed actions.

Extracellular vesicle communication pathways as regulatory targets of oncogenic transformation.

Science.gov (United States)

Choi, Dongsic; Lee, Tae Hoon; Spinelli, Cristiana; Chennakrishnaiah, Shilpa; D'Asti, Esterina; Rak, Janusz

2017-07-01

Pathogenesis of human cancers bridges intracellular oncogenic driver events and their impact on intercellular communication. Among multiple mediators of this 'pathological connectivity' the role of extracellular vesicles (EVs) and their subsets (exosomes, ectosomes, oncosomes) is of particular interest for several reasons. The release of EVs from cancer cells represents a unique mechanism of regulated expulsion of bioactive molecules, a process that also mediates cell-to-cell transfer of lipids, proteins, and nucleic acids. Biological effects of these processes have been implicated in several aspects of cancer-related pathology, including tumour growth, invasion, angiogenesis, metastasis, immunity and thrombosis. Notably, the emerging evidence suggests that oncogenic mutations may impact several aspects of EV-mediated cell-cell communication including: (i) EV release rate and protein content; (ii) molecular composition of cancer EVs; (iii) the inclusion of oncogenic and mutant macromolecules in the EV cargo; (iv) EV-mediated release of genomic DNA; (v) deregulation of mechanisms responsible for EV biogenesis (vesiculome) and (vi) mechanisms of EV uptake by cancer cells. Intriguingly, EV-mediated intercellular transfer of mutant and oncogenic molecules between subpopulations of cancer cells, their indolent counterparts and stroma may exert profound biological effects that often resemble (but are not tantamount to) oncogenic transformation, including changes in cell growth, clonogenicity and angiogenic phenotype, or cause cell stress and death. However, several biological barriers likely curtail a permanent horizontal transformation of normal cells through EV-mediated mechanisms. The ongoing analysis and targeting of EV-mediated intercellular communication pathways can be viewed as a new therapeutic paradigm in cancer, while the analysis of oncogenic cargo contained in EVs released from cancer cells into biofluids is being developed for clinical use as a biomarker

Comparison of the oncogenic potential of several chemotherapeutic agents

International Nuclear Information System (INIS)

Miller, R.C.; Hall, E.J.; Osmak, R.S.

1981-01-01

Several chemotherapeutic drugs that have been routinely used in cancer treatment were tested for their carcinogenic potential. Two antitumor antibiotics (adriamycin and vincristine), an alkalating agent (melphalan), 5-azacytidine and the bifunctional agent cis-platinum that mimics alkylating agents and/or binds Oxygen-6 or Nitrogen-7 atoms of quanine were tested. Cell killing and cancer induction was assessed using in vitro transformation system. C3H/10T 1/2 cells, while normally exhibiting contact inhibition, can undergo transformation from normal contact inhibited cells to tumorgenic cells when exposed to chemical carcinogens. These cells have been used in the past by this laboratory to study oncogenic transformation of cells exposed to ionizing radiation and electron affinic compounds that sensitize hypoxic cells to x-rays. The endpoints of cell killing and oncogenic transformation presented here give an estimate of the carcinogenic potential of these agents

A Poly-ADP-Ribose Trigger Releases the Auto-Inhibition of a Chromatin Remodeling Oncogene

DEFF Research Database (Denmark)

Singh, Hari R; Nardozza, Aurelio P; Möller, Ingvar R

2017-01-01

DNA damage triggers chromatin remodeling by mechanisms that are poorly understood. The oncogene and chromatin remodeler ALC1/CHD1L massively decompacts chromatin in vivo yet is inactive prior to DNA-damage-mediated PARP1 induction. We show that the interaction of the ALC1 macrodomain......-macrodomain interactions, promotes an ungated conformation, and activates the remodeler's ATPase. ALC1 fragments lacking the regulatory macrodomain relax chromatin in vivo without requiring PARP1 activation. Further, the ATPase restricts the macrodomain's interaction with PARP1 under non-DNA damage conditions. Somatic...... cancer mutants disrupt ALC1's auto-inhibition and activate chromatin remodeling. Our data show that the NAD+-metabolite and nucleic acid PAR triggers ALC1 to drive chromatin relaxation. Modular allostery in this oncogene tightly controls its robust, DNA-damage-dependent activation....

Structure of human POFUT1, its requirement in ligand-independent oncogenic Notch signaling, and functional effects of Dowling-Degos mutations

Energy Technology Data Exchange (ETDEWEB)

McMillan, Brian J.; Zimmerman, Brandon; Egan, Emily D.; Lofgren, Michael; Xu, Xiang; Hesser, Anthony; Blacklow, Stephen C.

2017-03-17

Protein O-fucosyltransferase-1 (POFUT1), which transfers fucose residues to acceptor sites on serine and threonine residues of epidermal growth factor-like repeats of recipient proteins, is essential for Notch signal transduction in mammals. Here, we examine the consequences of POFUT1 loss on the oncogenic signaling associated with certain leukemia-associated mutations of human Notch1, report the structures of human POFUT1 in free and GDP-fucose bound states, and assess the effects of Dowling-Degos mutations on human POFUT1 function. CRISPR-mediated knockout of POFUT1 in U2OS cells suppresses both normal Notch1 signaling, and the ligand-independent signaling associated with leukemogenic mutations of Notch1. Normal and oncogenic signaling are rescued by wild-type POFUT1 but rescue is impaired by an active-site R240A mutation. The overall structure of the human enzyme closely resembles that of the Caenorhabditis elegans protein, with an overall backbone RMSD of 0.93 Å, despite primary sequence identity of only 39% in the mature protein. GDP-fucose binding to the human enzyme induces limited backbone conformational movement, though the side chains of R43 and D244 reorient to make direct contact with the fucose moiety in the complex. The reported Dowling-Degos mutations of POFUT1, except for M262T, fail to rescue Notch1 signaling efficiently in the CRISPR-engineered POFUT1^-/- background. Together, these studies identify POFUT1 as a potential target for cancers driven by Notch1 mutations and provide a structural roadmap for its inhibition.

The oestrogen receptor alpha-regulated lncRNA NEAT1 is a critical modulator of prostate cancer

Science.gov (United States)

Chakravarty, Dimple; Sboner, Andrea; Nair, Sujit S.; Giannopoulou, Eugenia; Li, Ruohan; Hennig, Sven; Mosquera, Juan Miguel; Pauwels, Jonathan; Park, Kyung; Kossai, Myriam; MacDonald, Theresa Y.; Fontugne, Jacqueline; Erho, Nicholas; Vergara, Ismael A.; Ghadessi, Mercedeh; Davicioni, Elai; Jenkins, Robert B.; Palanisamy, Nallasivam; Chen, Zhengming; Nakagawa, Shinichi; Hirose, Tetsuro; Bander, Neil H.; Beltran, Himisha; Fox, Archa H.; Elemento, Olivier; Rubin, Mark A.

2014-01-01

The androgen receptor (AR) plays a central role in establishing an oncogenic cascade that drives prostate cancer progression. Some prostate cancers escape androgen dependence and are often associated with an aggressive phenotype. The oestrogen receptor alpha (ERα) is expressed in prostate cancers, independent of AR status. However, the role of ERα remains elusive. Using a combination of chromatin immunoprecipitation (ChIP) and RNA-sequencing data, we identified an ERα-specific non-coding transcriptome signature. Among putatively ERα-regulated intergenic long non-coding RNAs (lncRNAs), we identified nuclear enriched abundant transcript 1 (NEAT1) as the most significantly overexpressed lncRNA in prostate cancer. Analysis of two large clinical cohorts also revealed that NEAT1 expression is associated with prostate cancer progression. Prostate cancer cells expressing high levels of NEAT1 were recalcitrant to androgen or AR antagonists. Finally, we provide evidence that NEAT1 drives oncogenic growth by altering the epigenetic landscape of target gene promoters to favour transcription. PMID:25415230

Propuesta metodológica para la medición del desarrollo sostenible a través de índices sintéticos multivariantes

Directory of Open Access Journals (Sweden)

Gustavo Trujillo Calagua

2014-06-01

Full Text Available Objetivos: Establecer las bases metodológicas para el diseño de un índice sintético global de desarrollo sostenible que cumpla con dos condiciones: que se adapte a los principios de presión-estado-respuesta y que se adecúe a los cuatro componentes o dimensiones básicas de la sostenibilidad: institucional, medioambiental, económica y social. Métodos: Se construyó un índice sintético sobre el cómputo de una batería de variables, subindicadores e indicadores, agrupados estos en las cuatro dimensiones citadas para luego, proceder a su aplicación en el Perú. Según la forma, información seleccionada y relaciones preestablecidas entre los elementos considerados significativos de evaluar, obtendremos las claves que nos indican la interpretación del ideal de sostenibilidad impulsada por sus gestores. Resultados: Se formuló una nueva estrategia metodológica para la elaboración de un índice que recoja los aspectos asociados al desarrollo sostenible en el Perú, mediante la propuesta de análisis sintético multivariante. En el mismo, se identificó que la dimensión “institucional” es la dimensión más débil. Conclusiones: Se deduce que los mayores índices de sostenibilidad podrían ser alcanzados en aquellas economías en los que sus gobiernos vienen desarrollando estrategias de desarrollo sostenible. Asimismo, quedó demostrado que no existe relación alguna entre las medidas tradicionales de crecimiento económico (PBI y su variación y sostenibilidad.

Pokemon Silencing Leads to Bim-Mediated Anoikis of Human Hepatoma Cell QGY7703

OpenAIRE

Liu, Kun; Liu, Feng; Zhang, Nannan; Liu, Shiying; Jiang, Yuyang

2012-01-01

Pokemon is an important proto-oncogene that plays a critical role in cellular oncogenic transformation and tumorigenesis. Anoikis, which is regulated by Bim-mediated apoptosis, is critical to cancer cell invasion and metastasis. We investigated the role of Pokemon in anoikis, and our results show that Pokemon renders liver cells resistant to anoikis via suppression of Bim transcription. We knocked-down Pokemon in human hepatoma cells QGY7703 with small interfering RNAs (siRNA). Knockdown of P...

RET/PTC1-Driven Neoplastic Transformation and Proinvasive Phenotype of Human Thyrocytes Involve Met Induction and β-Catenin Nuclear Translocation

Directory of Open Access Journals (Sweden)

Giuliana Cassinelli

2009-01-01

Full Text Available Activation of the RET gene by chromosomal rearrangements generating RET/PTC oncogenes is a frequent, early, and causative event in papillary thyroid carcinoma (PTC. We have previously shown that, in human primary thyrocytes, RET/PTC1 induces a transcriptional program including the MET proto-oncogene. In PTCs, β-catenin is frequently mislocated to the cytoplasm nucleus. We investigated the interplay between Ret/ptc1 signaling and Met in regulating the proinvasive phenotype and β-catenin localization in cellular models of human PTC. Here, we show that Met protein is expressed and is constitutively active in human thyrocytes exogenously expressing RET/PTC1 as well as a mutant (Y451F devoid of the main Ret/ptc1 multidocking site. Both in transformed thyrocytes and in the human PTC cell line TPC-1, Ret/ptc1-Y451-dependent signaling and Met cooperated to promote a proinvasive phenotype. Accordingly, gene/functional silencing of either RET/PTC1 or MET abrogated early branching morphogenesis in TPC-1 cells. The same effect was obtained by blocking the common downstream effector Akt. Y451 of Ret/ptc1 was required to promote proliferation and nuclear translocation of β-catenin, suggesting that these oncogene-driven effects are Met-independent. Pharmacologic inhibition of Ret/ptc1 and Met tyrosine kinases by the multitarget small molecule RPI-1 blocked cell proliferation and invasive ability and dislocated β-catenin from the nucleus. Altogether, these results support that Ret/ptc1 cross talks with Met at transcriptional and signaling levels and promotes β-catenin transcriptional activity to drive thyrocyte neoplastic transformation. Such molecular network, promoting disease initiation and acquisition of a proinvasive phenotype, highlights new options to design multitarget therapeutic strategies for PTCs.

Human papillomavirus E6/E7 oncogenes promote mouse ear regeneration by increasing the rate of wound re-epithelization and epidermal growth.

Science.gov (United States)

Valencia, Concepción; Bonilla-Delgado, José; Oktaba, Katarzyna; Ocádiz-Delgado, Rodolfo; Gariglio, Patricio; Covarrubias, Luis

2008-12-01

Mammals have limited regeneration capacity. We report here that, in transgenic mice (Tg(bK6-E6/E7)), the expression of the E6/E7 oncogenes of human papilloma virus type 16 (HPV16) under the control of the bovine keratin 6 promoter markedly improves the mouse's capacity to repair portions of the ear after being wounded. Increased repair capacity correlates with an increased number of epidermal proliferating cells. In concordance with the expected effects of the E6 and E7 oncogenes, levels of p53 decreased and those of p16 in epidermal cells increased. In addition, we observed that wound re-epithelization proceeded faster in transgenic than in wild-type animals. After the initial re-epithelization, epidermal cell migration from the intact surrounding tissue appears to be a major contributor to the growing epidermis, especially in the repairing tissue of transgenic mice. We also found that there is a significantly higher number of putative epidermal stem cells in Tg(bK6-E6/E7) than in wild-type mice. Remarkably, hair follicles and cartilage regenerated within the repaired ear tissue, without evidence of tumor formation. We propose that the ability to regenerate ear portions is limited by the capacity of the epidermis to repair itself and grow.

Oncogenic osteomalacia due to FGF23-expressing colon adenocarcinoma.

Science.gov (United States)

Leaf, David E; Pereira, Renata C; Bazari, Hasan; Jüppner, Harald

2013-03-01

Oncogenic osteomalacia, a paraneoplastic syndrome associated with hypophosphatemia due to increased urinary phosphate excretion, is caused by excessive synthesis and secretion of fibroblast growth factor 23 (FGF23), a phosphaturic hormone that is normally produced by osteocytes. Most cases of oncogenic osteomalacia have been associated with benign tumors of bone or soft tissue; however, whether malignant neoplasms can also produce and secrete FGF23 is currently unknown. The aim was to determine whether a malignant neoplasm could cause oncogenic osteomalacia through excessive production and secretion of FGF23. We describe an 80-year-old woman with stage IV colon adenocarcinoma who presented with severe hypophosphatemia (0.4 mg/dL; reference, 2.6-4.5 mg/dL). Fractional excretion of phosphate was 34% (reference, osteomalacia should be considered in the differential diagnosis for patients with a malignant tumor who present with hypophosphatemia.

Mass outflow in the nearby proto-planetary system, Beta Pictoris

International Nuclear Information System (INIS)

Bruhweiler, F.C.; Grady, C.A.; Kondo, Yoji

1991-01-01

Previous spectral studies of circumstallar dust around the nearby, candidate proto-planetary system, Beta Pictoris, has detected only infalling gas. The lack of detectable mass outflow has been critical in the interpretation of the origin of the circumstellar gas and in our understanding of the evolutionary status of the Beta Pictoris system. IUE high-dispersion spectra are presented which show, in addition to infall, the presence of mass outflow, with a maximum observed outflow velocity of -60 km/s, and a corresponding instantaneous outflow rate of 1.1 x 10 to the -14th solar mass/yr, or 1.1 x 10 to the -11th Jupiter mass/yr. This mass outflow rate and terminal velocity are comparable to the magnitudes of mass infall rates and terminal velocities observed from late 1986 through early 1988. The implications of these observations on our understanding of the mechanisms producing infall from the surrounding circumstellar disk are discussed, as are the implications for our understanding of the evolutionary status of the Beta Pic system. 23 refs

Oncogenicity by adenovirus is not determined by the transforming region only

NARCIS (Netherlands)

Bernards, R.A.; Leeuw, M.G.W. de; Vaessen, M.J.; Houweling, A.; Eb, A.J. van der

1984-01-01

We have constructed a nondefective recombinant virus between the nononcogenic adenovirus 5 (Ad5) and the highly oncogenic Ad12. The recombinant genome consists essentially of Ad5 sequences, with the exception of the transforming early region 1 (E1) which is derived from Ad12. HeLa cells infected

Transit time magnetic pumping experiments in the proto-cleo stellarator

International Nuclear Information System (INIS)

Millar, W.

1975-04-01

Experiments are described in which magnetic field perturbations at frequencies approximately 100 kHz, of the type required for Transit Time Magnetic Pumping, are applied to the PROTO-CLEO stellarator. The chief effect is an increase in the plasma loss rate, which is investigated in some detail. The importance of electrostatic fields is discussed, and attention is drawn to the possibility of operating in a region not explored here, with long wavelength and low frequency. (author)

Stress-Induced Premature Senescence or Stress-Induced Senescence-Like Phenotype: One In Vivo Reality, Two Possible Definitions?

OpenAIRE

Toussaint, Olivier; Dumont, Patrick; Remacle, Jose; Dierick, Jean-Francois; Pascal, Thierry; Frippiat, Christophe; Magalhaes, Joao Pedro; Zdanov, Stephanie; Chainiaux, Florence

2002-01-01

No consensus exists so far on the definition of cellular senescence. The narrowest definition of senescence is irreversible growth arrest triggered by telomere shortening counting cell generations (definition 1). Other authors gave an enlarged functional definition encompassing any kind of irreversible arrest of proliferative cell types induced by damaging agents or cell cycle deregulations after overexpression of proto-oncogenes (definition 2). As stress increases, the proportion of cells in...

Oncogene-inducible organoids as a miniature platform to assess cancer characteristics

NARCIS (Netherlands)

Mizutani, Tomohiro; Tsukamoto, Yoshiyuki; Clevers, Hans

2017-01-01

Direct effects of oncogenic proteins or inhibitor treatments on signaling pathways are difficult to assess in transgenic mice. In this issue, Riemer et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201610058) demonstrate that oncogene-inducible organoids offer the experimental versatility of

Production of unstable heavy neutrinos in proto-neutron stars

Directory of Open Access Journals (Sweden)

C. Albertus

2015-12-01

Full Text Available We discuss the production of a class of heavy sterile neutrinos νh in proto-neutron stars. The neutrinos, of mass around 50 MeV, have a negligible mixing with the active species but relatively large dimension-5 electromagnetic couplings. In particular, a magnetic dipole moment μ≈10−6 GeV−1 implies that they are thermally produced through e+e−→ν¯hνh in the early phase of the core collapse, whereas a heavy–light transition moment μtr≈10−8 GeV−1 allows their decay νh→νiγ with a lifetime around 10−3 s. This type of electromagnetic couplings has been recently proposed to explain the excess of electron-like events in baseline experiments. We show that the production and decay of these heavy neutrinos would transport energy from the central regions of the star to distances d≈400 km, providing a very efficient mechanism to enhance the supernova shock front and heat the material behind it.

Classification of ISO SWS 01 spectra of proto-planetary nebulae: a search for precursors of planetary nebulae with [WR] central stars

OpenAIRE

Szczerba, R.; Stasi{ń}ska, G.; Siódmiak, N.; Górny, S. K.

2002-01-01

We have analyzed ISO SWS 01 observations for 61 proto-planetary nebulae candidates and classified their spectra according to their dominant chemistry. On the basis of our classification and the more general classification of SWS 01 spectra by Kraemer et al. (2002) we discuss the connection between proto-planetary nebulae candidates and planetary nebulae, with emphasis on possible precursors of planetary nebulae with [WR] central stars.

Identification of an intracellular protein that specifically interacts with photoaffinity-labeled oncogenic p21 protein.

Science.gov (United States)

Lee, G; Ronai, Z A; Pincus, M R; Brandt-Rauf, P W; Murphy, R B; Delohery, T M; Nishimura, S; Yamaizumi, Z; Weinstein, I B

1989-11-01

An oncogenic 21-kDa (p21) protein (Harvey RAS protein with Val-12) has been covalently modified with a functional reagent that contains a photoactivatable aromatic azide group. This modified p21 protein has been introduced quantitatively into NIH 3T3 cells using an erythrocyte-mediated fusion technique. The introduced p21 protein was capable of inducing enhanced pinocytosis and DNA synthesis in the recipient cells. To identify the putative intracellular protein(s) that specifically interact with the modified p21 protein, the cells were pulsed with [35S]methionine at selected times after fusion and then UV-irradiated to activate the azide group. The resulting nitrene covalently binds to amino acid residues in adjacent proteins, thus linking the p21 protein to these proteins. The cells were then lysed, and the lysate was immunoprecipitated with the anti-p21 monoclonal antibody Y13-259. The immunoprecipitate was analyzed by SDS/PAGE to identify p21-protein complexes. By using this technique, we found that three protein complexes of 51, 64, and 82 kDa were labeled specifically and reproducibly. The most prominent band is the 64-kDa protein complex that shows a time-dependent rise and fall, peaking within a 5-hr period after introduction of the p21 protein into the cells. These studies provide evidence that in vitro the p21 protein becomes associated with a protein whose mass is about 43 kDa. We suggest that the formation of this complex may play a role in mediating early events involved with cell transformation induced by RAS oncogenes.

Mesure de la violation de CP dans les désintégrations B$_{\\textrm{s}}^0 \\to$ $J/\\psi \\phi$, auprès du détecteur LHCb

CERN Document Server

Maurice, Emilie; Le Gac, Renaud

La mesure de la phase $\\phi_{\\textrm{s}}$ violant la symétrie CP dans les désintégrations B$^0_{\\textrm s} \\to$ J$/\\psi \\phi$ est une des analyses phares de l'expérience LHCb. Le Modèle Standard prédit cette observable avec une faible incertitude théorique. La présence de Nouvelle Physique notamment dans les diagrammes en boucle de l'oscillation B$^0_{\\textrm s}$-$\\overline{\\textrm{B}}^0_{\\textrm s}$ peut significativement modifier la mesure de cette phase. Durant cette thèse, nous avons participé à différents aspects de l'analyse des désintégrations B$^0_{\\textrm s} \\to$ J$/\\psi \\phi$. Nous avons proposé une sélection multi-variables, basée sur un algorithme d'arbres de décision boostés. Cette nouvelle sélection augmente le nombre de signal B$^0_{\\textrm s} \\to$ J$/\\psi \\phi$ de 19$\\%$ mais nécessite une correction temporelle. Une étude portant sur l'origine des distorsions angulaires caractéristiques des désintégrations B$^0_{\\textrm s} \\to $J$/\\psi \\phi$ a aussi été menée. Il...

Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1)

DEFF Research Database (Denmark)

Marzec, Michal; Zhang, Qian; Goradia, Ami

2008-01-01

The mechanisms of malignant cell transformation caused by the oncogenic, chimeric nucleophosmin (NPM)/anaplastic lymphoma kinase (ALK) remain only partially understood, with most of the previous studies focusing mainly on the impact of NPM/ALK on cell survival and proliferation. Here we report th...

Oncogenic osteomalacia presenting as bilateral stress fractures of the tibia

International Nuclear Information System (INIS)

Ohashi, Kenjirou; Ohnishi, Takeshi; Ishikawa, Tohru; Tani, Haruo; Uesugi, Keisuke; Takagi, Masayuki

1999-01-01

We report on a patient with bilateral stress fractures of the tibia who subsequently showed classic biochemical features of oncogenic osteomalacia. Conventional radiographs were normal. MR imaging revealed symmetric, bilateral, band-like low-signal lesions perpendicular to the medial cortex of the tibiae and corresponding to the only lesions subsequently seen on the bone scan. A maxillary sinus lesion was subsequently detected and surgically removed resulting in prompt alleviation of symptoms and normalization of hypophosphatemia and low 1,25-(OH) 2 vitamin D 3 . The lesion was pathologically diagnosed as a hemangiopericytoma-like tumor. Patients with oncogenic osteomalacia may present with stress fractures limited to the tibia, as seen in athletes. The clue to the real diagnosis lies in paying close attention to the serum phosphate levels, especially in patients suffering generalized symptoms of weakness and not given to unusual physical activity. (orig.)

Erotic Love and the Development of Proto-Capitalist Ideology in Early Modern Comedy

Science.gov (United States)

Damsen, Silver

2009-01-01

My dissertation, "Erotic Love and the Development of Proto-Capitalist Ideology in Early Modern Comedy" demonstrates how increased crown authority, and an expanded market combine with the mixed agency of the romantic comedy daughter to further encourage early modern economic growth. The triumph of rebelling daughter over blocking father has…

Pre-Cenozoic basement rocks of the Proto-Philippine Sea Plate: Constraints for the birthplace of the Izu-Bonin-Mariana Arc

Science.gov (United States)

Tani, K.; Ishizuka, O.; Horie, K.; Barth, A. P.; Harigane, Y.; Ueda, H.

2016-12-01

The Izu-Bonin-Mariana Arc is widely regarded to be a typical intra-oceanic arc, with the oceanic Pacific Plate subducting beneath the Philippine Sea Plate, an evolving complex of active and inactive arcs and back-arc basins. However, little is known about the origin of the proto-Philippine Sea Plate, which existed along with the Pacific Plate at the time of subduction initiation in the Eocene. To investigate the crustal structures of the proto-Philippine Sea Plate, we conducted manned-submersible and dredge surveys in the Daito Ridges and the Kyushu-Palau Ridge. The Daito Ridges comprise the northwestern Philippine Sea Plate along with what are regarded as remnants of the proto-Philippine Sea Plate. Submersible observations and rock sampling revealed that the Daito Ridges expose deep crustal sections of gabbroic, granitic, metamorphic, and ultra-mafic rocks, along with volcanic rocks ranging from basalt to andesite. Mesozoic magmatic zircon U-Pb ages have been obtained from the plutonic rocks, and whole-rock geochemistry of the igneous rocks indicates arc origins. Furthermore, mafic schist collected from the Daito Ridge has experienced amphibolite facies metamorphism, with phase assemblages suggesting that the crust was thicker than 20 km at the time. Similar amphibolite-facies metamorphic rocks with Proterozoic zircons have been recovered in the southern Kyushu-Palau Ridge, indicating that such distinctively older basement rocks exist as isolated tectonic blocks within the present Philippine Sea Plate. These finds show that the parts of the Daito Ridges and Kyushu-Palau Ridge represent developed crustal sections of the Pre-Cenozoic arc that comprises part of the proto-Philippine Sea Plate, and, together with the tectonic reconstruction of the proto-Philippine Sea Plate (Deschamps and Lallemand 2002, JGR), they suggest that subduction of the Izu-Bonin-Mariana Arc initiated at the continental margin of the Southeast Asia.

AZIN1 RNA editing confers cancer stemness and enhances oncogenic potential in colorectal cancer.

Science.gov (United States)

Shigeyasu, Kunitoshi; Okugawa, Yoshinaga; Toden, Shusuke; Miyoshi, Jinsei; Toiyama, Yuji; Nagasaka, Takeshi; Takahashi, Naoki; Kusunoki, Masato; Takayama, Tetsuji; Yamada, Yasuhide; Fujiwara, Toshiyoshi; Chen, Leilei; Goel, Ajay

2018-06-21

Adenosine-to-inosine (A-to-I) RNA editing, a process mediated by adenosine deaminases that act on the RNA (ADAR) gene family, is a recently discovered epigenetic modification dysregulated in human cancers. However, the clinical significance and the functional role of RNA editing in colorectal cancer (CRC) remain unclear. We have systematically and comprehensively investigated the significance of the expression status of ADAR1 and of the RNA editing levels of antizyme inhibitor 1 (AZIN1), one of the most frequently edited genes in cancers, in 392 colorectal tissues from multiple independent CRC patient cohorts. Both ADAR1 expression and AZIN1 RNA editing levels were significantly elevated in CRC tissues when compared with corresponding normal mucosa. High levels of AZIN1 RNA editing emerged as a prognostic factor for overall survival and disease-free survival and were an independent risk factor for lymph node and distant metastasis. Furthermore, elevated AZIN1 editing identified high-risk stage II CRC patients. Mechanistically, edited AZIN1 enhances stemness and appears to drive the metastatic processes. We have demonstrated that edited AZIN1 functions as an oncogene and a potential therapeutic target in CRC. Moreover, AZIN1 RNA editing status could be used as a clinically relevant prognostic indicator in CRC patients.

Ion Cyclotron Heating on Proto-MPEX

Science.gov (United States)

Goulding, R. H.; Caughman, J. B. O.; Rapp, J.; Biewer, T. M.; Campbell, I. H.; Caneses, J. F.; Kafle, N.; Ray, H. B.; Showers, M. A.; Piotrowicz, P. A.

2016-10-01

Ion cyclotron heating will be used on Proto-MPEX (Prototype Material Plasma Exposure eXperiment) to increase heat flux to the target, to produce varying ion energies without substrate biasing, and to vary the extent of the magnetic pre-sheath for the case of a tilted target. A 25 cm long, 9 cm diameter dual half-turn helical ion cyclotron antenna has been installed in the device located at the magnetic field maximum. It couples power to ions via single pass damping of the slow wave at the fundamental resonance, and operates with ω 0.8ωci at the antenna location. It is designed to operate at power levels up to 30 kW, with a later 200 kW upgrade planned. Near term experiments include measuring RF loading at low power as a function of frequency and antenna gap. The plasma is generated by a helicon plasma source that has achieved ne > 5 ×1019m-3 operating with deuterium, as measured downstream from the ion cyclotron antenna location. Measurements will be compared with 1-D and 2-D models of RF coupling. The latest results will be presented. This manuscript has been authored by UT-Battelle, LLC, under Contract No. DE-AC05-00OR22725 with the U.S. Department of Energy.

Purification, crystallization, small-angle X-ray scattering and preliminary X-ray diffraction analysis of the SH2 domain of the Csk-homologous kinase

International Nuclear Information System (INIS)

Gunn, Natalie J.; Gorman, Michael A.; Dobson, Renwick C. J.; Parker, Michael W.; Mulhern, Terrence D.

2011-01-01

The Src-homology 2 (SH2) domain of Csk-family protein tyrosine kinases acts as a conformational switch to regulate their catalytic activity, which in turn promotes the inhibition of their proto-oncogenic targets, the Src-family kinases. Here, the expression, purification, small-angle X-ray scattering and preliminary diffraction analysis of the SH2 domain of the Csk-homologous kinase is reported. The C-terminal Src kinase (Csk) and Csk-homologous kinase (CHK) are endogenous inhibitors of the proto-oncogenic Src family of protein tyrosine kinases (SFKs). Phosphotyrosyl peptide binding to their Src-homology 2 (SH2) domains activates Csk and CHK, enhancing their ability to suppress SFK signalling; however, the detailed mechanistic basis of this activation event is unclear. The CHK SH2 was expressed in Escherichia coli and the purified protein was characterized as monomeric by synchrotron small-angle X-ray scattering in-line with size-exclusion chromatography. The CHK SH2 crystallized in 0.2 M sodium bromide, 0.1 M bis-Tris propane pH 6.5 and 20% polyethylene glycol 3350 and the best crystals diffracted to ∼1.6 Å resolution. The crystals belonged to space group P2, with unit-cell parameters a = 25.8, b = 34.6, c = 63.2 Å, β = 99.4°

Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer. | Office of Cancer Genomics

Science.gov (United States)

Oncogenic gene fusions drive many human cancers, but tools to more quickly unravel their functional contributions are needed. Here we describe methodology permitting fusion gene construction for functional evaluation. Using this strategy, we engineered the known fusion oncogenes, BCR-ABL1, EML4-ALK, and ETV6-NTRK3, as well as 20 previously uncharacterized fusion genes identified in TCGA datasets.

Homotopy Lie algebras associated with a proto-bialgebra

International Nuclear Information System (INIS)

Bangoura, Momo

2003-10-01

Motivated by the search for examples of homotopy Lie algebras, to any Lie proto-bialgebra structure on a finite-dimensional vector space F, we associate two homotopy Lie algebra structures defined on the suspension of the exterior algebra of F and that of its dual F*, respectively, with a 0-ary map corresponding to the image of the empty set. In these algebras, all n-ary brackets for n ≥ 4 vanish. More generally, to any element of odd degree in Λ(F*+F), we associate a set of n-ary skew-symmetric mappings on the suspension of ΛF (resp. Λ F*), which satisfy the generalized Jacobi identities if the given element is of square zero. (author)

Proto-I switching and diode studies

International Nuclear Information System (INIS)

Prestwich, K.R.; Miller, P.A.; McDaniel, D.H.; Poukey, J.W.; Widner, M.M.; Goldstein, S.A.

1975-01-01

Proto-I is a 3 MV, 800 kA, 24 ns electron beam accelerator that is under development at Sandia Laboratories. It represents an initial effort to develop a scalable technology that is applicable to accelerators for electron beam driven, inertial confinement fusion studies. Energy is supplied to each of the two diodes from six oil-dielectric Blumlein transmission lines (PFL) operating in parallel. A Marx generator charges three intermediate storage, water-dielectric capacitors which subsequently transfer the stored energy to the PFL. The discharge of the PFL is initiated by the simultaneous closure of 12 triggered oil-dielectric rail switches. Data will be presented on the operation of these multichannel switches. The two diodes have a common anode. Cathode diameters can be varied from 10 to 60 cm. Results of initial diode experiments and comparisons with theory are discussed. Plasma filled diode experiments are also reported, indicating pinch collapse velocities in excess of 10 9 cm/s

Total decay heat estimates in a proto-type fast reactor

International Nuclear Information System (INIS)

Sridharan, M.S.

2003-01-01

Full text: In this paper, total decay heat values generated in a proto-type fast reactor are estimated. These values are compared with those of certain fast reactors. Simple analytical fits are also obtained for these values which can serve as a handy and convenient tool in engineering design studies. These decay heat values taken as their ratio to the nominal operating power are, in general, applicable to any typical plutonium based fast reactor and are useful inputs to the design of decay-heat removal systems

THE PHOTOECCENTRIC EFFECT AND PROTO-HOT JUPITERS. II. KOI-1474.01, A CANDIDATE ECCENTRIC PLANET PERTURBED BY AN UNSEEN COMPANION

Energy Technology Data Exchange (ETDEWEB)

Dawson, Rebekah I.; Murray-Clay, Ruth A. [Harvard-Smithsonian Center for Astrophysics, 60 Garden St, MS-10, Cambridge, MA 02138 (United States); Johnson, John Asher; Morton, Timothy D. [Department of Astronomy, California Institute of Technology, 1200 East California Boulevard, MC 249-17, Pasadena, CA 91125 (United States); Crepp, Justin R. [Department of Physics, University of Notre Dame, 225 Nieuwland Science Hall, Notre Dame, IN 46556 (United States); Fabrycky, Daniel C. [Department of Astronomy and Astrophysics, University of California Santa Cruz, Santa Cruz, California 95064 (United States); Howard, Andrew W., E-mail: rdawson@cfa.harvard.edu [Institute for Astronomy, University of Hawaii, 2680 Woodlawn Drive, Honolulu, HI 96822-1839 (United States)

2012-12-20

The exoplanets known as hot Jupiters-Jupiter-sized planets with periods of less than 10 days-likely are relics of dynamical processes that shape all planetary system architectures. Socrates et al. argued that high eccentricity migration (HEM) mechanisms proposed for situating these close-in planets should produce an observable population of highly eccentric proto-hot Jupiters that have not yet tidally circularized. HEM should also create failed-hot Jupiters, with periapses just beyond the influence of fast circularization. Using the technique we previously presented for measuring eccentricities from photometry (the ''photoeccentric effect''), we are distilling a collection of eccentric proto- and failed-hot Jupiters from the Kepler Objects of Interest (KOI). Here, we present the first, KOI-1474.01, which has a long orbital period (69.7340 days) and a large eccentricity e 0.81{sup +0.10}{sub -0.07}, skirting the proto-hot Jupiter boundary. Combining Kepler photometry, ground-based spectroscopy, and stellar evolution models, we characterize host KOI-1474 as a rapidly rotating F star. Statistical arguments reveal that the transiting candidate has a low false-positive probability of 3.1%. KOI-1474.01 also exhibits transit-timing variations of the order of an hour. We explore characteristics of the third-body perturber, which is possibly the ''smoking-gun'' cause of KOI-1474.01's large eccentricity. We use the host star's period, radius, and projected rotational velocity to measure the inclination of the stellar spin. Comparing KOI 1474.01's inclination, we find that its orbit is marginally consistent with being aligned with the stellar spin axis, although a reanalysis is warranted with future additional data. Finally, we discuss how the number and existence of proto-hot Jupiters will not only demonstrate that hot Jupiters migrate via HEM, but also shed light on the typical timescale for the mechanism.

A view on EGFR-targeted therapies from the oncogene-addiction perspective.

Science.gov (United States)

Perez, Rolando; Crombet, Tania; de Leon, Joel; Moreno, Ernesto

2013-01-01

Tumor cell growth and survival can often be impaired by inactivating a single oncogen- a phenomenon that has been called as "oncogene addiction." It is in such scenarios that molecular targeted therapies may succeed. among known oncogenes, the epidermal growth factor receptor (EGFR) has become the target of different cancer therapies. So far, however, the clinical benefit from EGFR-targeted therapies has been rather limited. a critical review of the large amount of clinical data obtained with anti-EGFR agents, carried out from the perspective of the oncogene addiction concept, may help to understand the causes of the unsatisfactory results. In this article we intend to do such an exercise taking as basis for the analysis a few case studies of anti-EGFR agents that are currently in the clinic. There, the "EGFR addiction" phenomenon becomes apparent in high-responder patients. We further discuss how the concept of oncogene addiction needs to be interpreted on the light of emerging experimental evidences and ideas; in particular, that EGFR addiction may reflect the interconnection of several cellular pathways. In this regard we set forth several hypotheses; namely, that requirement of higher glucose uptake by hypoxic tumor cells may reinforce EGFR addiction; and that chronic use of EGFR-targeted antibodies in EGFR-addicted tumors would induce stable disease by reversing the malignant phenotype of cancer stem cells and also by sustaining an anti-tumor T cell response. Finally, we discuss possible reasons for the failure of certain combinatorial therapies involving anti-EGFR agents, arguing that some of these agents might produce either a negative or a positive trans-modulation effect on other oncogenes. It becomes evident that we need operational definitions of EGFR addiction in order to determine which patient populations may benefit from treatment with anti-EGFR drugs, and to improve the design of these therapies.

A view on EGFR-targeted therapies from the oncogene-addiction perspective

Directory of Open Access Journals (Sweden)

Rolando ePerez

2013-04-01

Full Text Available Tumor cell growth and survival can often be impaired by inactivating a single oncogen – a phenomenon that has been called as 'oncogene addiction'. It is in such scenarios that molecular targeted therapies may succeed. Among known oncogenes, the epidermal growth factor receptor (EGFR has become the target of different cancer therapies. So far, however, the clinical benefit from EGFR-targeted therapies has been rather limited. A critical review of the large amount of clinical data obtained with anti-EGFR agents, carried out from the perspective of the oncogene addiction concept, may help to understand the causes of the unsatisfactory results. In this article we intend to do such an exercise taking as basis for the analysis a few case studies of anti-EGFR agents that are currently in the clinic. There, the 'EGFR addiction' phenomenon becomes apparent in high-responder patients. We further discuss how the concept of oncogene addiction needs to be interpreted on the light of emerging experimental evidences and ideas; in particular, that EGFR addiction may reflect the interconnection of several cellular pathways. In this regard we set forth several hypotheses; namely, that requirement of higher glucose uptake by hypoxic tumor cells may reinforce EGFR addiction; and that chronic use of EGFR-targeted antibodies in EGFR-addicted tumors would induce stable disease by reversing the malignant phenotype of cancer stem cells and also by sustaining an anti-tumor T cell response. Finally, we discuss possible reasons for the failure of certain combinatorial therapies involving anti-EGFR agents, arguing that some of these agents might produce either a negative or a positive trans-modulation effect on other oncogenes. It becomes evident that we need operational definitions of EGFR addiction in order to determine which patient populations may benefit from treatment with anti-EGFR drugs, and to improve the design of these therapies.

An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer

DEFF Research Database (Denmark)

Vallejo, Adrian; Perurena, Naiara; Guruceaga, Elisabet

2017-01-01

KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, a deeper understanding of the molecular mechanisms triggered by KRAS oncogene may yield alternative therapeutic strategies. Here we report the identifica...

TLR4, NOD1 and NOD2 mediate immune recognition of putative newly identified periodontal pathogens.

Science.gov (United States)

Marchesan, Julie; Jiao, Yizu; Schaff, Riley A; Hao, Jie; Morelli, Thiago; Kinney, Janet S; Gerow, Elizabeth; Sheridan, Rachel; Rodrigues, Vinicius; Paster, Bruce J; Inohara, Naohiro; Giannobile, William V

2016-06-01

Periodontitis is a polymicrobial inflammatory disease that results from the interaction between the oral microbiota and the host immunity. Although the innate immune response is important for disease initiation and progression, the innate immune receptors that recognize both classical and putative periodontal pathogens that elicit an immune response have not been elucidated. By using the Human Oral Microbe Identification Microarray (HOMIM), we identified multiple predominant oral bacterial species in human plaque biofilm that strongly associate with severe periodontitis. Ten of the identified species were evaluated in greater depth, six being classical pathogens and four putative novel pathogens. Using human peripheral blood monocytes (HPBM) and murine bone-marrow-derived macrophages (BMDM) from wild-type (WT) and Toll-like receptor (TLR)-specific and MyD88 knockouts (KOs), we demonstrated that heat-killed Campylobacter concisus, Campylobacter rectus, Selenomonas infelix, Porphyromonas endodontalis, Porphyromonas gingivalis, and Tannerella forsythia mediate high immunostimulatory activity. Campylobacter concisus, C. rectus, and S. infelix exhibited robust TLR4 stimulatory activity. Studies using mesothelial cells from WT and NOD1-specific KOs and NOD2-expressing human embryonic kidney cells demonstrated that Eubacterium saphenum, Eubacterium nodatum and Filifactor alocis exhibit robust NOD1 stimulatory activity, and that Porphyromonas endodontalis and Parvimonas micra have the highest NOD2 stimulatory activity. These studies allowed us to provide important evidence on newly identified putative pathogens in periodontal disease pathogenesis showing that these bacteria exhibit different immunostimulatory activity via TLR4, NOD1, and NOD2 (Clinicaltrials.gov NCT01154855). © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

TLR4, NOD1 and NOD2 Mediate Immune Recognition of Putative Newly-Identified Periodontal Pathogens

Science.gov (United States)

Schaff, Riley A.; Hao, Jie; Morelli, Thiago; Kinney, Janet S.; Gerow, Elizabeth; Sheridan, Rachel; Rodrigues, Vinicius; Paster, Bruce J.; Inohara, Naohiro; Giannobile, William V.

2015-01-01

SUMMARY Periodontitis is a polymicrobial inflammatory disease that results from the interaction between the oral microbiota and the host immunity. While the innate immune response is important for disease initiation and progression, the innate immune receptors that recognize both classical and putative periodontal pathogens that elicit an immune response have not been elucidated. By using the Human Oral Microbe Identification Microarray (HOMIM), we identified multiple predominant oral bacterial species in human plaque biofilm that strongly associate with severe periodontitis. Ten of the identified species were evaluated in greater depth, 6 being classical pathogens and 4 putative novel pathogens. Using human peripheral blood monocytes (HPBM) and murine bone marrow–derived macrophages (BMDM) from wild-type (WT) and toll-like receptor (TLR)-specific and MyD88 knockouts (KOs), we demonstrated that heat-killed Campylobacter concisus, Campylobacter rectus, Selenomonas infelix, Porphyromonas endodontalis, Porphyromonas gingivalis, and Tannerella forsythia mediate high immunostimulatory activity. C. concisus, C. rectus, and S. infelix exhibited robust TLR4 stimulatory activity. Studies using mesothelial cells from WT and NOD1-specific KOs and NOD2-expressing human embryonic kidney (HEK) cells demonstrated that Eubacterium saphenum, Eubacterium nodatum and Filifactor alocis exhibit robust NOD1 stimulatory activity, and that Porphyromonas endodontalis and Parvimonas micra have the highest NOD2-stimulatory activity. These studies allowed us to provide important evidence on newly-identified putative pathogens in periodontal disease pathogenesis showing that these bacteria exhibit different immunostimulatory activity via TLR4, NOD1, and NOD2 (Clinicaltrials.gov NCT01154855). PMID:26177212

Mass loss from the proto-sun: Formation and evolution of the solar nebula

International Nuclear Information System (INIS)

Trivedi, B.M.P.

1984-01-01

We consider the formation and evolution of the solar nebula in the light of observations of T Tauri stars, oxygen-isotopic anomalies in meteorites, and the mass and angular momentum distribution in the present solar system. It is argued that the solar nebula formed from the mass lost by the proto-Sun. The outflow of initially partially ionized material in the presence of a strong proto-solar magnetic field would lead to the transfer of angular momentum from the central Sun to the outflowing matter. This explains the present angular momentum distribution between the Sun and the planetary system. When the outflowing matter cooled sufficiently, to less than 2000 K, approx. l0 12 cm from the Sun, the material would neutralize, and the magnetic field would then decouple from the outflowing matter. Further motion would be governed by the gravitational field of the proto-Sun, the gas pressure, and the centrifugal force. When these forces balance, the radial flow would stop, and a rotating solar nebula would form. Chemical condensation would occur in the outflowing matter when suitable pressure-temperature conditions would develop. The condensation of the refractory mineral Al 2 O 3 would start at a distance of approx.2 x l0 12 cm from the Sun, where the pressure would be approx. 3 x l0 8 atm, and temperature approx. l450 K. The condensation sequence of other lower temperature minerals would follow this. All the refractory minerals and iron would condense within the orbit of the planet Mercury. All the volatiles would condense before the outflowing matter crossed the asteroid region. The grains would move to the outer part of the nebula along with the outflowing gas

Molecular biology III - Oncogenes and tumor suppressor genes

International Nuclear Information System (INIS)

Giaccia, Amato J.

1996-01-01

Purpose: The purpose of this course is to introduce to radiation oncologists the basic concepts of tumorigenesis, building on the information that will be presented in the first and second part of this series of lectures. Objective: Our objective is to increase the current understanding of radiation oncologists with the process of tumorigenesis, especially focusing on genes that are altered in many tumor types that are potential candidates for novel molecular strategies. As strategies to treat cancer of cancer are becoming more sophisticated, it will be important for both the practitioner and academician to develop a basic understanding of the function of cancer 'genes'. This will be the third in a series of refresher courses that are meant to address recent advances in Cancer Biology in a way that both clinicians without previous knowledge of molecular biology or experienced researchers will find interesting. The lecture will begin with a basic overview of tumorigenesis; methods of detecting chromosome/DNA alterations, approaches used to isolate oncogenes and tumor suppressor genes, and their role in cell killing by apoptosis. Special attention will be given to oncogenes and tumor suppressor genes that are modulated by ionizing radiation and the tumor microenvironment. We will relate the biology of oncogenes and tumor suppressor genes to basic aspects of radiation biology that would be important in clinical practice. Finally, we will review recent studies on the prognostic significance of p53 mutations and apoptosis in tumor specimens. The main point of this lecture is to relate both researcher and clinician what are the therapeutic ramifications of oncogene and tumor suppressor gene mutations found in human neoptasia

Oncogenic osteomalacia presenting as bilateral stress fractures of the tibia

Energy Technology Data Exchange (ETDEWEB)

Ohashi, Kenjirou; Ohnishi, Takeshi; Ishikawa, Tohru [Department of Radiology, St. Marianna University Hospital, Kanagawa (Japan); Tani, Haruo [Department of Internal Medicine III, St. Marianna University Hospital, Kawasaki City, Kanagawa (Japan); Uesugi, Keisuke [Department of Otolaryngology, St. Marianna University Hospital, Kawasaki City, Kanagawa (Japan); Takagi, Masayuki [Department of Pathology, St. Marianna University Hospital, Kawasaki City, Kanagawa (Japan)

1999-01-01

We report on a patient with bilateral stress fractures of the tibia who subsequently showed classic biochemical features of oncogenic osteomalacia. Conventional radiographs were normal. MR imaging revealed symmetric, bilateral, band-like low-signal lesions perpendicular to the medial cortex of the tibiae and corresponding to the only lesions subsequently seen on the bone scan. A maxillary sinus lesion was subsequently detected and surgically removed resulting in prompt alleviation of symptoms and normalization of hypophosphatemia and low 1,25-(OH){sub 2} vitamin D{sub 3}. The lesion was pathologically diagnosed as a hemangiopericytoma-like tumor. Patients with oncogenic osteomalacia may present with stress fractures limited to the tibia, as seen in athletes. The clue to the real diagnosis lies in paying close attention to the serum phosphate levels, especially in patients suffering generalized symptoms of weakness and not given to unusual physical activity. (orig.) With 4 figs., 6 refs.

Silencing Agrobacterium oncogenes in transgenic grapevine results in strain-specific crown gall resistance.

Science.gov (United States)

Galambos, A; Zok, A; Kuczmog, A; Oláh, R; Putnoky, P; Ream, W; Szegedi, E

2013-11-01

Grapevine rootstock transformed with an Agrobacterium oncogene-silencing transgene was resistant to certain Agrobacterium strains but sensitive to others. Thus, genetic diversity of Agrobacterium oncogenes may limit engineering crown gall resistance. Crown gall disease of grapevine induced by Agrobacterium vitis or Agrobacterium tumefaciens causes serious economic losses in viticulture. To establish crown gall-resistant lines, somatic proembryos of Vitis berlandieri × V. rupestris cv. 'Richter 110' rootstock were transformed with an oncogene-silencing transgene based on iaaM and ipt oncogene sequences from octopine-type, tumor-inducing (Ti) plasmid pTiA6. Twenty-one transgenic lines were selected, and their transgenic nature was confirmed by polymerase chain reaction (PCR). These lines were inoculated with two A. tumefaciens and three A. vitis strains. Eight lines showed resistance to octopine-type A. tumefaciens A348. Resistance correlated with the expression of the silencing genes. However, oncogene silencing was mostly sequence specific because these lines did not abolish tumorigenesis by A. vitis strains or nopaline-type A. tumefaciens C58.

PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling

OpenAIRE

Shrestha, Yashaswi; Schafer, Eric J.; Boehm, Jesse S.; Thomas, Sapana R.; He, Frank; Du, Jinyan; Wang, Shumei; Barretina, Jordi; Weir, Barbara A.; Zhao, Jean J.; Polyak, Kornelia; Golub, Todd R.; Beroukhim, Rameen; Hahn, William C.

2011-01-01

Activating mutations in the RAS family or BRAF frequently occur in many types of human cancers but are rarely detected in breast tumors. However, activation of the RAS-RAF-MEK-ERK Mitogen-Activated Protein Kinase (MAPK) pathway is commonly observed in human breast cancers, suggesting that other genetic alterations lead to activation of this signaling pathway. To identify breast cancer oncogenes that activate the MAPK pathway, we screened a library of human kinases for their ability to induce ...

Non-covalent interactions of the carcinogen (+)-anti-BPDE with exon 1 of the human K-ras proto-oncogene

Science.gov (United States)

Rodriguez, Jorge H.; Deligkaris, Christos

2013-03-01

Investigating the complementary, but different, effects of physical (non-covalent) and chemical (covalent) mutagen-DNA and carcinogen-DNA interactions is important for understanding possible mechanisms of development and prevention of mutagenesis and carcinogenesis. A highly mutagenic and carcinogenic metabolite of the polycyclic aromatic hydrocarbon benzo[ α]pyrene, namely (+)-anti-BPDE, is known to undergo both physical and chemical complexation with DNA. The major covalent adduct, a promutagenic, is known to be an external (+)-trans-anti-BPDE-N2-dGuanosine configuration whose origins are not fully understood. Thus, it is desirable to study the mechanisms of external non-covalent BPDE-DNA binding and their possible relationships to external covalent trans adduct formation. We present a detailed codon-by-codon computational study of the non-covalent interactions of (+)-anti-BPDE with DNA which explains and correctly predicts preferential (+)-anti-BPDE binding at minor groove guanosines. Due to its relevance to carcinogenesis, the interaction of (+)-anti-BPDE with exon 1 of the human K-ras gene has been studied in detail. Present address: Department of Physics, Drury University

Attempts on producing lymphoid cell line from Penaeus monodon by induction with SV40-T and 12S EIA oncogenes.

Science.gov (United States)

Puthumana, Jayesh; Prabhakaran, Priyaja; Philip, Rosamma; Singh, I S Bright

2015-12-01

In an attempt of in vitro transformation, transfection mediated expression of Simian virus-40 (T) antigen (SV40-T) and transduction mediated expression of Adenovirus type 12 early region 1A (12S E1A) oncogene were performed in Penaeus monodon lymphoid cells. pSV3-neo vector encoding SV40-T oncogene and a recombinant baculovirus BacP2-12S E1A-GFP encoding 12S E1A oncogene under the control of hybrid promoters were used. Electroporation and lipofection mediated transformation of SV40-T in lymphoid cells confirmed the transgene expression by phenotypic variation and the expression of GFP in co-transfection experiment. The cells transfected by lipofection (≥ 5%) survived for 14 days with lower toxicity (30%), whilst on electroporation, most of the cells succumbed to death (60%) and survived cells lived up to 7 days. Transduction efficiency in primary lymphoid cells was more than 80% within 14 days of post-transduction, however, an incubation period of 7 days post-transduction was observed without detectable expression of 12S E1A. High level of oncogenic 12S E1A expression were observed after 14 day post-transduction and the proliferating cells survived for more than 90 days with GFP expression, however, without in vitro transformation and immortalization. The study put forth the requirement of transduction mediated 'specific' oncogene expression along with telomerase activation and epigenetic induction for the immortalization and establishment of shrimp cell line. Copyright © 2015. Published by Elsevier Ltd.

bcr-abl oncogene activation in Philadelphia chromosome-positive acute lymphoblastic leukemia

NARCIS (Netherlands)

Hermans, A.; Gow, J.; Selleri, L.; von Lindern, M.; Hagemeijer, A.; Wiedemann, L. M.; Grosveld, G.

1988-01-01

Tumor-specific alterations in oncogenes are thought to play a central role in the development of cancer. An example is the consistent fusion of the bcr gene to the c-abl oncogene on the Ph chromosome in CML. The Ph chromosome can also be observed in ALL. About 50% of Ph+ ALL cases, in contrast to

[Genotyping of oncogenic human papilloma viruses in women with HG SIL diagnosis].

Science.gov (United States)

Kedzia, Witold; Pruski, Dominik; Józefiak, Agata; Rokita, Wojciech; Spaczyński, Marek

2010-10-01

Development of primary prevention of cervical cancer in other words a vaccination against selected, oncogenic HPV types, entails an increasing importance of epidemiological studies and prevalence of various types of human papilloma virus. The incidence of HPV varies depending on the geographic location of the population. The effectiveness of primary prevention against HPV 16, 18, in the context of reducing the incidence of cervical cancer will depend, among others, on the prevalence of these types in the population and virus-like antigens, which are partially cross-resistant. Identification of the most frequent, oncogenic HPV types in women with HG SIL diagnosis from Central and Western Poland to assess the merits of the development of primary prevention. For the purpose of molecular tests identifying the presence of 13 DNA oncogenic virus types, swabs were taken with the cyto-brush from 76 women diagnosed with CIN 2 or CIN 3 (HG SIL). Patients eligible for the study were diagnosed at the Laboratory of Pathophysiology of Uterine Cervix, Gynecology and Obstetrics Clinical Hospital of Karol Marcinkowski University of Medical Sciences. Patients came from Central and Western parts of Poland. Cell material in which the method of Amplicor HPV (Roche Diagnostics) identified the presence of DNA of oncogenic HPV types was in each case subsequently subjected to genotyping using the molecular test - Linear Array HPV Genotyping (Roche Diagnostics). Five most common oncogenic HPV types in order of detection included: 16, 33, 18, 31, 56. Together these five types of virus comprised 75.86% (88/116) of all detected HPV types. 1. In women from Central and Western Poland, diagnosed with HG SIL, the most common HPV genotypes were HPV 16, HPV33, HPV 18, HPV31, HPV56. 2. Two HPV types 16 and 18, against which vaccinations are directed, belong to the group of three genotypes of HPV most commonly identified in the evolution of CIN 2, CIN 3 diagnosed in women from Central and Western

The Human Cytomegalovirus Strain DB Activates Oncogenic Pathways in Mammary Epithelial Cells

Directory of Open Access Journals (Sweden)

Amit Kumar

2018-04-01

Full Text Available Background: Human cytomegalovirus (HCMV establishes a persistent life-long infection and increasing evidence indicates HCMV infection can modulate signaling pathways associated with oncogenesis. Breast milk is an important route of HCMV transmission in humans and we hypothesized that mammary epithelial cells could be one of the main cellular targets of HCMV infection. Methods: The infectivity of primary human mammary epithelial cells (HMECs was assessed following infection with the HCMV-DB strain, a clinical isolate with a marked macrophage-tropism. The impact of HCMV-DB infection on expression of p53 and retinoblastoma proteins, telomerase activity and oncogenic pathways (c-Myc, Akt, Ras, STAT3 was studied. Finally the transformation of HCMV-DB infected HMECs was evaluated using soft agar assay. CTH cells (CMV Transformed HMECs were detected in prolonged cultures of infected HMECs. Tumor formation was observed in NOD/SCID Gamma (NSG mice injected with CTH cells. Detection of long non coding RNA4.9 (lncRNA4.9 gene was assessed in CTH cells, tumors isolated from xenografted NSG mice and biopsies of patients with breast cancer using qualitative and quantitative PCR. Results: We found that HCMV, especially a clinical strain named HCMV-DB, infects HMECs in vitro. The clinical strain HCMV-DB replicates productively in HMECs as evidenced by detection of early and late viral transcripts and proteins. Following infection of HMECs with HCMV-DB, we observed the inactivation of retinoblastoma and p53 proteins, the activation of telomerase activity, the activation of the proto-oncogenes c-Myc and Ras, the activation of Akt and STAT3, and the upregulation of cyclin D1 and Ki67 antigen. Colony formation was observed in soft agar seeded with HCMV-DB-infected HMECs. Prolonged culture of infected HMECs resulted in the development of clusters of spheroid cells that we called CTH cells (CMV Transformed HMECs. CTH cells when injected in NOD/SCID Gamma (NSG mice

Multiple mechanisms of MYCN dysregulation in Wilms tumour

NARCIS (Netherlands)

Williams, Richard D.; Chagtai, Tasnim; Alcaide-German, Marisa; Apps, John; Wegert, Jenny; Popov, Sergey; Vujanic, Gordan; van Tinteren, Harm; van den Heuvel-Eibrink, Marry M.; Kool, Marcel; de Kraker, Jan; Gisselsson, David; Graf, Norbert; Gessler, Manfred; Pritchard-Jones, Kathy

2015-01-01

Genomic gain of the proto-oncogene transcription factor gene MYCN is associated with poor prognosis in several childhood cancers. Here we present a comprehensive copy number analysis of MYCN in Wilms tumour (WT), demonstrating that gain of this gene is associated with anaplasia and with poorer

Regulation of ARE-mRNA Stability by Cellular Signaling

DEFF Research Database (Denmark)

Damgaard, Christian Kroun; Lykke-Andersen, Jens

2013-01-01

but as a response to different cellular cues they can become either stabilized, allowing expression of a given gene, or further destabilized to silence their expression. These tightly regulated mRNAs include many that encode growth factors, proto-oncogenes, cytokines, and cell cycle regulators. Failure to properly...

Early bichemical markers of effects: Enzyme induction, oncogene activation and markers of oxidative damage

DEFF Research Database (Denmark)

Poulsen, Henrik E.; Loft, Steffen

1995-01-01

Early bichemical marker, enzyme induction, oncogene activation, oxidative damage, low-density lipoprotein......Early bichemical marker, enzyme induction, oncogene activation, oxidative damage, low-density lipoprotein...

ProtoBee: Hierarchical classification and annotation of the honey bee proteome

OpenAIRE

Kaplan, Noam; Linial, Michal

2006-01-01

The recently sequenced genome of the honey bee (Apis mellifera) has produced 10,157 predicted protein sequences, calling for a computational effort to extract biological insights from them. We have applied an unsupervised hierarchical protein-clustering method, which was previously used in the ProtoNet system, to nearly 200,000 proteins consisting of the predicted honey bee proteins, the SWISS-PROT protein database, and the complete set of proteins of the mouse (Mus musculus) and the fruit fl...

The WIP1 oncogene promotes progression and invasion of aggressive medulloblastoma variants.

Science.gov (United States)

Buss, M C; Remke, M; Lee, J; Gandhi, K; Schniederjan, M J; Kool, M; Northcott, P A; Pfister, S M; Taylor, M D; Castellino, R C

2015-02-26

Recent studies suggest that medulloblastoma, the most common malignant brain tumor of childhood, is comprised of four disease variants. The WIP1 oncogene is overexpressed in Group 3 and 4 tumors, which contain medulloblastomas with the most aggressive clinical behavior. Our data demonstrate increased WIP1 expression in metastatic medulloblastomas, and inferior progression-free and overall survival of patients with WIP1 high-expressing medulloblastoma. Microarray analysis identified upregulation of genes involved in tumor metastasis, including the G protein-coupled receptor CXCR4, in medulloblastoma cells with high WIP1 expression. Stimulation with the CXCR4 ligand SDF1α activated PI-3 kinase signaling, and promoted growth and invasion of WIP1 high-expressing medulloblastoma cells in a p53-dependent manner. When xenografted into the cerebellum of immunodeficient mice, medulloblastoma cells with stable or endogenous high WIP1 expression exhibited strong expression of CXCR4 and activated AKT in primary and invasive tumor cells. WIP1 or CXCR4 knockdown inhibited medulloblastoma growth and invasion. WIP1 knockdown also improved the survival of mice xenografted with WIP1 high-expressing medulloblastoma cells. WIP1 knockdown inhibited cell surface localization of CXCR4 by suppressing expression of the G protein receptor kinase 5, GRK5. Restoration of wild-type GRK5 promoted Ser339 phosphorylation of CXCR4 and inhibited the growth of WIP1-stable medulloblastoma cells. Conversely, GRK5 knockdown inhibited Ser339 phosphorylation of CXCR4, increased cell surface localization of CXCR4 and promoted the growth of medulloblastoma cells with low WIP1 expression. These results demonstrate crosstalk among WIP1, CXCR4 and GRK5, which may be important for the aggressive phenotype of a subclass of medulloblastomas in children.

Gravitational waves from rotating proto-neutron stars

International Nuclear Information System (INIS)

Ferrari, V; Gualtieri, L; Pons, J A; Stavridis, A

2004-01-01

We study the effects of rotation on the quasi-normal modes (QNMs) of a newly born proto-neutron star (PNS) at different evolutionary stages, until it becomes a cold neutron star (NS). We use the Cowling approximation, neglecting spacetime perturbations, and consider different models of evolving PNS. The frequencies of the modes of a PNS are considerably lower than those of a cold NS, and are further lowered by rotation; consequently, if QNMs were excited in a sufficiently energetic process, they would radiate waves that could be more easily detectable by resonant-mass and interferometric detectors than those emitted by a cold NS. We find that for high rotation rates, some of the g-modes become unstable via the CFS instability; however, this instability is likely to be suppressed by competing mechanisms before emitting a significant amount of gravitational waves

The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis

DEFF Research Database (Denmark)

Evangelou, K.; Bartkova, J.; Kotsinas, A.

2013-01-01

oncogenes showed that the delayed upregulation of ARF reflected a requirement for a higher, transcriptionally based threshold of oncogenic stress, elicited by at least two oncogenic 'hits', compared with lower activation threshold for DDR. We propose that relative to DDR activation, ARF provides...

Oncogenic p95HER2 regulates Na+-HCO3- cotransporter NBCn1 mRNA stability in breast cancer cells via 3'UTR-dependent processes.

Science.gov (United States)

Gorbatenko, Andrej; Olesen, Christina W; Loebl, Nathalie; Sigurdsson, Haraldur H; Bianchi, Carolina; Pedraz-Cuesta, Elena; Christiansen, Jan; Pedersen, Stine Falsig

2016-11-01

The Na + -HCO 3 - cotransporter NBCn1 (SLC4A7) is up-regulated in breast cancer, important for tumor growth, and a single nucleotide polymorphism (SNP), rs4973768, in its 3' untranslated region (3'UTR) correlates with increased breast cancer risk. We previously demonstrated that NBCn1 expression and promoter activity are strongly increased in breast cancer cells expressing a constitutively active oncogenic human epidermal growth factor receptor 2 (HER2) (p95HER2). Here, we address the roles of p95HER2 in regulating NBCn1 expression via post-transcriptional mechanisms. p95HER2 expression in MCF-7 cells reduced the rate of NBCn1 mRNA degradation. The NBCn1 3'UTR down-regulated luciferase reporter expression in control cells, and this was reversed by p95HER2, suggesting that p95HER2 counteracts 3'UTR-mediated suppression of NBCn1 expression. Truncation analyses identified three NBCn1 3'UTR regions of regulatory importance. Mutation of putative miRNA-binding sites (miR-374a/b, miR-200b/c, miR-29a/b/c, miR-488) in these regions did not have significant impact on 3'UTR activity. The NBCn1 3'UTR interacted directly with the RNA-binding protein human antigen R (HuR), and HuR knockdown reduced NBCn1 expression. Conversely, ablation of a distal AU-rich element increased 3'UTR-driven reporter activity, suggesting complex regulatory roles of these sites. The cancer-associated SNP variant decreased reporter expression in T-47D breast cancer cells, yet not in MCF-7, MDA-MB-231 and SK-BR-3 cells, arguing against a general role in regulating NBCn1 expression. Finally, p95HER2 expression increased total and plasma membrane NBCn1 protein levels and decreased the rate of NBCn1 protein degradation. Collectively, this is the first work to demonstrate 3'UTR-mediated NBCn1 regulation, shows that p95HER2 regulates NBCn1 expression at multiple levels, and substantiates the central position of p95HER2-NBCn1 signaling in breast cancer. © 2016 The Author(s); published by Portland Press

Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3 and KIT driven Leukemogenesis

Science.gov (United States)

Chatterjee, Anindya; Ghosh, Joydeep; Ramdas, Baskar; Mali, Raghuveer Singh; Martin, Holly; Kobayashi, Michihiro; Vemula, Sasidhar; Canela, Victor H.; Waskow, Emily R.; Visconte, Valeria; Tiu, Ramon V.; Smith, Catherine C.; Shah, Neil; Bunting, Kevin D.; Boswell, H. Scott; Liu, Yan; Chan, Rebecca J.; Kapur, Reuben

2015-01-01

SUMMARY Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN) and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK), whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis. PMID:25456130

Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis

Directory of Open Access Journals (Sweden)

Anindya Chatterjee

2014-11-01

Full Text Available Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML and myeloproliferative neoplasms (MPNs, and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription, is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis.

In silico Analysis of osr40c1 Promoter Sequence Isolated from Indica Variety Pokkali

Directory of Open Access Journals (Sweden)

W.S.I. de Silva

2017-07-01

Full Text Available The promoter region of a drought and abscisic acid (ABA inducible gene, osr40c1, was isolated from a salt-tolerant indica rice variety Pokkali, which is 670 bp upstream of the putative translation start codon. In silico promoter analysis of resulted sequence showed that at least 15 types of putative motifs were distributed within the sequence, including two types of common promoter elements, TATA and CAAT boxes. Additionally, several putative cis-acing regulatory elements which may be involved in regulation of osr40c1 expression under different conditions were found in the 5′-upstream region of osr40c1. These are ABA-responsive element, light-responsive elements (ATCT-motif, Box I, G-box, GT1-motif, Gap-box and Sp1, myeloblastosis oncogene response element (CCAAT-box, auxin responsive element (TGA-element, gibberellin-responsive element (GARE-motif and fungal-elicitor responsive elements (Box E and Box-W1. A putative regulatory element, required for endosperm-specific pattern of gene expression designated as Skn-1 motif, was also detected in the Pokkali osr40c1 promoter region. In conclusion, the bioinformatic analysis of osr40c1 promoter region isolated from indica rice variety Pokkali led to the identification of several important stress-responsive cis-acting regulatory elements, and therefore, the isolated promoter sequence could be employed in rice genetic transformation to mediate expression of abiotic stress induced genes.

In vitro modeling of human pancreatic duct epithelial cell transformation defines gene expression changes induced by K-ras oncogenic activation in pancreatic carcinogenesis.

Science.gov (United States)

Qian, Jiaying; Niu, Jiangong; Li, Ming; Chiao, Paul J; Tsao, Ming-Sound

2005-06-15

Genetic analysis of pancreatic ductal adenocarcinomas and their putative precursor lesions, pancreatic intraepithelial neoplasias (PanIN), has shown a multistep molecular paradigm for duct cell carcinogenesis. Mutational activation or inactivation of the K-ras, p16(INK4A), Smad4, and p53 genes occur at progressive and high frequencies in these lesions. Oncogenic activation of the K-ras gene occurs in >90% of pancreatic ductal carcinoma and is found early in the PanIN-carcinoma sequence, but its functional roles remain poorly understood. We show here that the expression of K-ras(G12V) oncogene in a near diploid HPV16-E6E7 gene immortalized human pancreatic duct epithelial cell line originally derived from normal pancreas induced the formation of carcinoma in 50% of severe combined immunodeficient mice implanted with these cells. A tumor cell line established from one of these tumors formed ductal cancer when implanted orthotopically. These cells also showed increased activation of the mitogen-activated protein kinase, AKT, and nuclear factor-kappaB pathways. Microarray expression profiling studies identified 584 genes whose expression seemed specifically up-regulated by the K-ras oncogene expression. Forty-two of these genes have been reported previously as differentially overexpressed in pancreatic cancer cell lines or primary tumors. Real-time PCR confirmed the overexpression of a large number of these genes. Immunohistochemistry done on tissue microarrays constructed from PanIN and pancreatic cancer samples showed laminin beta3 overexpression starting in high-grade PanINs and occurring in >90% of pancreatic ductal carcinoma. The in vitro modeling of human pancreatic duct epithelial cell transformation may provide mechanistic insights on gene expression changes that occur during multistage pancreatic duct cell carcinogenesis.

An S/T-Q cluster domain census unveils new putative targets under Tel1/Mec1 control

Directory of Open Access Journals (Sweden)

Cheung Hannah C

2012-11-01

Full Text Available Abstract Background The cellular response to DNA damage is immediate and highly coordinated in order to maintain genome integrity and proper cell division. During the DNA damage response (DDR, the sensor kinases Tel1 and Mec1 in Saccharomyces cerevisiae and ATM and ATR in human, phosphorylate multiple mediators which activate effector proteins to initiate cell cycle checkpoints and DNA repair. A subset of kinase substrates are recognized by the S/T-Q cluster domain (SCD, which contains motifs of serine (S or threonine (T followed by a glutamine (Q. However, the full repertoire of proteins and pathways controlled by Tel1 and Mec1 is unknown. Results To identify all putative SCD-containing proteins, we analyzed the distribution of S/T-Q motifs within verified Tel1/Mec1 targets and arrived at a unifying SCD definition of at least 3 S/T-Q within a stretch of 50 residues. This new SCD definition was used in a custom bioinformatics pipeline to generate a census of SCD-containing proteins in both yeast and human. In yeast, 436 proteins were identified, a significantly larger number of hits than were expected by chance. These SCD-containing proteins did not distribute equally across GO-ontology terms, but were significantly enriched for those involved in processes related to the DDR. We also found a significant enrichment of proteins involved in telophase and cytokinesis, protein transport and endocytosis suggesting possible novel Tel1/Mec1 targets in these pathways. In the human proteome, a wide range of similar proteins were identified, including homologs of some SCD-containing proteins found in yeast. This list also included high concentrations of proteins in the Mediator, spindle pole body/centrosome and actin cytoskeleton complexes. Conclusions Using a bioinformatic approach, we have generated a census of SCD-containing proteins that are involved not only in known DDR pathways but several other pathways under Tel1/Mec1 control suggesting new

Clinical implication of elevated human cervical cancer oncogene-1 expression in esophageal squamous cell carcinoma.

Science.gov (United States)

Liu, Ying; Li, Ke; Ren, Zhonghai; Li, Shenglei; Zhang, Hongyan; Fan, Qingxia

2012-07-01

The human cervical cancer oncogene 1 (HCCR-1), a novel human oncoprotein, has been shown to be upregulated in various human tumors and plays a critical role in tumorigenesis and tumor progression. Here, the authors investigated HCCR-1 level in esophageal squamous cell carcinoma (ESCC) tissues and assessed the correlation between HCCR-1 level and prognosis of the patients with ESCC. HCCR-1 levels were investigated by immunohistochemistry, in situ hybridization, real-time quantitative RT-PCR and Western blotting methods; Kaplan-Meier curve was used to evaluate the prognostic value of HCCR-1 level in patients with ESCC using log-rank test. HCCR-1 displayed high levels in ESCC tissues compared to squamous dysplasia tissues and normal esophageal epithelial tissues. No significant correlation was observed between the levels of HCCR-1 mRNA and protein and gender and age (all p>0.05) but obviously related to histological grade, clinical stage, and lymph node metastasis (all p<0.001). Moreover, the survival rate of the patients with low HCCR-1 levels was higher than that of the patients with high HCCR-1 levels (both p<0.05). These data demonstrate that HCCR-1 may be used as a novel predictor for the prognosis of the patients with ESCC.

MDM2 promoter SNP344T>A (rs1196333) status does not affect cancer risk

NARCIS (Netherlands)

S. Knappskog (Stian); L.B. Gansmo (Liv); P. Romundstad (Pål); M. Bjørnslett (Merete); J. Trovik (Jone); J. Sommerfelt-Pettersen (Jan); E. Løkkevik (Erik); R.A.E.M. Tollenaar (Rob); C.M. Seynaeve (Caroline); P. Devilee (Peter); H.B. Salvesen (Helga); A. Dørum (Anne); K. Hveem (Kristian); L.J. Vatten (Lars); P.E. Lønning (Per )

2012-01-01

textabstractThe MDM2 proto-oncogene plays a key role in central cellular processes like growth control and apoptosis, and the gene locus is frequently amplified in sarcomas. Two polymorphisms located in the MDM2 promoter P2 have been shown to affect cancer risk. One of these polymorphisms

Problem-Solving Test: The Mechanism of Action of a Human Papilloma Virus Oncoprotein

Science.gov (United States)

Szeberenyi, Jozsef

2009-01-01

Terms to be familiar with before you start to solve the test: human papilloma virus; cervical cancer; oncoproteins; malignant transformation; retinoblastoma protein; cell cycle; quiescent and cycling cells; cyclin/cyclin-dependent kinase (Cdk) complexes; E2F; S-phase genes; enhancer element; proto-oncogenes; tumor suppressor genes; radioactive…

Analysis of beta-catenin, Ki-ras, and microsatellite stability in azoxymethane-induced colon tumors of BDIX/Orl Ico rats

DEFF Research Database (Denmark)

Sørensen, Nanna Møller; Kobaek-Larsen, Morten; Bonne, Anita

2003-01-01

The aim of the study reported here was to investigate whether the azoxymethane (AOM)-induced colon cancer rat model mimics the human situation with regard to microsatellite stability, changes in expression of beta-catenin, and/or changes in the sequence of the proto-oncogene Ki-ras. Colon cancer ...

Translation elongation factor eEF1A2 is a potential oncoprotein that is overexpressed in two-thirds of breast tumours

International Nuclear Information System (INIS)

Tomlinson, Victoria AL; Newbery, Helen J; Wray, Naomi R; Jackson, Juliette; Larionov, Alexey; Miller, William R; Dixon, J Michael; Abbott, Catherine M

2005-01-01

The tissue-specific translation elongation factor eEF1A2 was recently shown to be a potential oncogene that is overexpressed in ovarian cancer. Although there is no direct evidence for an involvement of eEF1A2 in breast cancer, the genomic region to which EEF1A2 maps, 20q13, is frequently amplified in breast tumours. We therefore sought to establish whether eEF1A2 expression might be upregulated in breast cancer. eEF1A2 is highly similar (98%) to the near-ubiquitously expressed eEF1A1 (formerly known as EF1-α) making analysis with commercial antibodies difficult. We have developed specific anti-eEF1A2 antibodies and used them in immunohistochemical analyses of tumour samples. We report the novel finding that although eEF1A2 is barely detectable in normal breast it is moderately to strongly expressed in two-thirds of breast tumours. This overexpression is strongly associated with estrogen receptor positivity. eEF1A2 should be considered as a putative oncogene in breast cancer that may be a useful diagnostic marker and therapeutic target for a high proportion of breast tumours. The oncogenicity of eEF1A2 may be related to its role in protein synthesis or to its potential non-canonical functions in cytoskeletal remodelling or apoptosis

Reversal of oncogene transformation and suppression of tumor growth by the novel IGF1R kinase inhibitor A-928605

International Nuclear Information System (INIS)

Pappano, William N; Sheppard, George S; Donawho, Cherrie; Buchanan, Fritz G; Davidsen, Steven K; Bell, Randy L; Wang, Jieyi; Jung, Paul M; Meulbroek, Jonathan A; Wang, Yi-Chun; Hubbard, Robert D; Zhang, Qian; Grudzien, Meagan M; Soni, Niru B; Johnson, Eric F

2009-01-01

The insulin-like growth factor (IGF) axis is an important signaling pathway in the growth and survival of many cell and tissue types. This pathway has also been implicated in many aspects of cancer progression from tumorigenesis to metastasis. The multiple roles of IGF signaling in cancer suggest that inhibition of the pathway might yield clinically effective therapeutics. We describe A-928605, a novel pyrazolo [3,4-d]pyrimidine small molecule inhibitor of the receptor tyrosine kinases (IGF1R and IR) responsible for IGF signal transduction. This compound was first tested for its activity and selectivity via conventional in vitro kinome profiling and cellular IGF1R autophosphorylation. Additionally, cellular selectivity and efficacy of A-928605 were analyzed in an IGF1R oncogene-addicted cell line by proliferation, signaling and microarray studies. Finally, in vivo efficacy of A-928605 was assessed in the oncogene-addicted cell line and in a neuroblastoma model as a single agent as well as in combination with clinically approved therapeutics targeting EGFR in models of pancreatic and non-small cell lung cancers. A-928605 is a selective IGF1R inhibitor that is able to abrogate activation of the pathway both in vitro and in vivo. This novel compound dosed as a single agent is able to produce significant growth inhibition of neuroblastoma xenografts in vivo. A-928605 is also able to provide additive effects when used in combination with clinically approved agents directed against EGFR in non-small cell lung and human pancreatic tumor models. These results suggest that a selective IGF1R inhibitor such as A-928605 may provide a useful clinical therapeutic for IGF pathway affected tumors and warrants further investigation

Regulatory functional territory of PLK-1 and their substrates beyond mitosis.

Science.gov (United States)

Kumar, Shiv; Sharma, Garima; Chakraborty, Chiranjib; Sharma, Ashish Ranjan; Kim, Jaebong

2017-06-06

Polo-like kinase 1 (PLK-1) is a well-known (Ser/Thr) mitotic protein kinase and is considered as a proto-oncogene. As hyper-activation of PLK-1 is broadly associated with poor prognosis and cancer progression, it is one of the most extensively studied mitotic kinases. During mitosis, PLK-1 regulates various cell cycle events, such as spindle pole maturation, chromosome segregation and cytokinesis. However, studies have demonstrated that the role of PLK-1 is not only restricted to mitosis, but PLK-1 can also regulate other vital events beyond mitosis, including transcription, translation, ciliogenesis, checkpoint adaptation and recovery, apoptosis, chromosomes dynamics etc. Recent reviews have tried to define the regulatory role of PLK-1 during mitosis progression and tumorigenesis, but its' functional role beyond mitosis is still largely unexplored. PLK-1 can regulate the activity of many proteins that work outside of its conventional territory. The dysregulation of these proteins can cause diseases such as Alzheimer's disease, tumorigenesis etc. and may also lead to drug resistance. Thus, in this review, we discussed the versatile role of PLK-1 and tried to collect data to validate its' functional role in cell cycle regulation apart from mitosis.

IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma

OpenAIRE

Ramos, Juan Carlos; Ruiz, Phillip; Ratner, Lee; Reis, Isildinha M.; Brites, Carlos; Pedroso, Celia; Byrne, Gerald E.; Toomey, Ngoc L.; Andela, Valentine; Harhaj, Edward W.; Lossos, Izidore S.; Harrington, William J.

2007-01-01

Adult T-cell leukemia/lymphoma (ATLL) is a generally fatal malignancy. Most ATLL patients fare poorly with conventional chemotherapy; however, antiviral therapy with zidovudine (AZT) and interferon alpha (IFN-α) has produced long-term clinical remissions. We studied primary ATLL tumors and identified molecular features linked to sensitivity and resistance to antiviral therapy. Enhanced expression of the proto-oncogene c-Rel was noted in 9 of 27 tumors. Resistant tumors exhibited c-Rel (6 of 1...

Modelling of the PROTO-II crossover network

International Nuclear Information System (INIS)

Proulx, G.A.; Lackner, H.; Spence, P.; Wright, T.P.

1985-01-01

In order to drive a double ring, symmetrically fed bremsstrahlung diode, the PROTO II accelerator was redesigned. The radially converging triplate water line was reconfigured to drive two radial converging triplate lines in parallel. The four output lines were connected to the two input lines via an electrically enclosed tubular crossover network. Low-voltage Time Domain Reflectrometry (TDR) experiments were conducted on a full scale water immersed model of one section of the crossover network as an aid in this design. A lumped element analysis of the power flow through the network was inadequate in explaining the observed wave transmission and reflection characteristics. A more detailed analysis was performed with a circuit code in which we considered both localized lump-element and transmission line features of the crossover network. Experimental results of the model tests are given and compared with the circuit simulations. 7 figs

Using 18F FDG PET/CT to Detect an occult Mesenchymal Tumor Causing Oncogenic Osteomalacia

International Nuclear Information System (INIS)

Seo, Hyo Jung; Choi, Yun Jung; Kim, Hyun Jeong; Jeong, Yong Hyu; Cho, Arthur; Lee, Jae Hoon; Yun, Mijin; Lee, Jong Doo; Kang, Won Jun

2011-01-01

Oncogenic osteomalacia is a rare paraneoplastic syndrome characterized by renal phosphate excretion, hypophosphatemia, and osteomalacia. This syndrome is often caused by tumors of mesenchymal origin. Patients with oncogenic osteomalacia have abnormal bone mineralization, resulting in a high frequency of fractures. Tumor resection is the treatment of choice, as it will often correct the metabolic imbalance. Although oncogenic osteomalacia is a potentially curable disease, diagnosis is difficult and often delayed because of the small size and sporadic location of the tumor. Bone scintigraphy and radiography best characterize osteoma lacia; magnetic resonance imaging findings are nonspecific. Here, we report a case of oncogenic osteomalacia secondary to a phosphaturic mesenchymal tumor that was successfully detected by 18F fluorodeoxyglucose positron emission tomography/computed tomography ( 18F FDG PET/CT). This case illustrates the advantages of 18F FDG PET/CT in detecting the occult mesenchymal tumor that causes oncogenic osteomalacia.

Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer.

Science.gov (United States)

Kamerkar, Sushrut; LeBleu, Valerie S; Sugimoto, Hikaru; Yang, Sujuan; Ruivo, Carolina F; Melo, Sonia A; Lee, J Jack; Kalluri, Raghu

2017-06-22

The mutant form of the GTPase KRAS is a key driver of pancreatic cancer but remains a challenging therapeutic target. Exosomes are extracellular vesicles generated by all cells, and are naturally present in the blood. Here we show that enhanced retention of exosomes, compared to liposomes, in the circulation of mice is likely due to CD47-mediated protection of exosomes from phagocytosis by monocytes and macrophages. Exosomes derived from normal fibroblast-like mesenchymal cells were engineered to carry short interfering RNA or short hairpin RNA specific to oncogenic Kras G12D , a common mutation in pancreatic cancer. Compared to liposomes, the engineered exosomes (known as iExosomes) target oncogenic KRAS with an enhanced efficacy that is dependent on CD47, and is facilitated by macropinocytosis. Treatment with iExosomes suppressed cancer in multiple mouse models of pancreatic cancer and significantly increased overall survival. Our results demonstrate an approach for direct and specific targeting of oncogenic KRAS in tumours using iExosomes.

Género y mercado de trabajo en Galicia: Análisis de equidad mediante indicadores sintéticos

OpenAIRE

Riobóo Lestón, Irene; Martín López, Carolina

2011-01-01

El estudio de las desigualdades de género ha constituido un área de gran interés en el análisis económico en los últimos años, por lo que ha resultado necesario disponer de medi-das que permitieran su cuantificación. De entre las múltiples posibilidades que existen, cabe destacar la utilización de indicadores sintéticos, ya que permiten considerar las diversas dimen-siones que subyacen tras el complejo concepto de equidad de género. En este trabajo nos he-mos centrado en la medición del nivel...

EGFR, ALK, RET, KRAS and BRAF alterations in never-smokers with non-small cell lung cancer.

Science.gov (United States)

Dong, Y U; Ren, Weihong; Qi, Jun; Jin, B O; Li, Ying; Tao, Huiqing; Xu, Ren; Li, Yanqing; Zhang, Qinxian; Han, Baohui

2016-04-01

Non-small cell lung cancer (NSCLC), caused by various mutations in a spectrum of cancer driver genes, may have distinct pathological characteristics and drug responses. Extensive genetic screening and pathological characterization is required for the design of customized therapies to improve patient outcomes. Notably, NSCLC in never-smokers exhibits distinctive clinicopathological features, which are frequently associated with tumorigenic mutations, and thus may be treated as a unique disease entity. However, to the best of our knowledge, these mutations have not been extensively and accurately characterized in an NSCLC study with a large sample size. Therefore, the present study enrolled a large cohort of NSCLC patients, which consisted of 358 never-smokers, for the screening of genetic alterations in the epidermal growth factor receptor (EGFR), ret proto-oncogene (RET), anaplastic lymphoma kinase (ALK), Kirsten rat sarcoma viral oncogene homolog (KRAS) and B-Raf proto-oncogene serine/threonine kinase (BRAF) tumorigenic genes. It was identified that the mutation rate was 47.8, 7.5, 3.6, 1.4 and 0.3% for EGFR, ALK, KRAS, RET and BRAF, respectively. In addition, clinicopathological features associated with these mutations were characterized. EGFR mutations were more frequently observed in female and older patients. By contrast, KRAS mutations were more frequently detected in male patients, and ALK and RET translocations in younger patients. The cancer cells were frequently well-differentiated in carcinoma cases exhibiting EGFR mutations, however, were less differentiated in those with ALK translocations. In conclusion, the present study determined the frequency of oncogenic alterations and associated clinicopathological features in NSCLC exhibited by never-smokers using a large sample size. The results of the present study may enrich our knowledge of NSCLC in never-smokers and provide useful insights for improvement of the outcome of molecularly targeted therapies

Vestiges of the proto-Caribbean seaway: Origin of the San Souci Volcanic Group, Trinidad

Science.gov (United States)

Neill, Iain; Kerr, Andrew C.; Chamberlain, Kevin R.; Schmitt, Axel K.; Urbani, Franco; Hastie, Alan R.; Pindell, James L.; Barry, Tiffany L.; Millar, Ian L.

2014-06-01

Outcrops of volcanic-hypabyssal rocks in Trinidad document the opening of the proto-Caribbean seaway during Jurassic-Cretaceous break-up of the Americas. The San Souci Group on the northern coast of Trinidad comprises the San Souci Volcanic Formation (SSVF) and passive margin sediments of the ~ 130-125 Ma Toco Formation. The Group was trapped at the leading edge of the Pacific-derived Caribbean Plate during the Cretaceous-Palaeogene, colliding with the para-autochthonous margin of Trinidad during the Oligocene-Miocene. In-situ U-Pb ion probe dating of micro-zircons from a mafic volcanic breccia reveal the SSVF crystallised at 135.0 ± 7.3 Ma. The age of the SSVF is within error of the age of the Toco Formation. Assuming a conformable contact, geodynamic models indicate a likely origin for the SSVF on the passive margin close to the northern tip of South America. Immobile element and Nd-Hf radiogenic isotope signatures of the mafic rocks indicate the SSVF was formed by ≪10% partial melting of a heterogeneous spinel peridotite source with no subduction or continental lithospheric mantle component. Felsic breccias within the SSVF are more enriched in incompatible elements, with isotope signatures that are less radiogenic than the mafic rocks of the SSVF. The felsic rocks may be derived from re-melting of mafic crust. Although geochemical comparisons are drawn here with proto-Caribbean igneous outcrops in Venezuela and elsewhere in the Caribbean more work is needed to elucidate the development of the proto-Caribbean seaway and its rifted margins. In particular, ion probe dating of micro-zircons may yield valuable insights into magmatism and metamorphism in the Caribbean, and in altered basaltic terranes more generally.

O desencontro sintático-semântico em uma construção de tópico: a construção de argumento cindido com SN-artefato

Directory of Open Access Journals (Sweden)

Thais Fernandes Sampaio

2013-01-01

Full Text Available Assumindo a perspectiva da Gramática das Construções Baseada no Uso (GOLDBERG, 1995, 2006; TOMASELLO, 2006, este artigo apresenta e discute um caso de desencontro sintático-semântico em uma Construção de Tópico do Português do Brasil. A Construção de Argumento Cindido com SN-Artefato (Meu tênis descolou o solado; O computador queimou o HD foi inicialmente descrita e analisada em pesquisa que identificou uma Família de Construção de Argumento Cindido no PB (SAMPAIO, 2010. Em uma breve apresentação de nossos pressupostos teóricos, discutimos, especialmente, o conceito de Construção e de Construção de Estrutura Argumental (GOLDBERG, 1995, 2003 e o conceito de desencontro (ou mismatch, nos termos de Francis e Michaelis (2000, Michaelis (2004 e Traugott (2007. A partir da análise de dados de uso, o estudo procura oferecer um tratamento abrangente ao fenômeno, considerando aspectos sintáticos, semânticos e pragmáticos da Construção. A análise identifica, nas instanciações dessa Construção, um desencontro no número de argumentos (um argumento semântico e dois argumentos sintáticos, e confirma a motivação pragmática desta, caracterizando-a como uma Construção de Tópico.

O desencontro sintático-semântico em uma construção de tópico: a Construção de Argumento Cindido com SN-Artefato

Directory of Open Access Journals (Sweden)

Thais Fernandes Sampaio

2013-01-01

Full Text Available Assumindo a perspectiva da Gramática das Construções Baseada no Uso (GOLDBERG, 1995, 2006; TOMASELLO, 2006, este artigo apresenta e discute um caso de desencontro sintático-semântico em uma Construção de Tópico do Português do Brasil. A Construção de Argumento Cindido com SN-Artefato (Meu tênis descolou o solado; O computador queimou o HD foi inicialmente descrita e analisada em pesquisa que identificou uma Família de Construção de Argumento Cindido no PB (SAMPAIO, 2010. Em uma breve apresentação de nossos pressupostos teóricos, discutimos, especialmente, o conceito de Construção e de Construção de Estrutura Argumental (GOLDBERG, 1995, 2003 e o conceito de desencontro (ou mismatch, nos termos de Francis e Michaelis (2000, Michaelis (2004 e Traugott (2007. A partir da análise de dados de uso, o estudo procura oferecer um tratamento abrangente ao fenômeno, considerando aspectos sintáticos, semânticos e pragmáticos da Construção. A análise identifica, nas instanciações dessa Construção, um desencontro no número de argumentos (um argumento semântico e dois argumentos sintáticos, e confirma a motivação pragmática desta, caracterizando-a como uma Construção de Tópico.

Oncogenic IDH1 Mutations Promote Enhanced Proline Synthesis through PYCR1 to Support the Maintenance of Mitochondrial Redox Homeostasis

Directory of Open Access Journals (Sweden)

Kate E.R. Hollinshead

2018-03-01

Full Text Available Summary: Since the discovery of mutations in isocitrate dehydrogenase 1 (IDH1 in gliomas and other tumors, significant efforts have been made to gain a deeper understanding of the consequences of this oncogenic mutation. One aspect of the neomorphic function of the IDH1 R132H enzyme that has received less attention is the perturbation of cellular redox homeostasis. Here, we describe a biosynthetic pathway exhibited by cells expressing mutant IDH1. By virtue of a change in cellular redox homeostasis, IDH1-mutated cells synthesize excess glutamine-derived proline through enhanced activity of pyrroline 5-carboxylate reductase 1 (PYCR1, coupled to NADH oxidation. Enhanced proline biosynthesis partially uncouples the electron transport chain from tricarboxylic acid (TCA cycle activity through the maintenance of a lower NADH/NAD+ ratio and subsequent reduction in oxygen consumption. Thus, we have uncovered a mechanism by which tumor cell survival may be promoted in conditions associated with perturbed redox homeostasis, as occurs in IDH1-mutated glioma. : Hollinshead et al. demonstrate a role for PYCR1 in control of mitochondrial redox homeostasis. Expression of IDH1 R132H mutation leads to increased NADH-coupled proline biosynthesis, mediated by PYCR1. The resulting metabolic phenotype partially uncouples mitochondrial NADH oxidation from respiration, representing an oxygen-sparing metabolic phenotype. Keywords: glioma, IDH1, redox, metabolism, proline

Expression of Truncated Neurokinin-1 Receptor in Childhood Neuroblastoma is Independent of Tumor Biology and Stage.

Science.gov (United States)

Pohl, Alexandra; Kappler, Roland; Mühling, Jakob; VON Schweinitz, Dietrich; Berger, Michael

2017-11-01

Neuroblastoma is an embryonal malignancy arising from the aberrant growth of neural crest progenitor cells of the sympathetic nervous system. The tachykinin receptor 1 (TACR1) - substance P complex is associated with tumoral angiogenesis and cell proliferation in a variety of cancer types. Inhibition of TACR1 was recently described to impede growth of NB cell lines. However, the relevance of TACR1 in clinical settings is unknown. We investigated gene expression levels of full-length and truncated TACR1 in 59 neuroblastomas and correlated these data with the patients' clinical parameters such as outcome, metastasis, International Neuroblastoma Staging System (INSS) status, MYCN proto-oncogene, bHLH transcription factor (MYCN) status, gender and age. Our results indicated that TACR1 is ubiquitously expressed in neuroblastoma but expression levels are independent of clinical parameters. Our data suggest that TACR1 might serve as a potent anticancer target in a large variety of patients with neuroblastoma, independent of tumor biology and clinical stage. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

GSK3 is required for rapalogs to induce degradation of some oncogenic proteins and to suppress cancer cell growth.

Science.gov (United States)

Koo, Junghui; Wang, Xuerong; Owonikoko, Taofeek K; Ramalingam, Suresh S; Khuri, Fadlo R; Sun, Shi-Yong

2015-04-20

The single-agent activity of rapalogs (rapamycin and its analogues) in most tumor types has been modest at best. The underlying mechanisms are largely unclear. In this report, we have uncovered a critical role of GSK3 in regulating degradation of some oncogenic proteins induced by rapalogs and cell sensitivity to rapalogs. The basal level of GSK3 activity was positively correlated with cell sensitivity of lung cancer cell lines to rapalogs. GSK3 inhibition antagonized rapamycin's growth inhibitory effects both in vitro and in vivo, while enforced activation of GSK3β sensitized cells to rapamycin. GSK3 inhibition rescued rapamcyin-induced reduction of several oncogenic proteins such as cyclin D1, Mcl-1 and c-Myc, without interfering with the ability of rapamycin to suppress mTORC1 signaling and cap binding. Interestingly, rapamycin induces proteasomal degradation of these oncogenic proteins, as evidenced by their decreased stabilities induced by rapamcyin and rescue of their reduction by proteasomal inhibition. Moreover, acute or short-time rapamycin treatment dissociated not only raptor, but also rictor from mTOR in several tested cell lines, suggesting inhibition of both mTORC1 and mTORC2. Thus, induction of GSK3-dependent degradation of these oncogenic proteins is likely secondary to mTORC2 inhibition; this effect should be critical for rapamycin to exert its anticancer activity.

Enhanced sensitivity of the RET proto-oncogene to ionizing radiation in vitro.

Science.gov (United States)

Volpato, Claudia Béu; Martínez-Alfaro, Minerva; Corvi, Raffaella; Gabus, Coralie; Sauvaigo, Sylvie; Ferrari, Pietro; Bonora, Elena; De Grandi, Alessandro; Romeo, Giovanni

2008-11-01

Exposure to ionizing radiation is a well-known risk factor for a number of human cancers, including leukemia and thyroid cancer. It has been known for a long time that exposure of cells to radiation results in extensive DNA damage; however, a small number of studies have tried to explain the mechanisms of radiation-induced carcinogenesis. The high prevalence of RET/PTC rearrangements in patients who have received external radiation, and the evidence of in vitro induction of RET rearrangements in human cells, suggest an enhanced sensitivity of the RET genomic region to damage by ionizing radiation. To assess whether RET is indeed more sensitive to radiations than other genomic regions, we used a COMET assay coupled with fluorescence in situ hybridization, which allows the measurement of DNA fragmentation in defined genomic regions of single cells. We compared the initial DNA damage of the genomic regions of RET, CXCL12/SDF1, ABL, MYC, PLA2G2A, p53, and JAK2 induced by ionizing radiation in both a lymphoblastoid and a fetal thyroid cell line. In both cell lines, RET fragmentation was significantly higher than in other genomic regions. Moreover, a differential distribution of signals within the COMET was associated with a higher percentage of RET fragments in the tail. RET was more susceptible to fragmentation in the thyroid-derived cells than in lymphoblasts. This enhanced susceptibility of RET to ionizing radiation suggests the possibility of using it as a radiation exposure marker.

Proto-2, an ALICE detector prototype, part of the STAR experiment at the Brookhaven National Laboratory

CERN Multimedia

2002-01-01

Proto-2, an LAICE detector prototype, overcame its prototype status to become a real part of the SDTAR, epxeriment at the US Brookhaven National Laboratory. After more than two years across the ocean, it has just arrived back at CERN.

Structure of a putative trans-editing enzyme for prolyl-tRNA synthetase from Aeropyrum pernix K1 at 1.7 Å resolution

International Nuclear Information System (INIS)

Murayama, Kazutaka; Kato-Murayama, Miyuki; Katsura, Kazushige; Uchikubo-Kamo, Tomomi; Yamaguchi-Hirafuji, Machiko; Kawazoe, Masahito; Akasaka, Ryogo; Hanawa-Suetsugu, Kyoko; Hori-Takemoto, Chie; Terada, Takaho; Shirouzu, Mikako; Yokoyama, Shigeyuki

2004-01-01

The three-dimensional structure of the APE2540 protein from A. pernix K1 has been determined by the multiple anomalous dispersion method at 1.7 Å resolution. The structure includes two monomers in the asymmetric unit and shares structural similarity with the YbaK protein or cysteinyl-tRNA Pro deacylase from H. influenzae. The crystal structure of APE2540, the putative trans-editing enzyme ProX from Aeropyrum pernix K1, was determined in a high-throughput manner. The crystal belongs to the monoclinic space group P2 1 , with unit-cell parameters a = 47.4, b = 58.9, c = 53.6 Å, β = 106.8°. The structure was solved by the multiwavelength anomalous dispersion method at 1.7 Å and refined to an R factor of 16.8% (R free = 20.5%). The crystal structure includes two protein molecules in the asymmetric unit. Each monomer consists of eight β-strands and seven α-helices. A structure-homology search revealed similarity between the trans-editing enzyme YbaK (or cysteinyl-tRNA Pro deacylase) from Haemophilus influenzae (HI1434; 22% sequence identity) and putative ProX proteins from Caulobacter crescentus (16%) and Agrobacterium tumefaciens (21%)

Intracortical osteoblastic osteosarcoma with oncogenic rickets

International Nuclear Information System (INIS)

Hasegawa, T.; Hirohashi, Setsuo; Shimoda, Tadakazu; Yokoyama, Ryohei; Beppu, Yasuo; Maeda, Shotaro

1999-01-01

Intracortical osteosarcoma is the rarest variant of osteosarcoma, occurring within, and usually confined to, the cortical bone. Oncogenic osteomalacia, or rickets, is an unusual clinicopathologic entity in which vitamin D-resistant osteomalacia, or rickets, occurs in association with some tumors of soft tissue or bone. We present a case of oncogenic rickets associated with intracortical osteosarcoma of the tibia in a 9-year-old boy, whose roentgenographic abnormalities of rickets disappeared and pertinent laboratory data except for serum alkaline phosphatase became normal after surgical resection of the tumor. Histologically, the tumor was an osteosarcoma with a prominent osteoblastic pattern. An unusual microscopic feature was the presence of matrix mineralization showing rounded calcified structures (calcified spherules). Benign osteoblastic tumors, such as osteoid osteoma and osteoblastoma, must be considered in the differential diagnosis because of the relatively low cellular atypia and mitotic activity of this tumor. The infiltrating pattern with destruction or engulfment of normal bone is a major clue to the correct diagnosis of intracortical osteosarcoma. The co-existing radiographic changes of rickets were due to the intracortical osteosarcoma. (orig.)

TRAP1 Regulation of Cancer Metabolism: Dual Role as Oncogene or Tumor Suppressor

Directory of Open Access Journals (Sweden)

Danilo Swann Matassa

2018-04-01

Full Text Available Metabolic reprogramming is an important issue in tumor biology. An unexpected inter- and intra-tumor metabolic heterogeneity has been strictly correlated to tumor outcome. Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1 is a molecular chaperone involved in the regulation of energetic metabolism in cancer cells. This protein is highly expressed in several cancers, such as glioblastoma, colon, breast, prostate and lung cancers and is often associated with drug resistance. However, TRAP1 is also downregulated in specific tumors, such as ovarian, bladder and renal cancers, where its lower expression is correlated with the worst prognoses and chemoresistance. TRAP1 is the only mitochondrial member of the Heat Shock Protein 90 (HSP90 family that directly interacts with respiratory complexes, contributing to their stability and activity but it is still unclear if such interactions lead to reduced or increased respiratory capacity. The role of TRAP1 is to enhance or suppress oxidative phosphorylation; the effects of such regulation on tumor development and progression are controversial. These observations encourage the study of the mechanisms responsible for the dualist role of TRAP1 as an oncogene or oncosuppressor in specific tumor types. In this review, TRAP1 puzzling functions were recapitulated with a special focus on the correlation between metabolic reprogramming and tumor outcome. We wanted to investigate whether metabolism-targeting drugs can efficiently interfere with tumor progression and whether they might be combined with chemotherapeutics or molecular-targeted agents to counteract drug resistance and reduce therapeutic failure.

The proto-Earth geo-reactor: Reassessing the hypotheses

Directory of Open Access Journals (Sweden)

Claude Degueldre

2016-09-01

The present paper focuses on the geo-reactor hypothetical conditions including history, spatial extension and regimes. The discussion based on recent calculations involves investigations on the limits in term of fissile inventory, size and power, based on coupling of geochemical reactions and stratification through the gravitational field considering behavior through the inner mantle, the boundary with the core and the core. The reconstruction allows to formulating that from the history point of view it would have been possible that the geo-reactor reached criticality in a proto-Earth period as a reactor triggered by 235-uranium and that thorium may have worked as an absorber if the actinide concentration was locally large enough. Without actinide separation the initiation of the criticality is unlikely. However did the segregation of actinides occur in any Earth layer?

Novel Combinatorial Chemistry-Derived Inhibitors of Oncogenic Phosphatases

National Research Council Canada - National Science Library

Lazo, John

1999-01-01

Our overall goal of this US Army Breast Cancer Grant entitled "Novel Combinatorial Chemistry-Derived Inhibitors of Oncogenic Phosphatases" is to identity and develop novel therapeutic agents for human breast cancer...

A Spotlight on Chemical Constituents and Pharmacological Activities of Nigella glandulifera Freyn et Sint Seeds

Directory of Open Access Journals (Sweden)

Besma Boubertakh

2013-01-01

Full Text Available Plants belonging to the Ranunculaceae family, and particularly their seeds, have been a hot research topic in numerous pharmacognosy laboratories. Nigella glandulifera Freyn et Sint (NG is one of the promising, but relatively insufficiently studied, plants from this family. In this review, we summarize the recently isolated chemical constituents from the seeds of this plant including alkaloids, flavonol glycosides, isobenzofuranone derivatives, saponins, terpenes, terpenoids, and fatty acids. We put also a spotlight on the recently studied therapeutic potentials of such amazing herb seeds as antidiabetes, melanogenesis inhibition, anticancer, anti-inflammatory, antithrombosis, and antiplatelet aggregation effects. Herein, we illustrate certain properties and potentials via selected examples, and thus we suggest more studies to confirm the therapeutic hypotheses, find out new compounds, and eventually to discover novel properties.

Activation of oncogenes by radon progeny and x-rays

Energy Technology Data Exchange (ETDEWEB)

Ling, C.C.

1990-01-01

The overall goal of this proposal is to study the carcinogenic effect of both high and low LET radiation at the molecular level, utilizing techniques developed in molecular biology, cancer cell biology and radiation biology. The underlying assumption is that malignant transformation of normal cells is a multistep process requiring two or more molecular events in the genomic DNA. We hypothesize that radiation may induce such events in one or more steps of the multistep process. We will use in vitro models of transformation that reproduce the stepwise progression of normal cells toward the transformed phenotype and ask whether radiation can provide the necessary activating function at discrete steps along this path. Our strategy involves transfecting into normal primary cells a variety of cloned oncogenes that are known to supply only some of the functions necessary for full transformation. These partially transformed'' cells will be the targets for irradiation by x-rays and alpha particles. The results will provide the basis for assessing the ability of ionizing radiation to activate oncogenic functions that complement'' the oncogene already present in the transfected cells and produce the fully transformed phenotype. Progress is described. 121 refs.

Activation of oncogenes by radon progeny and x-rays

International Nuclear Information System (INIS)

Ling, C.C.

1990-01-01

The overall goal of this proposal is to study the carcinogenic effect of both high and low LET radiation at the molecular level, utilizing techniques developed in molecular biology, cancer cell biology and radiation biology. The underlying assumption is that malignant transformation of normal cells is a multistep process requiring two or more molecular events in the genomic DNA. We hypothesize that radiation may induce such events in one or more steps of the multistep process. We will use in vitro models of transformation that reproduce the stepwise progression of normal cells toward the transformed phenotype and ask whether radiation can provide the necessary activating function at discrete steps along this path. Our strategy involves transfecting into normal primary cells a variety of cloned oncogenes that are known to supply only some of the functions necessary for full transformation. These ''partially transformed'' cells will be the targets for irradiation by x-rays and alpha particles. The results will provide the basis for assessing the ability of ionizing radiation to activate oncogenic functions that ''complement'' the oncogene already present in the transfected cells and produce the fully transformed phenotype. Progress is described. 121 refs

The non-small cell lung cancer EGFR extracellular domain mutation, M277E, is oncogenic and drug-sensitive

Directory of Open Access Journals (Sweden)

Yu S

2017-09-01

Full Text Available Su Yu,1,2 Yang Zhang,1 Yunjian Pan,1 Chao Cheng,1,3 Yihua Sun,1,3 Haiquan Chen1–4 1Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; 2Cancer Research Center, Fudan University Shanghai Cancer Center, Shanghai, China; 3Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; 4Institutes of Biomedical Sciences, Fudan University, Shanghai, China Purpose: To identify novel oncogenic mutations in non-small cell lung cancer patient specimens that lack mutations in known targetable genes (“pan-negative” patients.Methods: Comprehensive mutational analyses were performed on 1,356 lung adenocarcinoma specimens. In this cohort of patients, common lung cancer oncogenic driver mutations were detected in the epidermal growth factor receptor (EGFR kinase domain, the human epidermal growth factor receptor 2 kinase domain, as well as the KRAS, BRAF, ALK, ROS1 and RET genes. A sub-cohort of pan-negative patient specimens was assayed for mutations in the EGFR extracellular domain (ECD. Additionally, EGFR mutant NIH-3T3 stable cell lines were constructed and assessed for protein content, anchorage-independent growth, and tumor formation in xenograft models to identify oncogenic mutations. BaF3 lymphocytes were also used to test sensitivities of the mutations to tyrosine kinase inhibitors.Results: In pan-negative lung adenocarcinoma cases, a novel oncogenic EGFR ECD mutation was identified (M277E. EGFR M277E mutations encoded oncoproteins that transformed NIH-3T3 cells to grow in the absence of exogenous epidermal growth factor. Transformation was further evidenced by anchorage-independent growth and tumor formation in immunocompromised xenograft mouse models. Finally, as seen in the canonical EGFR L858R mutation, the M277E mutation conferred sensitivity to both erlotinib and cetuximab in BaF3 cell lines and to erlotinib in xenograft models.Conclusion: Here, a new EGFR driver mutation, M277E

ARF and ATM/ATR cooperate in p53-mediated apoptosis upon oncogenic stress

International Nuclear Information System (INIS)

Pauklin, Siim; Kristjuhan, Arnold; Maimets, Toivo; Jaks, Viljar

2005-01-01

Induction of apoptosis is pivotal for eliminating cells with damaged DNA or deregulated proliferation. We show that tumor suppressor ARF and ATM/ATR kinase pathways cooperate in the induction of apoptosis in response to elevated expression of c-myc, β-catenin or human papilloma virus E7 oncogenes. Overexpression of oncogenes leads to the formation of phosphorylated H2AX foci, induction of Rad51 protein levels and ATM/ATR-dependent phosphorylation of p53. Inhibition of ATM/ATR kinases abolishes both induction of Rad51 and phosphorylation of p53, and remarkably reduces the level of apoptosis induced by co-expression of oncogenes and ARF. However, the induction of apoptosis is downregulated in p53-/- cells and does not depend on activities of ATM/ATR kinases, indicating that efficient induction of apoptosis by oncogene activation depends on coordinated action of ARF and ATM/ATR pathways in the regulation of p53

Repression of transcription mediated at a thyroid hormone response element by the v-erb-A oncogene product

DEFF Research Database (Denmark)

Sap, J; Muñoz, A; Schmitt, J

1989-01-01

Several recent observations, such as the identification of the cellular homologue of the v-erb-A oncogene as a thyroid-hormone receptor, have strongly implicated nuclear oncogenes in transcriptional control mechanisms. The v-erb-A oncogene blocks the differentiation of erythroid cells, and changes...

Course of c-myc mRNA expression in the regenerating mouse testis determined by competitive reverse transcriptase polymerase chain reaction.

Science.gov (United States)

Amendola, R

1994-11-01

The c-myc proto-oncogene is a reliable marker of the "G0-early G1" transition, and its down-regulation is believed to be necessary to obtain cellular differentiation. In murine spermatogenesis, the level of c-myc transcripts does not correlate with the rate of cellular division. Proliferation of supposed staminal spermatogonia to reproduce themselves is induced with a local 5 Gy X-ray dose in 90-day-old C57Bl/6 mice. c-myc quantification by a newly developed competitive reverse transcriptase polymerase chain reaction (RT-PCR) was carried out to follow the expression course of this proto-oncogene. Damage and restoration of spermatogenesis were analyzed at days 3, 6, 9, 10, 13, 30, and 60 after injury by relative testes/body weight determination and histological examination. Proliferative status was determined by histone H3 Northern blot analysis. c-myc mRNA level was 10 times higher after 3 days in the irradiated animals compared to the controls. An increasing number of copies were noted up to 10 days, but promptly decreased to the base level found for irradiated mice from 13 to 60 days. Interestingly, the expression of histone H3 detected S phase only in testes at 60 days from damage.

Tc-99m-HYNIC-TOC SPECT/CT in Oncogenic Osteomalacia

International Nuclear Information System (INIS)

Pusuwan, Pawana; Sriwijitkamol, Apiradee; Muangsomboon, Kobkun; Jantanayingyong, Jantanaras; Muangsomboon, Soranart; Poramatikul, Nipavan

2009-07-01

Full text: Oncogenic osteomalacia is a rare condition characterized by progressive bone pain, muscle weakness and multiple biochemical abnormalities such as hypophosphataemia, hyper phosphaturia and elevated serum alkaline phosphatase. The cause of this syndrome is most commonly from a benign mesenchymal tumor. The tumor is usually small and difficult to localize. We report two patients with oncogenic osteomalacia diagnosed and localized of the tumors by Tc-99m HYNIC-TOC SPECT/CT imaging. The tumors were localized at right thigh and right inguinal region. Tumor removal was successfully done

Characterization of the human oncogene SCL/TAL1 interrupting locus (Stil) mediated Sonic hedgehog (Shh) signaling transduction in proliferating mammalian dopaminergic neurons

Energy Technology Data Exchange (ETDEWEB)

Sun, Lei [Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556 (United States); Department of Physiology, Nankai University School of Medicine, Tianjin 300071 (China); Carr, Aprell L. [Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556 (United States); Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556 (United States); Li, Ping; Lee, Jessica; McGregor, Mary [Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556 (United States); Li, Lei, E-mail: Li.78@nd.edu [Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556 (United States); Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556 (United States)

2014-07-11

Highlights: • Stil is a human oncogene that is conserved in vertebrate species. • Stil functions in the Shh pathway in mammalian cells. • The expression of Stil is required for mammalian dopaminergic cell proliferation. - Abstract: The human oncogene SCL/TAL1 interrupting locus (Stil) is highly conserved in all vertebrate species. In humans, the expression of Stil is involved in cancer cell survival, apoptosis and proliferation. In this research, we investigated the roles of Stil expression in cell proliferation of mammalian dopaminergic (DA) PC12 cells. Stil functions through the Sonic hedgehog (Shh) signal transduction pathway. Co-immunoprecipitation tests revealed that STIL interacts with Shh downstream components, which include SUFU and GLI1. By examining the expression of Stil, Gli1, CyclinD2 (cell-cycle marker) and PCNA (proliferating cell nuclear antigen), we found that up-regulation of Stil expression (transfection with overexpression plasmids) increased Shh signaling transduction and PC12 cell proliferation, whereas down-regulation of Stil expression (by shRNA) inhibited Shh signaling transduction, and thereby decreased PC12 cell proliferation. Transient transfection of PC12 cells with Stil knockdown or overexpression plasmids did not affect PC12 cell neural differentiation, further indicating the specific roles of Stil in cell proliferation. The results from this research suggest that Stil may serve as a bio-marker for neurological diseases involved in DA neurons, such as Parkinson’s disease.

Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations.

Science.gov (United States)

Wang, Xia; Charng, Wu-Lin; Chen, Chun-An; Rosenfeld, Jill A; Al Shamsi, Aisha; Al-Gazali, Lihadh; McGuire, Marianne; Mew, Nicholas Ah; Arnold, Georgianne L; Qu, Chunjing; Ding, Yan; Muzny, Donna M; Gibbs, Richard A; Eng, Christine M; Walkiewicz, Magdalena; Xia, Fan; Plon, Sharon E; Lupski, James R; Schaaf, Christian P; Yang, Yaping

2017-04-01

ABL1 is a proto-oncogene well known as part of the fusion gene BCR-ABL1 in the Philadelphia chromosome of leukemia cancer cells. Inherited germline ABL1 changes have not been associated with genetic disorders. Here we report ABL1 germline variants cosegregating with an autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities, and failure to thrive. The variant c.734A>G (p.Tyr245Cys) was found to occur de novo or cosegregate with disease in five individuals (families 1-3). Additionally, a de novo c.1066G>A (p.Ala356Thr) variant was identified in a sixth individual (family 4). We overexpressed the mutant constructs in HEK 293T cells and observed increased tyrosine phosphorylation, suggesting increased ABL1 kinase activities associated with both the p.Tyr245Cys and p.Ala356Thr substitutions. Our clinical and experimental findings, together with previously reported teratogenic effects of selective BCR-ABL inhibitors in humans and developmental defects in Abl1 knockout mice, suggest that ABL1 has an important role during organismal development.

The prognostic value of oncogenic antigen 519 (OA-519) expression and proliferative activity detected by antibody MIB-1 in node-negative breast cancer

DEFF Research Database (Denmark)

Jensen, V; Ladekarl, M; Holm-Nielsen, P

1995-01-01

The prognostic value of oncogenic antigen 519 (OA-519) expression and tumour proliferative activity was evaluated in a retrospective series of 118 patients with low-risk breast cancer. Low risk was defined as negative axillary nodes, tumour diameter histological evidence...... analysis, both the MIB-1 index and OA-519 expression were of independent prognostic value (2p breast cancer who might benefit from adjuvant therapy....

Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis.

Science.gov (United States)

Chatterjee, Anindya; Ghosh, Joydeep; Ramdas, Baskar; Mali, Raghuveer Singh; Martin, Holly; Kobayashi, Michihiro; Vemula, Sasidhar; Canela, Victor H; Waskow, Emily R; Visconte, Valeria; Tiu, Ramon V; Smith, Catherine C; Shah, Neil; Bunting, Kevin D; Boswell, H Scott; Liu, Yan; Chan, Rebecca J; Kapur, Reuben

2014-11-20

Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription, is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK) whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Influence of x-rays and UV-light on the presence of oncogene proteins in spleen cells of leukemic mice

International Nuclear Information System (INIS)

Popovic Hadzija, M.; Poljak Blazi, M.

1996-01-01

Proto-oncogenes are involved in growth, defferentiation and proliferation of normal cells, and in process of neoplastic transformation. In genome of normal cells, exist also tumor-suppressor genes, which contribute to cancer when they are inactivated. Those genes are target for carcinogenesis provoked by radiation. However, species specific genetic factors are important in determing which, if any, gene will be transformed by radiation. It is possible to presume that oncogenes are involved in the development of radioresistant phenotype of ML. Because of that, we examined the presence of c-myc protein in ML cells during the growth of ML and after the irradiation of these cells. Also, we examined the presence of tumor-suppressor protein p53, because inactivation or loss of p53 gene is in connection with transformation of cells. ML is strain specific for RFM mice. Spleen cells were tested 9 (nonterminal phase NTP) or 12 days (terminal phase TP) after inoculation of ML. Cells from NTP were also irradiate with x-rays or UV-light. C-myc protein expresse 74.98% spleen cells of healthy RFM mice. Wild type of p53 protein was detected in 60% of these cells, but mp53 was found in only 5.3% of cells. These results could be explained by the role of c-myc and p53 proteins in regulation of biologic processes. A few spleen cells of NTP expressed c-myc (15%) and mp53 (9.6%) proteins. But, in the same phase higher expressions of wp53 protein (30.5%) was found. On the other hand, the number of c-myc positive cells in TP of leukemia explanation lies in connection of c-myc protein and process of programmed cell death (apoptosis). During growth of ML the number of mp53 positive cells increased (to 47.8%), but wp53 positive cells decreased (to13.4%9). Both types of irradiation provoked strong activation of cellular c-myc gene in ML cells of NTP. We found about 95% c-myc positive cells after x-rays and 93% after UV-light

Biología sintética: aspectos científicos y sociales

Directory of Open Access Journals (Sweden)

Alonso, Carlos

2014-08-01

Full Text Available On 20 May 2010, Craig Venter announced that he had created the first self-replicating synthetic genome capable of controlling the metabolic behaviour of host cells. The reaction to Venter’s announcement was surprise and amazement, but raised a range of alarms from enlightened enthusiasm to exclamations of uncertainty: What did this announcement mean? Biology had entered the digital age. Claims about potential risks and benefits invaded the scientific world. Were we approaching the “creation of life” by design? What is the difference between living and non-living matter? Was the organism generated by chemical synthesis the same as that which had been designed? The challenge was to find the conditions in which the genomes and the enucleated hosts could function in unison. Do we have enough knowledge to design interactions between biological units capable of generating new organisms? Scientists have used DNA to modify cells and organisms. In fact, a large industry has grown up based on recombinant DNA technology. Could synthetic biology play a clinical role?.El 20 de Mayo de 2010 Craig Venter anunció que se había creado el primer genoma sintético auto-replicativo capaz de controlar el comportamiento metabólico de las células huésped. La reacción al anuncio de Venter fue de sorpresa y asombro, pero levantó toda una gama de alarmas desde entusiasmos alumbrados a exclamaciones de incertidumbre: ¿Qué quería decir este anuncio? La biología entraba en la era digital y afirmaciones sobre potenciales riesgos y beneficios invadieron el mundo científico. ¿Estamos acercándonos a la “creación de vida” mediante diseño? ¿Se podría crear materia viva a partir de materia no viva? ¿Cuál es la diferencia entre materia viva y no-viva? ¿El organismo que se había generado por síntesis química era el que se había diseñado? El reto estaba en saber diseñar las condiciones para que los genomas y los huéspedes funcionaran al un

The offset dependent behavior of narrow optical emission features in the Red Rectangle proto-planetary nebula

NARCIS (Netherlands)

Wehres, N.; Linnartz, H.; Van Winckel, H.; Tielens, A. G. G. M.

Context. The Red Rectangle proto-planetary nebula provides a unique laboratory to study the physical conditions and chemical processes in stellar outflows. Snapshots of the ongoing chemical evolution are obtained by monitoring spectra as function of the offset from the central star. Aims. The focus

Estandarización de la TR-PCR para la detección de las fusiones génicas BCR-ABL en pacientes con leucemia Mieloide Crónica (LMC y Linfoide Aguda (LLA provenientes de HUSVP y Clíncia León XIII

Directory of Open Access Journals (Sweden)

Gonzálo Vásquez Palacio

2006-04-01

Full Text Available La translocación recíproca t(9:22(q34;q11 involucra el proto-oncogen ABL y el gen BCR, originando un gen de fusión BCR-ABL, que codifica una proteína con elevada actividad tirosina quinasa, implicada en la leucemogénesis.

Role of 18F FDG PET scan to localize tumor in patients of oncogenic osteomalacia

International Nuclear Information System (INIS)

Malhotra, Gaurav; Mukta, K.; Asopa, V.; Varsha, J.; Vijaya, S.; Shah, Nalini S.; Padmavathy, M.

2010-01-01

Full text: Oncogenic osteomalacia is a rare paraneoplastic syndrome of renal phosphate wasting which is usually caused by phosphaturic mesenchymal tumors. Conventional radiologic techniques usually fail to detect these small, slow growing neoplasms located at unusual sites. The objective of this study was to evaluate the role of 18 F FDG PET imaging in patients of oncogenic osteomalacia. Materials and Methods: Fifteen patients (8 males and 7 females) (mean age: 38.5 ± 12.2 years) with clinical and biochemical evidence of oncogenic osteomalacia were subjected to 'total' whole body 18 F FDG PET scan including both limbs and skull views. The images were reconstructed and the final output was displayed as per the standard institution protocol. Results: 18 F FDG PET imaging localized suspicious hypermetabolic foci of SUVmax ranging from 1.4 to 3.8 (Mean ± S.D.: 2.39 ± 0.63) suggesting presence of occult tumor in 11 of 15 patients. The suspected foci were localized in lower limbs in ten patients and in the petrous temporal region of skull in 1 patient. FDG localized tumors were histopathologically correlated in 6 patients who underwent surgical biopsy/excision after correlative radiological investigations. Four of these patients were cured after surgical excision while partial surgical excision/biopsy was performed in two patients. Conclusions: 18 F FDG PET imaging is a promising technique for detection of occult tumors in patients of oncogenic osteomalacia. It is mandatory to include limbs in the field as these tumors are common in limbs and may be easily missed. Preoperative localization increases odds for cure after surgical removal of tumor

RASOnD - A comprehensive resource and search tool for RAS superfamily oncogenes from various species

Directory of Open Access Journals (Sweden)

Singh Tej P

2011-07-01

Full Text Available Abstract Background The Ras superfamily plays an important role in the control of cell signalling and division. Mutations in the Ras genes convert them into active oncogenes. The Ras oncogenes form a major thrust of global cancer research as they are involved in the development and progression of tumors. This has resulted in the exponential growth of data on Ras superfamily across different public databases and in literature. However, no dedicated public resource is currently available for data mining and analysis on this family. The present database was developed to facilitate straightforward accession, retrieval and analysis of information available on Ras oncogenes from one particular site. Description We have developed the RAS Oncogene Database (RASOnD as a comprehensive knowledgebase that provides integrated and curated information on a single platform for oncogenes of Ras superfamily. RASOnD encompasses exhaustive genomics and proteomics data existing across diverse publicly accessible databases. This resource presently includes overall 199,046 entries from 101 different species. It provides a search tool to generate information about their nucleotide and amino acid sequences, single nucleotide polymorphisms, chromosome positions, orthologies, motifs, structures, related pathways and associated diseases. We have implemented a number of user-friendly search interfaces and sequence analysis tools. At present the user can (i browse the data (ii search any field through a simple or advance search interface and (iii perform a BLAST search and subsequently CLUSTALW multiple sequence alignment by selecting sequences of Ras oncogenes. The Generic gene browser, GBrowse, JMOL for structural visualization and TREEVIEW for phylograms have been integrated for clear perception of retrieved data. External links to related databases have been included in RASOnD. Conclusions This database is a resource and search tool dedicated to Ras oncogenes. It has

Oncogenic Radiation Abscopal Effects In Vivo: Interrogating Mouse Skin

International Nuclear Information System (INIS)

Mancuso, Mariateresa; Leonardi, Simona; Giardullo, Paola; Pasquali, Emanuela; Tanori, Mirella; De Stefano, Ilaria; Casciati, Arianna; Naus, Christian C.; Pazzaglia, Simonetta; Saran, Anna

2013-01-01

Purpose: To investigate the tissue dependence in transmission of abscopal radiation signals and their oncogenic consequences in a radiosensitive mouse model and to explore the involvement of gap junction intercellular communication (GJIC) in mediating radiation tumorigenesis in off-target mouse skin. Methods and Materials: Patched1 heterozygous (Ptch1 +/− ) mice were irradiated at postnatal day 2 (P2) with 10 Gy of x-rays. Individual lead cylinders were used to protect the anterior two-thirds of the body, whereas the hindmost part was directly exposed to radiation. To test the role of GJICs and their major constituent connexin43 (Cx43), crosses between Ptch1 +/− and Cx43 +/− mice were similarly irradiated. These mouse groups were monitored for their lifetime, and skin basal cell carcinomas (BCCs) were counted and recorded. Early responses to DNA damage - Double Strand Breaks (DSBs) and apoptosis - were also evaluated in shielded and directly irradiated skin areas. Results: We report abscopal tumor induction in the shielded skin of Ptch1 +/− mice after partial-body irradiation. Endpoints were induction of early nodular BCC-like tumors and macroscopic infiltrative BCCs. Abscopal tumorigenesis was significantly modulated by Cx43 status, namely, Cx43 reduction was associated with decreased levels of DNA damage and oncogenesis in out-of-field skin, suggesting a key role of GJIC in transmission of oncogenic radiation signals to unhit skin. Conclusions: Our results further characterize the nature of abscopal responses and the implications they have on pathologic processes in different tissues, including their possible underlying mechanistic bases

Oncogenic Radiation Abscopal Effects In Vivo: Interrogating Mouse Skin

Energy Technology Data Exchange (ETDEWEB)

Mancuso, Mariateresa, E-mail: mariateresa.mancuso@enea.it [Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l' Energia e lo Sviluppo Economico Sostenibile (ENEA), Casaccia Research Centre, Rome (Italy); Leonardi, Simona [Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l' Energia e lo Sviluppo Economico Sostenibile (ENEA), Casaccia Research Centre, Rome (Italy); Giardullo, Paola; Pasquali, Emanuela [Department of Radiation Physics, Guglielmo Marconi University, Rome (Italy); Tanori, Mirella [Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l' Energia e lo Sviluppo Economico Sostenibile (ENEA), Casaccia Research Centre, Rome (Italy); De Stefano, Ilaria [Department of Radiation Physics, Guglielmo Marconi University, Rome (Italy); Casciati, Arianna [Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l' Energia e lo Sviluppo Economico Sostenibile (ENEA), Casaccia Research Centre, Rome (Italy); Naus, Christian C. [Department of Cellular and Physiological Sciences, The Life Sciences Institute, University of British Columbia, Vancouver, British Columbia (Canada); Pazzaglia, Simonetta; Saran, Anna [Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l' Energia e lo Sviluppo Economico Sostenibile (ENEA), Casaccia Research Centre, Rome (Italy)

2013-08-01

Purpose: To investigate the tissue dependence in transmission of abscopal radiation signals and their oncogenic consequences in a radiosensitive mouse model and to explore the involvement of gap junction intercellular communication (GJIC) in mediating radiation tumorigenesis in off-target mouse skin. Methods and Materials: Patched1 heterozygous (Ptch1{sup +/−}) mice were irradiated at postnatal day 2 (P2) with 10 Gy of x-rays. Individual lead cylinders were used to protect the anterior two-thirds of the body, whereas the hindmost part was directly exposed to radiation. To test the role of GJICs and their major constituent connexin43 (Cx43), crosses between Ptch1{sup +/−} and Cx43{sup +/−} mice were similarly irradiated. These mouse groups were monitored for their lifetime, and skin basal cell carcinomas (BCCs) were counted and recorded. Early responses to DNA damage - Double Strand Breaks (DSBs) and apoptosis - were also evaluated in shielded and directly irradiated skin areas. Results: We report abscopal tumor induction in the shielded skin of Ptch1{sup +/−} mice after partial-body irradiation. Endpoints were induction of early nodular BCC-like tumors and macroscopic infiltrative BCCs. Abscopal tumorigenesis was significantly modulated by Cx43 status, namely, Cx43 reduction was associated with decreased levels of DNA damage and oncogenesis in out-of-field skin, suggesting a key role of GJIC in transmission of oncogenic radiation signals to unhit skin. Conclusions: Our results further characterize the nature of abscopal responses and the implications they have on pathologic processes in different tissues, including their possible underlying mechanistic bases.

Spike synchrony reveals emergence of proto-objects in visual cortex.

Science.gov (United States)

Martin, Anne B; von der Heydt, Rüdiger

2015-04-29

Neurons at early stages of the visual cortex signal elemental features, such as pieces of contour, but how these signals are organized into perceptual objects is unclear. Theories have proposed that spiking synchrony between these neurons encodes how features are grouped (binding-by-synchrony), but recent studies did not find the predicted increase in synchrony with binding. Here we propose that features are grouped to "proto-objects" by intrinsic feedback circuits that enhance the responses of the participating feature neurons. This hypothesis predicts synchrony exclusively between feature neurons that receive feedback from the same grouping circuit. We recorded from neurons in macaque visual cortex and used border-ownership selectivity, an intrinsic property of the neurons, to infer whether or not two neurons are part of the same grouping circuit. We found that binding produced synchrony between same-circuit neurons, but not between other pairs of neurons, as predicted by the grouping hypothesis. In a selective attention task, synchrony emerged with ignored as well as attended objects, and higher synchrony was associated with faster behavioral responses, as would be expected from early grouping mechanisms that provide the structure for object-based processing. Thus, synchrony could be produced by automatic activation of intrinsic grouping circuits. However, the binding-related elevation of synchrony was weak compared with its random fluctuations, arguing against synchrony as a code for binding. In contrast, feedback grouping circuits encode binding by modulating the response strength of related feature neurons. Thus, our results suggest a novel coding mechanism that might underlie the proto-objects of perception. Copyright © 2015 the authors 0270-6474/15/356860-11$15.00/0.

Enzymatic activity of anthropogenic proto-organic soils in soilless farming

Science.gov (United States)

Bireescu, Geanina; Dazzi, Carmelo; Laudicina, Vito Armando; Lo Papa, Giuseppe

2017-04-01

In soilless agriculture and horticulture coir is the more used substratum to grow plants because it is widely available and more environmentally friendly than sphagnum or peat. In Italy, soilless agriculture concerns an area of about 1,000 hectares, particularly concentrated in Sicily. The southern coastal belt of this region is the area interested by the most significant experiences in the application of techniques of soilless cultivation that, recently, has been used also for growing table grapes. Starting from the above consideration we suppose that the features of the coconut fiber underlay an evident transformation and that even after few years of table grape cultivation, such organic material undergone to a transformation that allows for the formation of a proto-organic soil (a proto-Histosol, we supposed). If this is true, we believe that, in this case, to speak about soilless cultivation is for sure misleading for the common people, as we should define this cultivation "on anthropogenic soils" instead. To fit the aims of this survey we used a big greenhouse devoted to soilless cultivation of table grape in a farm in the Southern Sicily We have considered the enzymatic activity that characterized the coconut fiber after 3 cycles of cultivation of table grapes. We used as a control the coconut fiber that the farmer used to prepare pots for soilless cultivation and coconut fiber of: 6 pots at the end of the first productive cycle 6 pots at the end of the second cycle and 3 pots at the end of the third cycle. On these organic samples we investigated three enzymes, belonging to oxydoreductase (catalase and dehydrogenase) and hydrolase (urease) classes. Statistical analysis of the investigated enzymes was developed using IBM Statistic SPSS v20 by ANOVA, Tukey test HSD for p ≤ 0.01 and Multivariate Statistical Analysis. Results have shown significant differences in enzymes content and quality among coir tests. The use of the coco fiber, as nutritive substratum

Using {sup 18F} FDG PET/CT to Detect an occult Mesenchymal Tumor Causing Oncogenic Osteomalacia

Energy Technology Data Exchange (ETDEWEB)

Seo, Hyo Jung; Choi, Yun Jung; Kim, Hyun Jeong; Jeong, Yong Hyu; Cho, Arthur; Lee, Jae Hoon; Yun, Mijin; Lee, Jong Doo; Kang, Won Jun [Yonsei Univ. College of Medicine, Seoul (Korea, Republic of)

2011-09-15

Oncogenic osteomalacia is a rare paraneoplastic syndrome characterized by renal phosphate excretion, hypophosphatemia, and osteomalacia. This syndrome is often caused by tumors of mesenchymal origin. Patients with oncogenic osteomalacia have abnormal bone mineralization, resulting in a high frequency of fractures. Tumor resection is the treatment of choice, as it will often correct the metabolic imbalance. Although oncogenic osteomalacia is a potentially curable disease, diagnosis is difficult and often delayed because of the small size and sporadic location of the tumor. Bone scintigraphy and radiography best characterize osteoma lacia; magnetic resonance imaging findings are nonspecific. Here, we report a case of oncogenic osteomalacia secondary to a phosphaturic mesenchymal tumor that was successfully detected by {sup 18F} fluorodeoxyglucose positron emission tomography/computed tomography ({sup 18F} FDG PET/CT). This case illustrates the advantages of {sup 18F} FDG PET/CT in detecting the occult mesenchymal tumor that causes oncogenic osteomalacia.

Fattori di crescita e recettori tirosin chinasici nelle neoplasie e displasie degli animali domestici

OpenAIRE

Muscatello, Luisa Vera

2016-01-01

La perdita della comunicazione cellulare può portare ad una crescita deregolata e dunque alla trasformazione neoplastica. Gli scopi dello studio di dottorato sono stati di individuare il rapporto funzionale di alcuni fattori di crescita (FC) e dei loro recettori (RTC) in tipi di neoplasie e displasie degli animali domestici, quali: 1. Amplificazione del proto-oncogene ERBB2 e sovra-espressione del RTC erb-b2. in tumori mammari della gatta. 2. Espressione di erb-b2, di recettori ormonal...

The oncogenic action of ionizing radiation on rat skin

International Nuclear Information System (INIS)

Burns, F.J.; Garte, S.J.

1990-01-01

An extensive experiment involving approximately 400 rats exposed to the neon ion beam at the Bevalac in Berkeley, CA and to electrons is nearing completion. Progress is described in three areas corresponding to the specific aims of the proposal: (1) carcinogenesis and DNA strand breaks in rat skin following exposure by the neon ions or electrons; (2) oncogene activation in radiation-induced rat skin cancers; (3) DNA strand breaks in the epidermis as a function of radiation penetration. 59 refs., 4 tabs

MSH3-deficiency initiates EMAST without oncogenic transformation of human colon epithelial cells.

Directory of Open Access Journals (Sweden)

Christoph Campregher

Full Text Available BACKGROUND/AIM: Elevated microsatellite instability at selected tetranucleotide repeats (EMAST is a genetic signature in certain cases of sporadic colorectal cancer and has been linked to MSH3-deficiency. It is currently controversial whether EMAST is associated with oncogenic properties in humans, specifically as cancer development in Msh3-deficient mice is not enhanced. However, a mutator phenotype is different between species as the genetic positions of repetitive sequences are not conserved. Here we studied the molecular effects of human MSH3-deficiency. METHODS: HCT116 and HCT116+chr3 (both MSH3-deficient and primary human colon epithelial cells (HCEC, MSH3-wildtype were stably transfected with an EGFP-based reporter plasmid for the detection of frameshift mutations within an [AAAG]17 repeat. MSH3 was silenced by shRNA and changes in protein expression were analyzed by shotgun proteomics. Colony forming assay was used to determine oncogenic transformation and double strand breaks (DSBs were assessed by Comet assay. RESULTS: Despite differential MLH1 expression, both HCT116 and HCT116+chr3 cells displayed comparable high mutation rates (about 4×10(-4 at [AAAG]17 repeats. Silencing of MSH3 in HCECs leads to a remarkable increased frameshift mutations in [AAAG]17 repeats whereas [CA]13 repeats were less affected. Upon MSH3-silencing, significant changes in the expression of 202 proteins were detected. Pathway analysis revealed overexpression of proteins involved in double strand break repair (MRE11 and RAD50, apoptosis, L1 recycling, and repression of proteins involved in metabolism, tRNA aminoacylation, and gene expression. MSH3-silencing did not induce oncogenic transformation and DSBs increased 2-fold. CONCLUSIONS: MSH3-deficiency in human colon epithelial cells results in EMAST, formation of DSBs and significant changes of the proteome but lacks oncogenic transformation. Thus, MSH3-deficiency alone is unlikely to drive human colon

Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors.

Science.gov (United States)

Henry, Curtis J; Casás-Selves, Matias; Kim, Jihye; Zaberezhnyy, Vadym; Aghili, Leila; Daniel, Ashley E; Jimenez, Linda; Azam, Tania; McNamee, Eoin N; Clambey, Eric T; Klawitter, Jelena; Serkova, Natalie J; Tan, Aik Choon; Dinarello, Charles A; DeGregori, James

2015-12-01

The incidence of cancer is higher in the elderly; however, many of the underlying mechanisms for this association remain unexplored. Here, we have shown that B cell progenitors in old mice exhibit marked signaling, gene expression, and metabolic defects. Moreover, B cell progenitors that developed from hematopoietic stem cells (HSCs) transferred from young mice into aged animals exhibited similar fitness defects. We further demonstrated that ectopic expression of the oncogenes BCR-ABL, NRAS(V12), or Myc restored B cell progenitor fitness, leading to selection for oncogenically initiated cells and leukemogenesis specifically in the context of an aged hematopoietic system. Aging was associated with increased inflammation in the BM microenvironment, and induction of inflammation in young mice phenocopied aging-associated B lymphopoiesis. Conversely, a reduction of inflammation in aged mice via transgenic expression of α-1-antitrypsin or IL-37 preserved the function of B cell progenitors and prevented NRAS(V12)-mediated oncogenesis. We conclude that chronic inflammatory microenvironments in old age lead to reductions in the fitness of B cell progenitor populations. This reduced progenitor pool fitness engenders selection for cells harboring oncogenic mutations, in part due to their ability to correct aging-associated functional defects. Thus, modulation of inflammation--a common feature of aging--has the potential to limit aging-associated oncogenesis.

Multiple oncogenic viruses identified in Ocular surface squamous neoplasia in HIV-1 patients

Directory of Open Access Journals (Sweden)

Bisson Gregory

2010-03-01

Full Text Available Abstract Background Ocular surface squamous neoplasia (OSSN is a rare cancer that has increased in incidence with the HIV pandemic in Africa. The underlying cause of this cancer in HIV-infected patients from Botswana is not well defined. Results Tissues were obtained from 28 OSSN and 8 pterygia patients. The tissues analyzed from OSSN patients were 83% positive for EBV, 75% were HPV positive, 70% were KSHV positive, 75% were HSV-1/2 positive, and 61% were CMV positive by PCR. Tissues from pterygium patients were 88% positive for EBV, 75% were HPV positive, 50% were KSHV positive, and 60% were CMV positive. None of the patients were JC or BK positive. In situ hybridization and immunohistochemistry analyses further identified HPV, EBV, and KSHV in a subset of the tissue samples. Conclusion We identified the known oncogenic viruses HPV, KSHV, and EBV in OSSN and pterygia tissues. The presence of these tumor viruses in OSSN suggests that they may contribute to the development of this malignancy in the HIV population. Further studies are necessary to characterize the molecular mechanisms associated with viral antigens and their potential role in the development of OSSN.

Identification of a novel group of putative Arabidopsis thaliana beta-(1,3)-galactosyltransferases

DEFF Research Database (Denmark)

Qu, Yongmei; Egelund, Jack; Gilson, Paul R

2008-01-01

To begin biochemical and molecular studies on the biosynthesis of the type II arabinogalactan chains on arabinogalactan-proteins (AGPs), we adopted a bioinformatic approach to identify and systematically characterise the putative galactosyltransferases (GalTs) responsible for synthesizing the beta......-(1,3)-Gal linkage from CAZy GT-family-31 from Arabidopsis thaliana. These analyses confirmed that 20 members of the GT-31 family contained domains/motifs typical of biochemically characterised beta-(1,3)-GTs from mammalian systems. Microarray data confirm that members of this family are expressed......,3)-GalT activity. This bioinformatic/molecular study of CAZy GT-family-31 was validated by the recent report of Strasser et al. (Plant Cell 19:2278-2292, 2007) that another member of this family (At1g26810; GALT1) encodes a beta-(1,3)-GalT involved in the biosynthesis of the Lewis a epitope of N...

Ras oncogenes in oral cancer: the past 20 years.

Science.gov (United States)

Murugan, Avaniyapuram Kannan; Munirajan, Arasambattu Kannan; Tsuchida, Nobuo

2012-05-01

Oral squamous cell carcinoma (OSCC) of head and neck is associated with high morbidity and mortality in both Western and Asian countries. Several risk factors for the development of oral cancer are very well established, including tobacco chewing, betel quid, smoking, alcohol drinking and human papilloma virus (HPV) infection. Apart from these risk factors, many genetic factors such as oncogenes, tumor suppressor genes and regulatory genes are identified to involve in oral carcinogenesis with these risk factors dependent and independent manner. Ras is one of the most frequently genetically deregulated oncogene in oral cancer. In this review, we analyze the past 22years of literature on genetic alterations such as mutations and amplifications of the isoforms of the ras oncogene in oral cancer. Further, we addressed the isoform-specific role of the ras in oral carcinogenesis. We also discussed how targeting the Akt and MEK, downstream effectors of the PI3K/Akt and MAPK pathways, respectively, would probably pave the possible molecular therapeutic target for the ras driven tumorigenesis in oral cancer. Analysis of these ras isoforms may critically enlighten specific role of a particular ras isoform in oral carcinogenesis, enhance prognosis and pave the way for isoform-specific molecular targeted therapy in OSCC. Copyright © 2011 Elsevier Ltd. All rights reserved.

Intracortical osteoblastic osteosarcoma with oncogenic rickets

Energy Technology Data Exchange (ETDEWEB)

Hasegawa, T.; Hirohashi, Setsuo [Pathology Division, National Cancer Center Research Institute, Tokyo (Japan); Shimoda, Tadakazu [Clinical Laboratory Division, National Cancer Center Hospital, Tokyo (Japan); Yokoyama, Ryohei; Beppu, Yasuo [Orthopedic Division, National Cancer Center Hospital, Tokyo (Japan); Maeda, Shotaro [Department of Pathology, Nippon Medical School Hospital, Tokyo (Japan)

1999-01-01

Intracortical osteosarcoma is the rarest variant of osteosarcoma, occurring within, and usually confined to, the cortical bone. Oncogenic osteomalacia, or rickets, is an unusual clinicopathologic entity in which vitamin D-resistant osteomalacia, or rickets, occurs in association with some tumors of soft tissue or bone. We present a case of oncogenic rickets associated with intracortical osteosarcoma of the tibia in a 9-year-old boy, whose roentgenographic abnormalities of rickets disappeared and pertinent laboratory data except for serum alkaline phosphatase became normal after surgical resection of the tumor. Histologically, the tumor was an osteosarcoma with a prominent osteoblastic pattern. An unusual microscopic feature was the presence of matrix mineralization showing rounded calcified structures (calcified spherules). Benign osteoblastic tumors, such as osteoid osteoma and osteoblastoma, must be considered in the differential diagnosis because of the relatively low cellular atypia and mitotic activity of this tumor. The infiltrating pattern with destruction or engulfment of normal bone is a major clue to the correct diagnosis of intracortical osteosarcoma. The co-existing radiographic changes of rickets were due to the intracortical osteosarcoma. (orig.) With 8 figs., 25 refs.

Scintigraphic imaging of oncogenes with antisense probes: does it make sense?

International Nuclear Information System (INIS)

Urbain, J.L.C.; Shore, S.K.; Vekemans, M.C.; Cosenza, S.C.; DeRiel, K.; Patel, G.V.; Charkes, N.D.; Malmud, L.S.; Reddy, E.P.

1995-01-01

The aim of this study was to demonstrate that cells which are expressing a particular mRNA transcript do preferentially and specifically retain the antisense probe targeting that mRNA. Using a mouse plasmacytoma cell line (MOPC315) which produces high levels of IgA heavy chain mRNA, a control mouse pre B cell line (7OZ/3B), a human mammary cell line (MCF7) which expresses the erbB2 or neu oncogene, MOPC315 cells as neu-negative controls, and antisense DNA oligonucleotides complementary to the 5' region of the mRNAs and the sense sequence, we have shown that there is a preferential, specific retention of the IgA and neu antisense sequence in MOPC315 and MCF7 cells, respectively. We have further demonstrated that this retention is time and concentration dependent with a maximum at 24 h. We conclude that cancer cells which express a particular oncogene are suitable targets for radiolabeled antisense deoxyoligonucleotides directed toward the oncogene transcript. (orig.)

Translation elongation factor eEF1A2 is a potential oncoprotein that is overexpressed in two-thirds of breast tumours

Directory of Open Access Journals (Sweden)

Miller William R

2005-09-01

Full Text Available Abstract Background The tissue-specific translation elongation factor eEF1A2 was recently shown to be a potential oncogene that is overexpressed in ovarian cancer. Although there is no direct evidence for an involvement of eEF1A2 in breast cancer, the genomic region to which EEF1A2 maps, 20q13, is frequently amplified in breast tumours. We therefore sought to establish whether eEF1A2 expression might be upregulated in breast cancer. Methods eEF1A2 is highly similar (98% to the near-ubiquitously expressed eEF1A1 (formerly known as EF1-α making analysis with commercial antibodies difficult. We have developed specific anti-eEF1A2 antibodies and used them in immunohistochemical analyses of tumour samples. We report the novel finding that although eEF1A2 is barely detectable in normal breast it is moderately to strongly expressed in two-thirds of breast tumours. This overexpression is strongly associated with estrogen receptor positivity. Conclusion eEF1A2 should be considered as a putative oncogene in breast cancer that may be a useful diagnostic marker and therapeutic target for a high proportion of breast tumours. The oncogenicity of eEF1A2 may be related to its role in protein synthesis or to its potential non-canonical functions in cytoskeletal remodelling or apoptosis.

Dietary turmeric modulates DMBA-induced p21ras, MAP kinases and AP-1/NF-κB pathway to alter cellular responses during hamster buccal pouch carcinogenesis

International Nuclear Information System (INIS)

Garg, Rachana; Ingle, Arvind; Maru, Girish

2008-01-01

The chemopreventive efficacy of turmeric has been established in experimental systems. However, its mechanism(s) of action are not fully elucidated in vivo. The present study investigates the mechanism of turmeric-mediated chemoprevention in 7,12-dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis at 2, 4, 6, 10 and 12 weeks. Dietary turmeric (1%) led to decrease in DMBA-induced tumor burden and multiplicity, and enhanced the latency period in parallel, to its modulatory effects on oncogene products and various cellular responses during HBP tumorigenesis. DMBA-induced expression of ras oncogene product, p21 and downstream target, the mitogen-activated protein kinases were significantly decreased by turmeric during HBP carcinogenesis. Turmeric also diminished the DMBA-induced mRNA expression of proto-oncogenes (c-jun, c-fos) and NF-κB, leading to decreased protein levels and in further attenuation of DMBA-induced AP-1/NF-κB DNA-binding in the buccal pouch nuclear extracts. Besides, buccal pouch of hamsters receiving turmeric diet showed significant alterations in DMBA-induced effects: (a) decrease in cell proliferation (diminished PCNA and Bcl2 expression), (b) enhanced apoptosis (increased expression of Bax, caspase-3 and apoptotic index), (c) decrease in inflammation (levels of Cox-2, the downstream target of AP-1/NF-κB, and PGE2) and (d) aberrant expression of differentiation markers, the cytokeratins (1, 5, 8, and 18). Together, the protective effects of dietary turmeric converge on augmenting apoptosis of the initiated cells and decreasing cell proliferation in DMBA-treated animals, which in turn, is reflected in decreased tumor burden, multiplicity and enhanced latency period. Some of these biomarkers are likely to be helpful in monitoring clinical trials and evaluating drug effect measurements

A Poly-ADP-Ribose Trigger Releases the Auto-Inhibition of a Chromatin Remodeling Oncogene.

Science.gov (United States)

Singh, Hari R; Nardozza, Aurelio P; Möller, Ingvar R; Knobloch, Gunnar; Kistemaker, Hans A V; Hassler, Markus; Harrer, Nadine; Blessing, Charlotte; Eustermann, Sebastian; Kotthoff, Christiane; Huet, Sébastien; Mueller-Planitz, Felix; Filippov, Dmitri V; Timinszky, Gyula; Rand, Kasper D; Ladurner, Andreas G

2017-12-07

DNA damage triggers chromatin remodeling by mechanisms that are poorly understood. The oncogene and chromatin remodeler ALC1/CHD1L massively decompacts chromatin in vivo yet is inactive prior to DNA-damage-mediated PARP1 induction. We show that the interaction of the ALC1 macrodomain with the ATPase module mediates auto-inhibition. PARP1 activation suppresses this inhibitory interaction. Crucially, release from auto-inhibition requires a poly-ADP-ribose (PAR) binding macrodomain. We identify tri-ADP-ribose as a potent PAR-mimic and synthetic allosteric effector that abrogates ATPase-macrodomain interactions, promotes an ungated conformation, and activates the remodeler's ATPase. ALC1 fragments lacking the regulatory macrodomain relax chromatin in vivo without requiring PARP1 activation. Further, the ATPase restricts the macrodomain's interaction with PARP1 under non-DNA damage conditions. Somatic cancer mutants disrupt ALC1's auto-inhibition and activate chromatin remodeling. Our data show that the NAD + -metabolite and nucleic acid PAR triggers ALC1 to drive chromatin relaxation. Modular allostery in this oncogene tightly controls its robust, DNA-damage-dependent activation. Copyright © 2017 Elsevier Inc. All rights reserved.

Fused pyrazine mono-N-oxides as bioreductive drugs. II cytotoxicity in human cells and oncogenicity in a rodent transformation assay

International Nuclear Information System (INIS)

Langmuir, Virginia K.; Laderoute, Keith R.; Mendonca, Holly L.; Sutherland, Robert M.; Hei, Tom K.; Liu, S.-X.; Hall, Eric J.; Naylor, Matthew A.; Adams, Gerald E.

1996-01-01

Purpose: To determine what structural moieties of the fused pyrazine mono-N-oxides are determining factors in their in vitro cytotoxicity and oncogenicity. Methods and Materials: A new series of experimental bioreductive drugs, fused pyrazine mono-N-oxides, was evaluated in vitro for aerobic and hypoxic cytotoxicity in the HT29 human colon adenocarcinoma cell line by using clonogenic assays. The relative oncogenicities of these compounds were also determined in aerobic cultures of C3H 10T1/2 mouse embryo fibroblasts by using a standard transformation assay. Results: Removal of the 4-methyl piperazine side chain from the parent compound, RB 90740, reduced the potency of the hypoxic cytotoxin. Reduction of the N-oxide function increased the aerobic cytotoxicity and eliminated most of the hypoxic/aerobic cytotoxic differential. The reduced N-oxide also had significant oncogenicity, consistent with a mechanism of genotoxicity following bioreduction of RB 90740. Conclusion: This new series of bioreductive compounds may be effective in cancer therapy, particularly the lead compound RB 90740. The oncogenic potential of these compounds is similar to that for other cancer therapies. Further studies should include evaluation of these compounds in vivo and the development of analogs with reduced oncogenic potential and retention of the hypoxic/aerobic cytotoxicity differential

Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells

International Nuclear Information System (INIS)

Lee, Tae Hoon; Chennakrishnaiah, Shilpa; Audemard, Eric; Montermini, Laura; Meehan, Brian; Rak, Janusz

2014-01-01

Highlights: • Oncogenic H-ras stimulates emission of extracellular vesicles containing double-stranded DNA. • Vesicle-associated extracellular DNA contains mutant N-ras sequences. • Vesicles mediate intercellular transfer of mutant H-ras DNA to normal fibroblasts where it remains for several weeks. • Fibroblasts exposed to vesicles containing H-ras DNA exhibit increased proliferation. - Abstract: Cell free DNA is often regarded as a source of genetic cancer biomarkers, but the related mechanisms of DNA release, composition and biological activity remain unclear. Here we show that rat epithelial cell transformation by the human H-ras oncogene leads to an increase in production of small, exosomal-like extracellular vesicles by viable cancer cells. These EVs contain chromatin-associated double-stranded DNA fragments covering the entire host genome, including full-length H-ras. Oncogenic N-ras and SV40LT sequences were also found in EVs emitted from spontaneous mouse brain tumor cells. Disruption of acidic sphingomyelinase and the p53/Rb pathway did not block emission of EV-related oncogenic DNA. Exposure of non-transformed RAT-1 cells to EVs containing mutant H-ras DNA led to the uptake and retention of this material for an extended (30 days) but transient period of time, and stimulated cell proliferation. Thus, our study suggests that H-ras-mediated transformation stimulates vesicular emission of this histone-bound oncogene, which may interact with non-transformed cells

Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells

Energy Technology Data Exchange (ETDEWEB)

Lee, Tae Hoon; Chennakrishnaiah, Shilpa [Montreal Children’s Hospital, Research Institute of McGill University Health Centre, McGill University, Montreal, Quebec (Canada); Audemard, Eric [McGill University and Genome Quebec Innovation Centre, Montreal, Quebec (Canada); Montermini, Laura; Meehan, Brian [Montreal Children’s Hospital, Research Institute of McGill University Health Centre, McGill University, Montreal, Quebec (Canada); Rak, Janusz, E-mail: janusz.rak@mcgill.ca [Montreal Children’s Hospital, Research Institute of McGill University Health Centre, McGill University, Montreal, Quebec (Canada)

2014-08-22

Highlights: • Oncogenic H-ras stimulates emission of extracellular vesicles containing double-stranded DNA. • Vesicle-associated extracellular DNA contains mutant N-ras sequences. • Vesicles mediate intercellular transfer of mutant H-ras DNA to normal fibroblasts where it remains for several weeks. • Fibroblasts exposed to vesicles containing H-ras DNA exhibit increased proliferation. - Abstract: Cell free DNA is often regarded as a source of genetic cancer biomarkers, but the related mechanisms of DNA release, composition and biological activity remain unclear. Here we show that rat epithelial cell transformation by the human H-ras oncogene leads to an increase in production of small, exosomal-like extracellular vesicles by viable cancer cells. These EVs contain chromatin-associated double-stranded DNA fragments covering the entire host genome, including full-length H-ras. Oncogenic N-ras and SV40LT sequences were also found in EVs emitted from spontaneous mouse brain tumor cells. Disruption of acidic sphingomyelinase and the p53/Rb pathway did not block emission of EV-related oncogenic DNA. Exposure of non-transformed RAT-1 cells to EVs containing mutant H-ras DNA led to the uptake and retention of this material for an extended (30 days) but transient period of time, and stimulated cell proliferation. Thus, our study suggests that H-ras-mediated transformation stimulates vesicular emission of this histone-bound oncogene, which may interact with non-transformed cells.

Electronic Properties of SiNTs Under External Electric and Magnetic Fields Using the Tight-Binding Method

Science.gov (United States)

Chegel, Raad; Behzad, Somayeh

2014-02-01

We investigated the electronic properties of silicon nanotubes (SiNTs) under external transverse electric fields and axial magnetic fields using the tight-binding approximation. It was found that, after switching on the electric and magnetic fields, band modifications such as distortion of degeneracy, change in energy dispersion and subband spacing, and bandgap size reduction occur. The bandgap of silicon gear-like nanotubes (Si g-NTs) decreases linearly with increasing electric field strength, but the bandgap for silicon hexagonal nanotubes (Si h-NTs) first increases and then decreases (metallic) or first remains constant and then decreases (semiconducting). Our results show that the bandgap of Si h-NTs is very sensitive to both electric and magnetic fields, unlike Si g-NTs, which are more sensitive to electric than magnetic fields.

Malignant transformation of diploid human fibroblasts by transfection of oncogenes. Part 2, Progress report, July 1989--June 1992

Energy Technology Data Exchange (ETDEWEB)

McCormick, J.J.

1992-12-31

This document consist of brief reports prepared by postdoctoral students supported by the project, each describing his accomplishments under the grant. Topics include (1) Malignant Transformation of MSU-1. 1 Cells by Gamma Radiation, (2) Correlation between Levels of ras Expression and Presence of Transformed Phenotypes Including Tumorigenicity, Using a Modulatable Promoter, (3) Relation between Specific rad Oncogene Expression, (4) Correlation of Genetic Changes in Fibroblastic Tumors with Malignancies, (5)Transformation of MSU-1.1 Cells by sis Oncogene, (6) Malignant Transformation of MSU-1.0 Cells, (7) Correlation of Urokinase Plasminogen Activation (mu-PA) with Malignant Phenotype, (8)Two Dimensional Gel Electrophoresis Studies of the Proteins of the Major Cell Strains of the MSU-1 Family of Cells, and (9) Correlation between Proteinase Activity Levels and Malignancy.

Differential p53 engagement in response to oxidative and oncogenic stresses in Fanconi anemia mice

Science.gov (United States)

Rani, Reena; Li, Jie; Pang, Qishen

2008-01-01

Members of the Fanconi anemia (FA) protein family are involved in repair of genetic damage caused by DNA cross-linkers. It is not clear whether the FA proteins function in oxidative DNA damage and oncogenic stress response. Here we report that deficiency in the Fanca gene in mice elicits a p53-dependent growth arrest and DNA damage response to oxidative DNA damage and oncogenic stress. Using a Fanca-/- Trp53-/- double knockout model and a functionally switchable p53 retrovirus, we define the kinetics, dependence, and persistence of p53-mediated response to oxidative and oncogenic stresses in Fanca-/- cells. Notably, oxidative stress induces persistent p53 response in Fanca-/- cells, likely due to accumulation of unrepaired DNA damage. On the other hand, whereas WT cells exhibit prolonged response to oncogene activation, the p53-activating signals induced by oncogenic ras are short-lived in Fanca-/- cells, suggesting that Fanca may be required for the cell to engage p53 during constitutive ras activation. We propose that the FA proteins protect cells from stress-induced proliferative arrest and tumor evolution by acting as a modulator of the signaling pathways that link FA to p53. PMID:19047147

Differential p53 engagement in response to oxidative and oncogenic stresses in Fanconi anemia mice.

Science.gov (United States)

Rani, Reena; Li, Jie; Pang, Qishen

2008-12-01

Members of the Fanconi anemia (FA) protein family are involved in repair of genetic damage caused by DNA cross-linkers. It is not clear whether the FA proteins function in oxidative DNA damage and oncogenic stress response. Here, we report that deficiency in the Fanca gene in mice elicits a p53-dependent growth arrest and DNA damage response to oxidative DNA damage and oncogenic stress. Using a Fanca-/-Trp53-/- double knockout model and a functionally switchable p53 retrovirus, we define the kinetics, dependence, and persistence of p53-mediated response to oxidative and oncogenic stresses in Fanca-/- cells. Notably, oxidative stress induces persistent p53 response in Fanca-/- cells, likely due to accumulation of unrepaired DNA damage. On the other hand, whereas wild-type cells exhibit prolonged response to oncogene activation, the p53-activating signals induced by oncogenic ras are short-lived in Fanca-/- cells, suggesting that Fanca may be required for the cell to engage p53 during constitutive ras activation. We propose that the FA proteins protect cells from stress-induced proliferative arrest and tumor evolution by acting as a modulator of the signaling pathways that link FA to p53.

Four regulatory elements in the human c-fos promoter mediate transactivation by HTLV-1 Tax protein.

Science.gov (United States)

Alexandre, C; Verrier, B

1991-04-01

Expression of the human c-fos proto-oncogene is activated in trans by the Tax protein encoded by human T-cell leukemia virus type-1 (HTLV-1). Indeed, we show here that a HeLa clone stably transfected by Tax expresses Fos at a high level. We also show that multiple elements of the human c-fos promoter, i.e. the v-sis conditioned medium inducible element (SIE), the dyad symmetry element (DSE) necessary for growth factor induction, the octanucleotide direct repeat element (DR), and the cyclic AMP response element (CRE) centred at -60, can all mediate Tax transactivation. In the DSE, the 10bp central core that binds the serum response factor (SRF) is, by itself, sufficient to mediate Tax transactivation. Moreover, a CRE-binding protein is involved in Tax activation through the CRE-60 element. Since Fos is a transregulator of cellular genes, our results suggest that the oncoprotein plays a crucial role in T-cell transformation by HTLV-1 in conjunction with other Tax-inducible genes.

The Expression, Purification, and Characterization of a Ras Oncogene (Bras2) in Silkworm (Bombyx mori)

OpenAIRE

Lv, Zhengbing; Wang, Tao; Zhuang, Wenhua; Wang, Dan; Chen, Jian; Nie, Zuoming; Liu, Lili; Zhang, Wenping; Wang, Lisha; Wang, Deming; Wu, Xiangfu; Li, Jun; Qian, Lian; Zhang, Yaozhou

2013-01-01

The Ras oncogene of silkworm pupae (Bras2) may belong to the Ras superfamily. It shares 77% of its amino acid identity with teratocarcinoma oncogene 21 (TC21) related ras viral oncogene homolog-2 (R-Ras2) and possesses an identical core effector region. The mRNA of Bombyx mori Bras2 has 1412 bp. The open reading frame contains 603 bp, which encodes 200 amino acid residues. This recombinant BmBras2 protein was subsequently used as an antigen to raise a rabbit polyclonal antibody. Western blott...

Oncogenic osteomalacia secondary to a hemangiopericytoma of the hip: case report

International Nuclear Information System (INIS)

Baronofsky, S.I.; Kalbhen, C.L.; Demos, T.C.; Sizemore, G.W.

1999-01-01

Osteomalacia is characterized by abnormally increased unmineralized osteoid within the bone matrix. This metabolic bone disease is usually the result of decreased uptake or abnormal metabolism of vitamin D or of renal tubular phosphate loss. Dietary deficiency, malabsorption, cirrhosis, renal tubular acidosis and certain drugs can cause osteomalacia., Oncogenic osteomalacia - osteomalacia secondary to tumours - is rare, and the exact mechanisms by which neoplasms induce osteomalacia are not known. We describe a patient with chronic osteomalacia of unknown origin who was subsequently found to have oncogenic osteomalacia secondary to a hemangiopericytoma of the hip. (author)

Oncogenic osteomalacia secondary to a hemangiopericytoma of the hip: case report

Energy Technology Data Exchange (ETDEWEB)

Baronofsky, S.I.; Kalbhen, C.L.; Demos, T.C.; Sizemore, G.W. [Loyola Univ. Medical Center, Dept. of Medicine, Maywood, IL (United States)

1999-02-01

Osteomalacia is characterized by abnormally increased unmineralized osteoid within the bone matrix. This metabolic bone disease is usually the result of decreased uptake or abnormal metabolism of vitamin D or of renal tubular phosphate loss. Dietary deficiency, malabsorption, cirrhosis, renal tubular acidosis and certain drugs can cause osteomalacia., Oncogenic osteomalacia - osteomalacia secondary to tumours - is rare, and the exact mechanisms by which neoplasms induce osteomalacia are not known. We describe a patient with chronic osteomalacia of unknown origin who was subsequently found to have oncogenic osteomalacia secondary to a hemangiopericytoma of the hip. (author)

Identification of protein tyrosine phosphatase 1B and casein as substrates for 124-v-Mos

Directory of Open Access Journals (Sweden)

Stabel Silvia

2002-04-01

Full Text Available Abstract Background The mos proto-oncogene encodes a cytoplasmic serine/threonine-specific protein kinase with crucial function during meiotic cell division in vertebrates. Based on oncogenic amino acid substitutions the viral derivative, 124-v-Mos, displays constitutive protein kinase activity and functions independent of unknown upstream effectors of mos protein kinase. We have utilized this property of 124-v-Mos and screened for novel mos substrates in immunocomplex kinase assays in vitro. Results We generated recombinant 124-v-Mos using the baculovirus expression system in Spodoptera frugiperda cells and demonstrated constitutive kinase activity by the ability of 124-v-Mos to auto-phosphorylate and to phosphorylate vimentin, a known substrate of c-Mos. Using this approach we analyzed a panel of acidic and basic substrates in immunocomplex protein kinase assays and identified novel in vitro substrates for 124-v-Mos, the protein tyrosine phosphatase 1B (PTP1B, alpha-casein and beta-casein. We controlled mos-specific phosphorylation of PTP1B and casein in comparative assays using a synthetic kinase-inactive 124-v-Mos mutant and further, tryptic digests of mos-phosphorylated beta-casein identified a phosphopeptide specifically targeted by wild-type 124-v-Mos. Two-dimensional phosphoamino acid analyses showed that 124-v-mos targets serine and threonine residues for phosphorylation in casein at a 1:1 ratio but auto-phosphorylation occurs predominantly on serine residues. Conclusion The mos substrates identified in this study represent a basis to approach the identification of the mos-consensus phosphorylation motif, important for the development of specific inhibitors of the Mos protein kinase.

EBNA1: Oncogenic Activity, Immune Evasion and Biochemical Functions Provide Targets for Novel Therapeutic Strategies against Epstein-Barr Virus- Associated Cancers

Directory of Open Access Journals (Sweden)

Joanna B. Wilson

2018-04-01

Full Text Available The presence of the Epstein-Barr virus (EBV-encoded nuclear antigen-1 (EBNA1 protein in all EBV-carrying tumours constitutes a marker that distinguishes the virus-associated cancer cells from normal cells and thereby offers opportunities for targeted therapeutic intervention. EBNA1 is essential for viral genome maintenance and also for controlling viral gene expression and without EBNA1, the virus cannot persist. EBNA1 itself has been linked to cell transformation but the underlying mechanism of its oncogenic activity has been unclear. However, recent data are starting to shed light on its growth-promoting pathways, suggesting that targeting EBNA1 can have a direct growth suppressing effect. In order to carry out its tasks, EBNA1 interacts with cellular factors and these interactions are potential therapeutic targets, where the aim would be to cripple the virus and thereby rid the tumour cells of any oncogenic activity related to the virus. Another strategy to target EBNA1 is to interfere with its expression. Controlling the rate of EBNA1 synthesis is critical for the virus to maintain a sufficient level to support viral functions, while at the same time, restricting expression is equally important to prevent the immune system from detecting and destroying EBNA1-positive cells. To achieve this balance EBNA1 has evolved a unique repeat sequence of glycines and alanines that controls its own rate of mRNA translation. As the underlying molecular mechanisms for how this repeat suppresses its own rate of synthesis in cis are starting to be better understood, new therapeutic strategies are emerging that aim to modulate the translation of the EBNA1 mRNA. If translation is induced, it could increase the amount of EBNA1-derived antigenic peptides that are presented to the major histocompatibility (MHC class I pathway and thus, make EBV-carrying cancers better targets for the immune system. If translation is further suppressed, this would provide another

Regulamentação do estrogênio sintético 17α-etinilestradiol em matrizes aquáticas na Europa, Estados Unidos e Brasil

Directory of Open Access Journals (Sweden)

Danieli Lima da Cunha

2016-01-01

Full Text Available O estrogênio sintético 17α-etinilestradiol, principal componente utilizado em formulações de contraceptivos orais, tem sido apontado como um dos principais compostos responsáveis por provocar efeitos adversos no sistema endócrino de várias espécies. O objetivo deste estudo foi analisar o estado da arte dos dispositivos legais e normativos referentes ao controle desse estrogênio sintético nas águas da Europa e dos Estados Unidos, e traçar um paralelo com a realidade brasileira. No geral, os países têm buscado ampliar a regulamentação e monitoramento de alguns micropoluentes emergentes que antes não eram objeto de atenção por parte dos dispositivos legais. A Europa está mais avançada no que tange à qualidade dos corpos hídricos, enquanto que nos Estados Unidos esta substância é alvo de regulamentação apenas para a água destinada ao consumo humano. No Brasil, ainda não há nenhum dispositivo legal ou normativo que aborde esse estrogênio, o que pode ser associado a uma baixa maturidade do sistema brasileiro quanto ao controle de poluentes hídricos.

Radiative Transfer Modeling in Proto-planetary Disks

Science.gov (United States)

Kasper, David; Jang-Condell, Hannah; Kloster, Dylan

2016-01-01

Young Stellar Objects (YSOs) are rich astronomical research environments. Planets form in circumstellar disks of gas and dust around YSOs. With ever increasing capabilities of the observational instruments designed to look at these proto-planetary disks, most notably GPI, SPHERE, and ALMA, more accurate interfaces must be made to connect modeling of the disks with observation. PaRTY (Parallel Radiative Transfer in YSOs) is a code developed previously to model the observable density and temperature structure of such a disk by self-consistently calculating the structure of the disk based on radiative transfer physics. We present upgrades we are implementing to the PaRTY code to improve its accuracy and flexibility. These upgrades include: creating a two-sided disk model, implementing a spherical coordinate system, and implementing wavelength-dependent opacities. These upgrades will address problems in the PaRTY code of infinite optical thickness, calculation under/over-resolution, and wavelength-independent photon penetration depths, respectively. The upgraded code will be used to better model disk perturbations resulting from planet formation.

Equipotential surfaces in the Proto-Cleo Torsatron

International Nuclear Information System (INIS)

Trost, P.; Shohet, J.L.

1984-01-01

Space potential measurements have been made with the use of an emissive probe in the Proto-Cleo Torsatron. The emissive probe surface is heated to a temperature at which thermionic emission of electrons can occur. When the potential of the probe is less than the space potential, the probe predominately emits electrons, thus raising its potential. If the potential of the probe becomes greater than the space potential, the probe emits electrons at a much lower rate than it collects electrons, and thus the probe drops in potential. The dependence of the emitted and collected electron currents on the potential difference provides an accurate method to determine the space potential in the plasma. Space potential measurements have been made with this probe. The data are plotted as equipotential contours. A good correlation is seen between the equipotential measurements and the numerically predicted E.C.R.H. absorption layer, while the E.C.R.H. is on. During the time after the E.C.R.H. has been turned off, there is good correspondence between numerically calculated magnetic surfaces and the equipotential plots

B-Raf mutation: a key player in molecular biology of cancer.

Science.gov (United States)

Rahman, M A; Salajegheh, A; Smith, R A; Lam, A K-Y

2013-12-01

B-Raf is one of the more commonly mutated proto-oncogenes implicated in the development of cancers. In this review, we consider the mechanisms and clinical impacts of B-Raf mutations in cancer and discuss the implications for the patient in melanoma, thyroid cancer and colorectal cancer, where B-Raf mutations are particularly common. © 2013.

Rescue of avian leukosis subgroup-J-associated acutely transforming viruses carrying different lengths of the v-fps oncogene and analysis of their tumorigenicity.

Science.gov (United States)

Wang, Yixin; Fang, Lichun; Li, Jianliang; Li, Yang; Cui, Shuai; Sun, Xiaolong; Chang, Shuang; Zhao, Peng; Cui, Zhizhong

2016-12-01

In our previous study, six subgroup J strains of avian leukosis virus (ALV-J)-associated acutely transforming viruses carrying different lengths of the v-fps oncogene, designated as Fu-J and Fu-J1-5, were isolated and characterized from fibrosarcomas in ALV-J-infected chickens. In the present study, the oncogenic potential of Fu-J and Fu-J1-5 was investigated using a reverse genetics technique. Six replication-defective viruses, named rFu-J and rFu-J1-5, were rescued with the replication-competent rescued ALV-J strain rSDAU1005 as a helper virus by co-transfection of chicken embryo fibroblast monolayers with infectious clone plasmids. Experimental bird studies were performed, demonstrating that only the rescued rFu-J virus carrying the complete v-fps oncogene with rSDAU1005 as the helper virus could induce acute fibrosarcoma after inoculation in specific-pathogen-free (SPF) chickens. These results provide direct evidence that the replication-defective acutely transforming Fu-J virus, with the complete v-fps oncogene, was associated with acute fibrosarcoma in chickens infected with ALV-J in the field, as reported previously.