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Sample records for impacts multiple oncogenic

  1. Oncogenes

    SciTech Connect

    Compans, R.W.; Cooper, M.; Koprowski, H.; McConell, I.; Melchers, F.; Nussenzweig, V.; Oldstone, M.; Olsnes, S.; Saedler, H.; Vogt, P.K.

    1989-01-01

    This book covers the following topics: Roles of drosophila proto-oncogenes and growth factor homologs during development of the fly; Interaction of oncogenes with differentiation programs; Genetics of src: structure and functional organization of a protein tyrosine kinase; Structures and activities of activated abl oncogenes; Eukaryotic RAS proteins and yeast proteins with which they interact. This book presents up-to-data review articles on oncogenes. The editor includes five contributions which critically evaluate recent research in the field.

  2. Oncogenic Ras influences the expression of multiple lncRNAs.

    PubMed

    Kotake, Yojiro; Naemura, Madoka; Kitagawa, Kyoko; Niida, Hiroyuki; Tsunoda, Toshiyuki; Shirasawa, Senji; Kitagawa, Masatoshi

    2016-08-01

    Recent ultrahigh-density tiling array and large-scale transcriptome analysis have revealed that large numbers of long non-coding RNAs (lncRNAs) are transcribed in mammals. Several lncRNAs have been implicated in transcriptional regulation, organization of nuclear structure, and post-transcriptional processing. However, the regulation of expression of lncRNAs is less well understood. Here, we show that the exogenous and endogenous expression of an oncogenic form of small GTPase Ras (called oncogenic Ras) decrease the expression of lncRNA ANRIL (antisense non-coding RNA in the INK4 locus), which is involved in the regulation of cellular senescence. We also show that forced expression of oncogenic Ras increases the expression of lncRNA PANDA (p21 associated ncRNA DNA damage activated), which is involved in the regulation of apoptosis. Microarray analysis demonstrated that expression of multiple lncRNAs fluctuated by forced expression of oncogenic Ras. These findings indicate that oncogenic Ras regulates the expression of a large number of lncRNAs including functional lncRNAs, such as ANRIL and PANDA. PMID:25501747

  3. Knockin of mutant PIK3CA activates multiple oncogenic pathways

    PubMed Central

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

    2009-01-01

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

  4. Multiple endocrine neoplasias type 2B and RET proto-oncogene

    PubMed Central

    2012-01-01

    Multiple Endocrine Neoplasia type 2B (MEN 2B) is an autosomal dominant complex oncologic neurocristopathy including medullary thyroid carcinoma, pheochromocytoma, gastrointestinal disorders, marphanoid face, and mucosal multiple ganglioneuromas. Medullary thyroid carcinoma is the major cause of mortality in MEN 2B syndrome, and it often appears during the first years of life. RET proto-oncogene germline activating mutations are causative for MEN 2B. The 95% of MEN 2B patients are associated with a point mutation in exon 16 (M918/T). A second point mutation at codon 883 has been found in 2%-3% of MEN 2B cases. RET proto-oncogene is also involved in different neoplastic and not neoplastic neurocristopathies. Other RET mutations cause MEN 2A syndrome, familial medullary thyroid carcinoma, or Hirschsprung's disease. RET gene expression is also involved in Neuroblastoma. The main diagnosis standards are the acetylcholinesterase study of rectal mucosa and the molecular analysis of RET. In our protocol the rectal biopsy is, therefore, the first approach. RET mutation detection offers the possibility to diagnose MEN 2B predisposition at a pre-clinical stage in familial cases, and to perform an early total prophylactic thyroidectomy. The surgical treatment of MEN 2B is total thyroidectomy with cervical limphadenectomy of the central compartment of the neck. When possible, this intervention should be performed with prophylactic aim before 1 year of age in patients with molecular genetic diagnosis. Recent advances into the mechanisms of RET proto-oncogene signaling and pathways of RET signal transduction in the development of MEN 2 and MTC will allow new treatment possibilities. PMID:22429913

  5. MTDH is an oncogene in multiple myeloma, which is suppressed by Bortezomib treatment

    PubMed Central

    Yang, Hongbao; Feng, Zhenqing; Yang, Ye

    2016-01-01

    Metadherin (MTDH) is identified as an oncogene in multiple cancers including breast cancer, bladder cancer and endometrial cancer. However, the function of MTDH in multiple myeloma (MM) is still unexplored. In this study, we disclose that MTDH is an oncogene in MM. This is characterized by an elevation mRNA level of MTDH and chromosomal gain of MTDH locus in MM cells compared to normal samples. Moreover, MTDH expression significantly increased in MMSET translocation (MS) subgroup, one of the high-risk subgroups in MM, and was significantly correlated with MM patients' poor outcomes in Total Therapy 2 (TT2) cohort. Further knockdown of MTDH expression by shRNA in MM cells induced cell apoptosis, inhibited MM cells growth in vitro and decreased xenograft tumor formation in vivo. Interestingly, opposite to TT2, MM patients with high-MTDH expression showed favorable survival outcomes in the TT3 cohort, while Bortezomib treatment was the major difference between TT2 and TT3 cohort. Furthermore we proved that Bortezomib suppressed pre- and post-transcription levels of MTDH expression of MM cells in vitro and in vivo. Finally, our studies demonstrated that MTDH is a transcriptional gene of MMSET/NFκB /MYC signaling in MM cells, which is inhibited by Bortezomib treatment. PMID:26683226

  6. [Advances Research on C-MYC Proto-oncogene in Multiple Myeloma -Review].

    PubMed

    Huang, He; Guo, Wen-Jian; Yao, Ron-Xin

    2016-08-01

    Multiple myeloma(MM) as one of the most common tumors of hmatologic system, is characterized by malignant proliferation of plasma cells, and the chemotherapy is the main therapeutic method. MM is an incurable disease because of drug-resistance of MM cells. Although the pathogenesis of MM remains unknown, the chromosome abnormalities exit in half of the patients, particularly the highly expressed gene C-MYC. Furthermore, plenty of clinical researches indicated a high expression level of C-MYC implied worse progression and/or poor prognosis of MM. Recently, the work exploiting the compounds targeting MYC has made substantial progress, even in the MM therapy. In this article, briefly the recent advances of the research on C-MYC proto-oncogene in multiple myeloma are reviewed. PMID:27531809

  7. Targeting TopBP1 at a convergent point of multiple oncogenic pathways for cancer therapy

    PubMed Central

    Chowdhury, Pinki; Lin, Gregory E.; Liu, Kang; Song, Yongcheng; Lin, Fang-Tsyr; Lin, Weei-Chin

    2014-01-01

    The progression of many solid tumors is driven by de-regulation of multiple common pathways, particularly Rb, PI (3) K/Akt and p53. Prior studies identified TopBP1as a key mediator for the oncogenic gain-of-function activities of mutant p53 (mutp53) in cancer. In Akt-hyperactive cancer, TopBP1 forms oligomers and represses E2F1-dependent apoptosis. Here we perform a molecular docking screening and identify a lead compound, calcein, capable of blocking TopBP1 oligomerization and p53 binding, resulting in re-activation of E2F1-dependent apoptosis and blockade of mutp53 gain-of-function. Calcein AM, the cell permeable derivative of calcein, shows significant anti-tumor activity in a wide-spectrum of cultured cancer cells harboring high TopBP1 levels. These biochemical findings are recapitulated in breast cancer xenograft models. Thus, our study provides proof-of-concept evidence for targeting TopBP1, a convergent point of multiple pathways, as a cancer therapy. PMID:25400145

  8. Global Impact of Oncogenic Src on a Phosphotyrosine Proteome

    PubMed Central

    Luo, Weifeng; Slebos, Robbert J.; Hill, Salisha; Li, Ming; Brábek, Jan; Amanchy, Ramars; Chaerkady, Raghothama; Pandey, Akhilesh; Ham, Amy-Joan L.; Hanks, Steven K.

    2008-01-01

    Elevated activity of Src, the first characterized protein-tyrosine kinase, is associated with progression of many human cancers, and Src has attracted interest as a therapeutic target. Src is known to act in various receptor signaling systems to impact cell behavior, yet it remains likely that the spectrum of Src protein substrates relevant to cancer is incompletely understood. To better understand the cellular impact of deregulated Src kinase activity, we extensively applied a mass spectrometry shotgun phosphotyrosine (pTyr) proteomics strategy to obtain global pTyr profiles of Src-transformed mouse fibroblasts as well as their nontransformed counterparts. A total of 867 peptides representing 563 distinct pTyr sites on 374 different proteins were identified from the Src-transformed cells, while 514 peptides representing 275 pTyr sites on 167 proteins were identified from nontransformed cells. Distinct characteristics of the two profiles were revealed by spectral counting, indicative of pTyr site relative abundance, and by complementary quantitative analysis using stable isotope labeling with amino acids in cell culture (SILAC). While both pTyr profiles are replete with sites on signaling and adhesion/cytoskeletal regulatory proteins, the Src-transformed profile is more diverse with enrichment in sites on metabolic enzymes and RNA and protein synthesis and processing machinery. Forty-three pTyr sites (32 proteins) are predicted as major biologically relevant Src targets on the basis of frequent identification in both cell populations. This select group, of particular interest as diagnostic biomarkers, includes well-established Src sites on signaling/adhesion/cytoskeletal proteins, but also uncharacterized sites of potential relevance to the transformed cell phenotype. PMID:18563927

  9. Expression of EBV-encoded oncogenes and EBV-like virions in multiple canine tumors.

    PubMed

    Chiu, Hung-Chuan; Chow, Kuan-Chih; Fan, Yi-Hsin; Chang, Shih-Chieh; Chiou, Shiow-Her; Chiang, Shu-Fen; Chiou, Che-Hao; Wu, Guo-Hua; Yang, Hsiu-Ching; Ho, Shu-Peng; Chen, Yuh-Kun; Lee, Wei-Cheng; Sun, H Sunny

    2013-04-12

    Epstein-Barr virus (EBV) is a ubiquitous human oncovirus. Previous studies by us and others have indicated that pet dogs frequently encounter EBV or EBV-related viral infection. In this study, we explored whether EBV is involved in canine malignancies in dogs. EBV-specific BamHI W sequence was detected by polymerase chain reaction (PCR) in 10 of 12 canine tumor specimens, including 8 of 10 oral tumors. Using reverse transcription-PCR, gene expressions of latent membrane protein 1 (LMP 1) and BamHI H rightward reading frame 1 (BHRF1) were identified in 8 and 7 of 12 specimens, respectively. A novel LMP1 variant, T0905, was predominant in 5 canine tumor specimens and found to exist in EBV positive human BC-2 cells. Another LMP1 variant, T0902, was similar to human tumor variant JB7. The BHRF1 sequence identified from these canine tumors was identical to that of the B95-8 viral strain. LMP1 protein and EBV-encoded RNA (EBER) were detected by immunohistochemistry and fluorescent in situ hybridization, respectively, in several tumors, particularly in tumor nests of oral amelanotic melanomas. Furthermore, EBV-like virions adopting a herpesvirus egress pathway were detected in a canthal fibroblastic osteosarcoma and an oral amelanotic melanoma. In conclusion, we report the expressions of BHRF1 transcript (a viral anti-apoptotic protein), LMP1 (a viral oncoprotein) transcript and protein, EBER (a viral oncogenic RNA), and EBV-like virions in multiple canine tumors. The identity of BHRF1 and the resemblance of LMP1 variants between canine and human tumors indicate either a close evolutionary relationship between canine and human EBV, or the possibility of zoonotic transmission. PMID:23380461

  10. The regulation of MDM2 oncogene and its impact on human cancers

    PubMed Central

    Zhao, Yuhan; Yu, Haiyang; Hu, Wenwei

    2014-01-01

    Tumor suppressor p53 plays a central role in preventing tumor formation. The levels and activity of p53 is under tight regulation to ensure its proper function. Murine double minute 2 (MDM2), a p53 target gene, is an E3 ubiquitin ligase. MDM2 is a key negative regulator of p53 protein, and forms an auto-regulatory feedback loop with p53. MDM2 is an oncogene with both p53-dependent and p53-independent oncogenic activities, and often has increased expression levels in a variety of human cancers. MDM2 is highly regulated; the levels and function of MDM2 are regulated at the transcriptional, translational and post-translational levels. This review provides an overview of the regulation of MDM2. Dysregulation of MDM2 impacts significantly upon the p53 functions, and in turn the tumorigenesis. Considering the key role that MDM2 plays in human cancers, a better understanding of the regulation of MDM2 will help us to develop novel and more effective cancer therapeutic strategies to target MDM2 and activate p53 in cells. PMID:24389645

  11. Multiple proto-oncogene activations in avian leukosis virus-induced lymphomas: evidence for stage-specific events.

    PubMed Central

    Clurman, B E; Hayward, W S

    1989-01-01

    We have examined avian leukosis virus-induced B-cell lymphomas for multiple, stage-specific oncogene activations. Three targets for viral integration were identified: c-myb, c-myc, and a newly identified locus termed c-bic. The c-myb and c-myc genes were associated with different lymphoma phenotypes. The c-bic locus was a target for integration in one class of lymphomas, usually in conjunction with c-myc activation. The data indicate that c-myc and c-bic may act synergistically during lymphomagenesis and that c-bic is involved in late stages of tumor progression. Images PMID:2548084

  12. PPM1D exerts its oncogenic properties in human pancreatic cancer through multiple mechanisms.

    PubMed

    Wu, Bo; Guo, Bo-Min; Kang, Jie; Deng, Xian-Zhao; Fan, You-Ben; Zhang, Xiao-Ping; Ai, Kai-Xing

    2016-03-01

    Protein phosphatase, Mg(2+)/Mn(2+) dependent, 1D (PPM1D) is emerging as an oncogene by virtue of its negative control on several tumor suppressor pathways. However, the clinical significance of PPM1D in pancreatic cancer (PC) has not been defined. In this study, we determined PPM1D expression in human PC tissues and cell lines and their irrespective noncancerous controls. We subsequently investigated the functional role of PPM1D in the migration, invasion, and apoptosis of MIA PaCa-2 and PANC-1 PC cells in vitro and explored the signaling pathways involved. Furthermore, we examined the role of PPM1D in PC tumorigenesis in vivo. Our results showed that PPM1D is overexpressed in human PC tissues and cell lines and significantly correlated with tumor growth and metastasis. PPM1D promotes PC cell migration and invasion via potentiation of the Wnt/β-catenin pathway through downregulation of apoptosis-stimulating of p53 protein 2 (ASPP2). In contrast to PPM1D, our results showed that ASPP2 is downregulated in PC tissues. Additionally, PPM1D suppresses PC cell apoptosis via inhibition of the p38 MAPK/p53 pathway through both dephosphorylation of p38 MAPK and downregulation of ASPP2. Furthermore, PPM1D promotes PC tumor growth in vivo. Our results demonstrated that PPM1D is an oncogene in PC. PMID:26714478

  13. Multiple tumor types appear in a transgenic mouse with the ras oncogene.

    PubMed Central

    Cardiff, R. D.; Leder, A.; Kuo, A.; Pattengale, P. K.; Leder, P.

    1993-01-01

    A transgenic mouse strain with the zeta-globin promoter and the vHa-ras oncogene develops an array of mesenchymal and epithelial neoplasms described here. The predominate mesenchymal tumors were dermal spindle cell tumors, which resembled malignant fibrous histiocytomas found in humans. They were associated with hepatosplenomegaly and developed beneath squamous papillomas. The hepatosplenomegaly was associated with infiltrates of cells that tended toward myelocytic or monocytic differentiation. Other epithelial tumors included keratoacanthomas and squamous cell carcinomas. Squamous cysts, some with squamous cell carcinomas, of the salivary glands and mammary carcinomas were also found. Odontogenic tumors, which sometimes differentiated into ameloblastomas, were one of the more unusual tumor types observed. Other, less frequent tumors were also noted. The tumors described here are a potentially valuable experimental resource that may lead to an understanding of malignant fibrous histiocytoma-like lesions, odontogenic tumors, and tumor progression. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:8475993

  14. The impact of age on oncogenic potential: tumor-initiating cells and the brain microenvironment.

    PubMed

    Stoll, Elizabeth A; Horner, Philip J; Rostomily, Robert C

    2013-10-01

    Paradoxically, aging leads to both decreased regenerative capacity in the brain and an increased risk of tumorigenesis, particularly the most common adult-onset brain tumor, glioma. A shared factor contributing to both phenomena is thought to be age-related alterations in neural progenitor cells (NPCs), which function normally to produce new neurons and glia, but are also considered likely cells of origin for malignant glioma. Upon oncogenic transformation, cells acquire characteristics known as the hallmarks of cancer, including unlimited replication, altered responses to growth and anti-growth factors, increased capacity for angiogenesis, potential for invasion, genetic instability, apoptotic evasion, escape from immune surveillance, and an adaptive metabolic phenotype. The precise molecular pathogenesis and temporal acquisition of these malignant characteristics is largely a mystery. Recent studies characterizing NPCs during normal aging, however, have begun to elucidate mechanisms underlying the age-associated increase in their malignant potential. Aging cells are dependent upon multiple compensatory pathways to maintain cell cycle control, normal niche interactions, genetic stability, programmed cell death, and oxidative metabolism. A few multi-functional proteins act as 'critical nodes' in the coordination of these various cellular activities, although both intracellular signaling and elements within the brain environment are critical to maintaining a balance between senescence and tumorigenesis. Here, we provide an overview of recent progress in our understanding of how mechanisms underlying cellular aging inform on glioma pathogenesis and malignancy. PMID:23711239

  15. The oncogenic PIM kinase family regulates drug resistance through multiple mechanisms.

    PubMed

    Isaac, Methvin; Siu, Allan; Jongstra, Jan

    2011-01-01

    Resistance to chemotherapeutic drugs is a significant clinical problem for the treatment of cancer patients and has been linked to the activation of survival pathways and expression of multidrug efflux transporters. Thus inhibition of these survival pathways or efflux transporter expression may increase the efficacy of drug treatment. Here we review the role of the oncogenic PIM kinase family in regulating important proliferation and survival pathways in cancer cells and the involvement of PIM kinases in the expression and activity of MDR-1 and BCRP, two of the most important drug efflux transporters. PIM kinases are over expressed in various types of tumors and regulate the activation of signaling pathways that are important for tumor cell proliferation, survival and expression of drug efflux proteins. This makes PIM kinases attractive targets for the development of anti-cancer chemotherapeutic drugs. Focussing mainly on solid tumors, we provide an update on the literature describing the tumorigenic functions of PIM kinases. Also we provide an overview of the development of selective small molecule PIM kinase inhibitors. Because of the intense effort by pharmaceutical companies and academia it is reasonable to expect that PIM kinase inhibitors will enter the clinic in the foreseeable future. We therefore finish this review with a discussion on the most efficient application of these PIM inhibitors. This includes a consideration of which tumor type is the most appropriate target for treatment, how to select the patient population that stands to gain the most from treatment with PIM inhibitors, which molecular markers are suitable to follow the course of treatment and whether PIM kinase inhibitors should be used as monotherapy or in combination with other cytotoxic agents. PMID:21601509

  16. Multiple meteoroid impact in Antarctica

    NASA Astrophysics Data System (ADS)

    Weihoupt, J. W.; Rice, A.; van der Hoeven, F.

    2006-12-01

    In the late 1950's, geophysical field parties undertaking gravity surveys across Antarctica observed over a large area of Wilkes Land (> 240km across) an exceptionally pronounced negative free air anomaly ((to -158.3 mgal). This area was later interpreted as a possible meteor impact site because the gravity profiles were similar to those of known impact sites (apparent rim structures, circular basins, central peaks or rings), they possessed appropriate aspect ratios (e.g., crater diameter vs crater depth), anomalously steep negative free air gravity anomaly gradients (to 4.71 mgal/km) were characteristic of impact craters and uncharacteristic of solely mantle-related or geologic crustal variations, etc. The condition of the ice covering the anomaly (heavily crevassed), the apparent lack of isostatic compensation with surrounding environs, etc suggested the impact was geologically recent and that perhaps a tektite strewn field was associated with it. The distance from the postulated impact to the Australian strewn field was appropriate as are the ages of the tektites there. This early work has been augmented with the detection of a dominant cluster of negative free air gravity anomalies crossing the continental-oceanic boundary, and the East and West Antarctic structural boundary (i.e., Transantarctic Mountains). These anomalies are coincident with complex subglacial craterform topographic features inferred from radiosounding (to -500m below MSL). The major interior positive free air gravity anomalies are associated with subglacial topographic highs. The elliptical distribution of the negative gravity anomalies resemble known multiple impact distributions (scatter ellipses with the larger anomalies forward and the lesser ones aft). This more recent information favors expanding the original proposal to that of a multiple meteoroid impact. The multiple impact hypotheses would explain aeromagnetic surveys revealing ring-shaped structures in the subglacial rock surface

  17. Multiple-Integrations of HPV16 Genome and Altered Transcription of Viral Oncogenes and Cellular Genes Are Associated with the Development of Cervical Cancer

    PubMed Central

    Lin, Mao; Duan, Ping; Ye, Lulu; Chen, Jun; Chen, Xiangmin; Zhang, Lifang; Xue, Xiangyang

    2014-01-01

    The constitutive expression of the high-risk HPV E6 and E7 viral oncogenes is the major cause of cervical cancer. To comprehensively explore the composition of HPV16 early transcripts and their genomic annotation, cervical squamous epithelial tissues from 40 HPV16-infected patients were collected for analysis of papillomavirus oncogene transcripts (APOT). We observed different transcription patterns of HPV16 oncogenes in progression of cervical lesions to cervical cancer and identified one novel transcript. Multiple-integration events in the tissues of cervical carcinoma (CxCa) are significantly more often than those of low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL). Moreover, most cellular genes within or near these integration sites are cancer-associated genes. Taken together, this study suggests that the multiple-integrations of HPV genome during persistent viral infection, which thereby alters the expression patterns of viral oncogenes and integration-related cellular genes, play a crucial role in progression of cervical lesions to cervix cancer. PMID:24992025

  18. Multiple impacts of dusty projectiles

    NASA Astrophysics Data System (ADS)

    Kothe, Stefan; Güttler, Carsten; Blum, Jurgen

    In the context of early stages of planetesimal formation we performed laboratory and drop tower experiments to study multiple impacts of small dust-aggregate projectiles into solid sintered dust targets. Both collision partners consisted of 1.5 µm monodisperse spherical SiO2 monomers with volume filling factors of 0.15 (projectiles) and 0.35 (targets), respectively. The fragile projectiles were accelerated by a solenoid accelerator with a linear projectile magazine, which enabled us to perform 25 impacts within 4.5 s of microgravity time in the Bremen drop tower. We measured the mass-accretion efficiency for different impact velocities between 3 and 5 m s-1 , using an analytical balance and imaging methods. Furthermore, we observed random collisions among small dust aggregates with sizes around 1 mm and collision velocities of the order of 0.25 m s-1 and used them to improve the dust-aggregate collision model of Güttler et al. (2010). u

  19. C-MAF oncogene dysregulation in multiple myeloma: frequency and biological relevance.

    PubMed

    Rasmussen, Thomas; Knudsen, Lene Meldgaard; Dahl, Inger Marie S; Johnsen, Hans Erik

    2003-10-01

    To investigate the frequency and possible biological consequences of c-maf dysregulation, we designed c-maf and IL-4 real-time RT-PCR assays for determination of c-maf and IL-4 mRNA levels. Using the c-maf real-time RT-PCR assay, we tested a panel of 14 B-cell lines, 135 diagnostic bone marrow (BM) samples from patients with multiple myeloma and 10 BM samples from normal donors. In B cell lines and flowsorted CD38++/CD19-/CD56++ myeloma plasma cells (N = 14) the c-maf/GAPDH and IL-4/GAPDH ratios were determined simultaneously using real time RT-PCR. All B cell lines used in the study were characterized by flow cytometry and tested for the presence of Ebstein-Barr virus (EBV). B-cell lines, that were PCR negative for EBV and had a phenotype typical for primary myeloma cells, expressed medium to high levels of c-maf mRNA. However, all EBV PCR positive cell lines, showed a more immature phenotype, lacked expression of aberrant surface markers and contained very low levels of c-maf mRNA. In 4.4% (6/135) of MM patients tested, a c-maf mRNA level comparable to the cell line RPMI 8226 containing at (16:22), translocation was found. In addition, all c-maf positive myeloma cell lines and CD38++/CD19-/CD56++ myeloma plasma cells tested were IL-4 negative. In conclusion, high levels of c-maf mRNA were observed in "true MM cell lines" and 4.4% of MM patients. Further, c-maf dysregulation in myeloma plasma cells did not cause induction of IL-4 transcription. PMID:14692531

  20. A Hybrid Chalcone Combining the Trimethoxyphenyl and Isatinyl Groups Targets Multiple Oncogenic Proteins and Pathways in Hepatocellular Carcinoma Cells.

    PubMed

    Cao, Lili; Zhang, Lijun; Zhao, Xiang; Zhang, Ye

    2016-01-01

    Small molecule inhibitors that can simultaneously inhibit multiple oncogenic proteins in essential pathways are promising therapeutic chemicals for hepatocellular carcinoma (HCC). To combine the anticancer effects of combretastatins, chalcones and isatins, we synthesized a novel hybrid molecule 3',4',5'-trimethoxy-5-chloro-isatinylchalcone (3MCIC). 3MCIC inhibited proliferation of cultured HepG2 cells, causing rounding-up of the cells and massive vacuole accumulation in the cytoplasm. Paxillin and focal adhesion plaques were downregulated by 3MCIC. Surprisingly, unlike the microtubule (MT)-targeting agent CA-4 that inhibits tubulin polymerization, 3MCIC stabilized tubulin polymers both in living cells and in cell lysates. 3MCIC treatment reduced cyclin B1, CDK1, p-CDK1/2, and Rb, but increased p53 and p21. Moreover, 3MCIC caused GSK3β degradation by promoting GSK3β-Ser9 phosphorylation. Nevertheless, 3MCIC inhibited the Wnt/β-catenin pathway by downregulating β-catenin, c-Myc, cyclin D1 and E2F1. 3MCIC treatment not only activated the caspase-3-dependent apoptotic pathway, but also caused massive autophagy evidenced by rapid and drastic changes of LC3 and p62. 3MCIC also promoted cleavage and maturation of the lysosomal protease cathepsin D. Using ligand-affinity chromatography (LAC), target proteins captured onto the Sephacryl S1000-C12-3MCIC resins were isolated and analyzed by mass spectrometry (MS). Some of the LAC-MS identified targets, i.e., septin-2, vimentin, pan-cytokeratin, nucleolin, EF1α1/2, EBP1 (PA2G4), cyclin B1 and GSK3β, were further detected by Western blotting. Moreover, both septin-2 and HIF-1α decreased drastically in 3MCIC-treated HepG2 cells. Our data suggest that 3MCIC is a promising anticancer lead compound with novel targeting mechanisms, and also demonstrate the efficiency of LAC-MS based target identification in anticancer drug development. PMID:27525972

  1. A Hybrid Chalcone Combining the Trimethoxyphenyl and Isatinyl Groups Targets Multiple Oncogenic Proteins and Pathways in Hepatocellular Carcinoma Cells

    PubMed Central

    Cao, Lili; Zhang, Lijun; Zhao, Xiang; Zhang, Ye

    2016-01-01

    Small molecule inhibitors that can simultaneously inhibit multiple oncogenic proteins in essential pathways are promising therapeutic chemicals for hepatocellular carcinoma (HCC). To combine the anticancer effects of combretastatins, chalcones and isatins, we synthesized a novel hybrid molecule 3’,4’,5’-trimethoxy-5-chloro-isatinylchalcone (3MCIC). 3MCIC inhibited proliferation of cultured HepG2 cells, causing rounding-up of the cells and massive vacuole accumulation in the cytoplasm. Paxillin and focal adhesion plaques were downregulated by 3MCIC. Surprisingly, unlike the microtubule (MT)-targeting agent CA-4 that inhibits tubulin polymerization, 3MCIC stabilized tubulin polymers both in living cells and in cell lysates. 3MCIC treatment reduced cyclin B1, CDK1, p-CDK1/2, and Rb, but increased p53 and p21. Moreover, 3MCIC caused GSK3β degradation by promoting GSK3β-Ser9 phosphorylation. Nevertheless, 3MCIC inhibited the Wnt/β-catenin pathway by downregulating β-catenin, c-Myc, cyclin D1 and E2F1. 3MCIC treatment not only activated the caspase-3-dependent apoptotic pathway, but also caused massive autophagy evidenced by rapid and drastic changes of LC3 and p62. 3MCIC also promoted cleavage and maturation of the lysosomal protease cathepsin D. Using ligand-affinity chromatography (LAC), target proteins captured onto the Sephacryl S1000-C12-3MCIC resins were isolated and analyzed by mass spectrometry (MS). Some of the LAC-MS identified targets, i.e., septin-2, vimentin, pan-cytokeratin, nucleolin, EF1α1/2, EBP1 (PA2G4), cyclin B1 and GSK3β, were further detected by Western blotting. Moreover, both septin-2 and HIF-1α decreased drastically in 3MCIC-treated HepG2 cells. Our data suggest that 3MCIC is a promising anticancer lead compound with novel targeting mechanisms, and also demonstrate the efficiency of LAC-MS based target identification in anticancer drug development. PMID:27525972

  2. Multiple ionization of xenon by proton impact

    SciTech Connect

    Manson, S.T.; DuBois, R.D.

    1987-12-01

    An experimental and theoretical study of multiple ionization of xenon for 0.2- to 2.0-MeV proton impact was made. Absolute cross sections for producing xenon ions with charges from +1 to +3 were measured, and calculations of subshell cross sections were performed. Experiment and theory are consistent and indicate that multiple ionization of xenon by fast protons occurs via inner-shell ionization. This is in contrast to the lighter noble gases where direct multiple outer shell ionization can be predominant.

  3. MicroRNA-7 Inhibits Multiple Oncogenic Pathways to Suppress HER2Δ16 Mediated Breast Tumorigenesis and Reverse Trastuzumab Resistance

    PubMed Central

    Huynh, Felicia C.; Jones, Frank E.

    2014-01-01

    The oncogenic isoform of HER2, HER2Δ16, is expressed with HER2 in nearly 50% of HER2 positive breast tumors where HER2Δ16 drives metastasis and resistance to multiple therapeutic interventions including tamoxifen and trastuzumab. In recent years microRNAs have been shown to influence multiple aspects of tumorigenesis and tumor cell response to therapy. Accordingly, the HER2Δ16 oncogene alters microRNA expression to promote endocrine resistance. With the goal of identifying microRNA suppressors of HER2Δ16 oncogenic activity we investigated the contribution of altered microRNA expression to HER2Δ16 mediated tumorigenesis and trastuzumab resistance. Using a gene array strategy comparing microRNA expression profiles of MCF-7 to MCF-7/HER2Δ16 cells, we found that expression of HER2Δ16 significantly altered expression of 16 microRNAs by 2-fold or more including a 4.8 fold suppression of the miR-7 tumor suppressor. Reestablished expression of miR-7 in the MCF-7/HER2Δ16 cell line caused a G1 cell cycle arrest and reduced both colony formation and cell migration activity to levels of parental MCF-7 cells. Suppression of miR-7 in the MCF-7 cell line resulted in enhanced colony formation activity but not cell migration, indicating that miR-7 suppression is sufficient to drive tumor cell proliferation but not migration. MiR-7 inhibited MCF-7/HER2Δ16 cell migration through a mechanism involving suppression of the miR-7 target gene EGFR. In contrast, miR-7 inhibition of MCF-7/HER2Δ16 cell proliferation involved a pathway where miR-7 expression resulted in the inactivation of Src kinase independent of suppressed EGFR expression. Also independent of EGFR suppression, reestablished miR-7 expression sensitized refractory MCF-7/HER2Δ16 cells to trastuzumab. Our results demonstrate that reestablished miR-7 expression abolishes HER2Δ16 induced cell proliferation and migration while sensitizing HER2Δ16 expressing cells to trastuzumab therapy. We propose that miR-7 regulated

  4. Analysis of Multiple HPV E6 PDZ Interactions Defines Type-Specific PDZ Fingerprints That Predict Oncogenic Potential

    PubMed Central

    Thomas, Miranda; Myers, Michael P.; Guarnaccia, Corrado; Banks, Lawrence

    2016-01-01

    The high-risk Human Papillomavirus (HPV) E6 oncoproteins are characterised by the presence of a class I PDZ-binding motif (PBM) on their extreme carboxy termini. The PBM is present on the E6 proteins derived from all cancer-causing HPV types, but can also be found on some related non-cancer-causing E6 proteins. We have therefore been interested in investigating the potential functional differences between these different E6 PBMs. Using an unbiased proteomic approach in keratinocytes, we have directly compared the interaction profiles of these different PBMs. This has allowed us to identify the potential PDZ target fingerprints of the E6 PBMs from 7 different cancer-causing HPV types, from 3 HPV types with weak cancer association, and from one benign HPV type that possesses an ancestral PBM. We demonstrate a striking increase in the number of potential PDZ targets bound by each E6 PBM as cancer-causing potential increases, and show that the HPV-16 and HPV-18 PBMs have the most flexibility in their PDZ target selection. Furthermore, the specific interaction with hScrib correlates directly with increased oncogenic potential. In contrast, hDlg is bound equally well by all the HPV E6 PBMs analysed, indicating that this is an evolutionarily conserved interaction, and was most likely one of the original E6 PBM target proteins that was important for the occupation of a potential new niche. Finally, we present evidence that the cell junction components ZO-2 and β-2 syntrophin are novel PDZ domain–containing targets of a subset of high-risk HPV types. PMID:27483446

  5. Klf5 Deletion Promotes Pten Deletion–Initiated Luminal-Type Mouse Prostate Tumors through Multiple Oncogenic Signaling Pathways12

    PubMed Central

    Xing, Changsheng; Ci, Xinpei; Sun, Xiaodong; Fu, Xiaoying; Zhang, Zhiqian; Dong, Eric N.; Hao, Zhao-Zhe; Dong, Jin-Tang

    2014-01-01

    Krüppel-like factor 5 (KLF5) regulates multiple biologic processes. Its function in tumorigenesis appears contradictory though, showing both tumor suppressor and tumor promoting activities. In this study, we examined whether and how Klf5 functions in prostatic tumorigenesis using mice with prostate-specific deletion of Klf5 and phosphatase and tensin homolog (Pten), both of which are frequently inactivated in human prostate cancer. Histologic analysis demonstrated that when one Pten allele was deleted, which causes mouse prostatic intraepithelial neoplasia (mPIN), Klf5 deletion accelerated the emergence and progression of mPIN. When both Pten alleles were deleted, which causes prostate cancer, Klf5 deletion promoted tumor growth, increased cell proliferation, and caused more severe morphologic and molecular alterations. Homozygous deletion of Klf5 was more effective than hemizygous deletion. Unexpectedly, while Pten deletion alone expanded basal cell population in a tumor as reported, Klf5 deletion in the Pten-null background clearly reduced basal cell population while expanding luminal cell population. Global gene expression profiling, pathway analysis, and experimental validation indicate that multiple mechanisms could mediate the tumor-promoting effect of Klf5 deletion, including the up-regulation of epidermal growth factor and its downstream signaling molecules AKT and ERK and the inactivation of the p15 cell cycle inhibitor. KLF5 also appears to cooperate with several transcription factors, including CREB1, Sp1, Myc, ER and AR, to regulate gene expression. These findings validate the tumor suppressor function of KLF5. They also yield a mouse model that shares two common genetic alterations with human prostate cancer—mutation/deletion of Pten and deletion of Klf5. PMID:25425963

  6. A proto-oncogene BCL6 is up-regulated in the bone marrow microenvironment in multiple myeloma cells.

    PubMed

    Hideshima, Teru; Mitsiades, Constantine; Ikeda, Hiroshi; Chauhan, Dharminder; Raje, Noopur; Gorgun, Gullu; Hideshima, Hiromasa; Munshi, Nikhil C; Richardson, Paul G; Carrasco, Daniel R; Anderson, Kenneth C

    2010-05-01

    Constitutive B-cell lymphoma 6 (Bcl-6) expression was undetectable in multiple myeloma (MM) cell lines, except U266 cells. However, it was up-regulated by coculture with bone marrow (BM) stromal cell-culture supernatant (SCCS). Bcl-6 expression in patient MM cells in the BM was positive. Anti-interleukin-6 (IL-6)-neutralizing antibody significantly blocked SCCS-induced Bcl-6 in MM cells. Indeed, IL-6 strongly triggered Bcl-6 expression in MM cells, whereas Janus kinase inhibitor and STAT3 siRNA down-regulated Bcl-6. Tumor necrosis factor-alpha (TNF-alpha) also triggered Bcl-6, but independently of STAT3, whereas IkappaB kinasebeta inhibitor down-regulated TNF-alpha-induced Bcl-6, indicating that the canonical nuclear factor-kappaB pathway mediates TNF-alpha-induced Bcl-6 expression. Importantly, down-regulation of Bcl-6 by shRNA significantly inhibited MM cell growth in the presence of SCCS. Our results therefore suggest that Bcl-6 expression in MM cells is modulated, at least in part, via Janus kinase/STAT3 and canonical nuclear factor-kappaB pathways and that targeting Bcl-6, either directly or via these cascades, inhibits MM cell growth in the BM milieu. PMID:20228272

  7. Targeting of multiple oncogenic signaling pathways by Hsp90 inhibitor alone or in combination with berberine for treatment of colorectal cancer.

    PubMed

    Su, Yen-Hao; Tang, Wan-Chun; Cheng, Ya-Wen; Sia, Peik; Huang, Chi-Chen; Lee, Yi-Chao; Jiang, Hsin-Yi; Wu, Ming-Heng; Lai, I-Lu; Lee, Jun-Wei; Lee, Kuen-Haur

    2015-10-01

    There is a wide range of drugs and combinations under investigation and/or approved over the last decade to treat colorectal cancer (CRC), but the 5-year survival rate remains poor at stages II-IV. Therefore, new, more-efficient drugs still need to be developed that will hopefully be included in first-line therapy or overcome resistance when it appears, as part of second- or third-line treatments in the near future. In this study, we revealed that heat shock protein 90 (Hsp90) inhibitors have high therapeutic potential in CRC according to combinative analysis of NCBI's Gene Expression Omnibus (GEO) repository and chemical genomic database of Connectivity Map (CMap). We found that second generation Hsp90 inhibitor, NVP-AUY922, significantly downregulated the activities of a broad spectrum of kinases involved in regulating cell growth arrest and death of NVP-AUY922-sensitive CRC cells. To overcome NVP-AUY922-induced upregulation of survivin expression which causes drug insensitivity, we found that combining berberine (BBR), a herbal medicine with potency in inhibiting survivin expression, with NVP-AUY922 resulted in synergistic antiproliferative effects for NVP-AUY922-sensitive and -insensitive CRC cells. Furthermore, we demonstrated that treatment of NVP-AUY922-insensitive CRC cells with the combination of NVP-AUY922 and BBR caused cell growth arrest through inhibiting CDK4 expression and induction of microRNA-296-5p (miR-296-5p)-mediated suppression of Pin1-β-catenin-cyclin D1 signaling pathway. Finally, we found that the expression level of Hsp90 in tumor tissues of CRC was positively correlated with CDK4 and Pin1 expression levels. Taken together, these results indicate that combination of NVP-AUY922 and BBR therapy can inhibit multiple oncogenic signaling pathways of CRC. PMID:25982393

  8. Venus - Multiple-Floored, Irregular Impact Crater

    NASA Technical Reports Server (NTRS)

    1991-01-01

    Magellan imaged this multiple-floored, irregular impact crater at latitude 16.4 degrees north, longitude 352.1 degrees east, during orbits 481 and 482 on 27 September 1990. This crater, about 9.2 kilometers in maximum diameter, was formed on what appears to be a slightly fractured, radar-dark (smooth) plain. The abundant, low viscosity flows associated with this cratering event have, however, filled local, fault-controlled troughs (called graben). These shallow graben are well portrayed on this Magellan image but would be unrecognizable but for their coincidental infilling by the radar-bright crater flows. This fortuitous enhancement by the crater flows of fault structures that are below the resolution of the Magellan synthetic aperture radar is providing the Magellan Science Team with valuable geologic information. The flow deposits from the craters are thought to consist primarily of shock melted rock and fragmented debris resulting from the nearly simultaneous impacts of two projectile fragments into the hot (800 degrees Fahrenheit) surface rocks of Venus. The presence of the various floors of this irregular crater is interpreted to be the result of crushing, fragmentation, and eventual aerodynamic dispersion of a single entry projectile during passage through the dense Venusian atmosphere.

  9. RAS oncogenes: weaving a tumorigenic web

    PubMed Central

    Pylayeva-Gupta, Yuliya; Grabocka, Elda; Bar-Sagi, Dafna

    2013-01-01

    RAS proteins are essential components of signalling pathways that emanate from cell surface receptors. Oncogenic activation of these proteins owing to missense mutations is frequently detected in several types of cancer. A wealth of biochemical and genetic studies indicates that RAS proteins control a complex molecular circuitry that consists of a wide array of interconnecting pathways. In this Review, we describe how RAS oncogenes exploit their extensive signalling reach to affect multiple cellular processes that drive tumorigenesis. PMID:21993244

  10. Proto-oncogenes II.

    PubMed

    Rosen, P

    1988-12-01

    In reviewing recent literature on activated proto-oncogenes including retroviral infection (without oncogene), translocation and inherited childhood cancer, I have come to the conclusion that activated proto-oncogenes are not involved in development of tumors. There is one exception in which a translocated proto-myc leads to transformation. That is the case of the trangenic mouse embryo where faulty development occurs. PMID:3226361

  11. Management of Multiple Impacted Teeth: A Case Report and Review

    PubMed Central

    Ajith, Sreedevi D; Shetty, Smitha; Hussain, Huma; Nagaraj, Tejavathy; Srinath, M

    2014-01-01

    Interdisciplinary care for the management of impacted teeth provides a holistic method of treating patients. Careful planning is necessary to reach the desired treatment goals. This article attempts to highlight the importance of diagnosis and adequate treatment planning for successful eruption of impacted teeth. The concept of forced eruption to improve the bone morphology of the impacted teeth has been used to treat a case of multiple impacted teeth. This paper reviews the diagnosis and management of impacted teeth. A case report of multiple impacted maxillary anterior teeth of a 13-year-old female patient has been presented. How to cite the article: Ajith SD, Shetty S, Hussain H, Nagaraj T, Srinath M. Management of multiple impacted teeth: A case report and review. J Int Oral Health 2014;6(3):93-8. PMID:25083041

  12. K-ras oncogene DNA sequences in pink salmon in streams impacted by the Exxon Valdez oil spill: no evidence of oil-induced heritable mutations.

    PubMed

    Cronin, Matthew A; Wickliffe, Jeffrey K; Dunina, Yelena; Baker, Robert J

    2002-08-01

    It was hypothesized in previous studies that the Exxon Valdez oil spill in Prince William Sound, Alaska, induced heritable mutations and resulted in mortality of pink salmon (Oncorhynchus gorbuscha) embryos. In one of these studies, laboratory exposure of pink salmon embryos to crude oil resulted in apparent mutation-induction in exon 1 and exon 2 of the K-ras oncogene, but no fish from the area impacted by the oil spill were analyzed. We assessed K-ras exon 1 and exon 2 DNA sequences in pink salmon from five streams that were oiled and five streams that were not oiled by the Exxon Valdez oil spill in Prince William Sound, and two streams with natural oil seeps and one stream without seeps on the Alaska Peninsula. Of the 79 fish analyzed for exon 1 and the 89 fish analyzed for exon 2, none had the nucleotide substitutions representing the mutations induced in the laboratory study. Other variable nucleotides occurred in similar proportions in oiled and non-oiled streams and probably represent natural allelic variation. These data do not support the hypothesis that heritable mutations in the K-ras gene were induced by the Exxon Valdez oil spill or oil seeps. PMID:12211696

  13. The Multiple Impacts of Teacher Misbehaviour

    ERIC Educational Resources Information Center

    Page, Damien

    2016-01-01

    Purpose: The purpose of this paper is to investigate the impacts of serious teacher misbehaviour (TMB) in schools from the perspective of headteachers, a largely un-researched area. Design/methodology/approach: Data were collected via the documentary analysis of misconduct cases from the Teaching Agency and semi-structured interviews with five…

  14. Oncogenic Brain Metazoan Parasite Infection

    PubMed Central

    Spurgeon, Angela N.; Cress, Marshall C.; Gabor, Oroszi; Ding, Qing-Qing; Miller, Douglas C.

    2013-01-01

    Multiple observations suggest that certain parasitic infections can be oncogenic. Among these, neurocysticercosis is associated with increased risk for gliomas and hematologic malignancies. We report the case of a 71-year-old woman with colocalization of a metazoan parasite, possibly cysticercosis, and a WHO grade IV neuroepithelial tumor with exclusively neuronal differentiation by immunohistochemical stains (immunopositive for synaptophysin, neurofilament protein, and Neu-N and not for GFAP, vimentin, or S100). The colocalization and temporal relationship of these two entities suggest a causal relationship. PMID:24151568

  15. Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure

    PubMed Central

    Pagliarini, Raymond; Shao, Wenlin; Sellers, William R

    2015-01-01

    A key goal of cancer therapeutics is to selectively target the genetic lesions that initiate and maintain cancer cell proliferation and survival. While most cancers harbor multiple oncogenic mutations, a wealth of preclinical and clinical data supports that many cancers are sensitive to inhibition of single oncogenes, a concept referred to as ‘oncogene addiction’. Herein, we describe the clinical evidence supporting oncogene addiction and discuss common mechanistic themes emerging from the response and acquired resistance to oncogene-targeted therapies. Finally, we suggest several opportunities toward exploiting oncogene addiction to achieve curative cancer therapies. PMID:25680965

  16. Multiple Case Study on Cyberbullying's Impacts on Adolescent Technology Use

    ERIC Educational Resources Information Center

    Thompson, Kent W.

    2013-01-01

    This multiple case study focused on whether and how cyberbullying had an impact on students' use of technology. Analysis of the lived experiences of the participants in this study added depth to the quantitative research previously conducted by others in this area. The conceptual framework was based on social learning theory, which suggested that…

  17. Multiple electron processes of He and Ne by proton impact

    NASA Astrophysics Data System (ADS)

    Terekhin, Pavel Nikolaevich; Montenegro, Pablo; Quinto, Michele; Monti, Juan; Fojon, Omar; Rivarola, Roberto

    2016-05-01

    A detailed investigation of multiple electron processes (single and multiple ionization, single capture, transfer-ionization) of He and Ne is presented for proton impact at intermediate and high collision energies. Exclusive absolute cross sections for these processes have been obtained by calculation of transition probabilities in the independent electron and independent event models as a function of impact parameter in the framework of the continuum distorted wave-eikonal initial state theory. A binomial analysis is employed to calculate exclusive probabilities. The comparison with available theoretical and experimental results shows that exclusive probabilities are needed for a reliable description of the experimental data. The developed approach can be used for obtaining the input database for modeling multiple electron processes of charged particles passing through the matter.

  18. Oncogenes and growth control

    SciTech Connect

    Kahn, P.; Graf, T.

    1986-01-01

    This book contains six sections, each consisting of several papers. Some of the paper titles are: A Role for Proto-Oncogenes in Differentiation.; The ras Gene Family; Regulation of Human Globin Gene Expression; Regulation of Gene Expression by Steroid Hormones; The Effect of DNA Methylation on DNA-Protein Interactions and on the Regulation of Gene Expression; and Trans-Acting Elements Encoded in Immediate Early Genes of DNA Tumor Viruses.

  19. The human oncogenic viruses

    SciTech Connect

    Luderer, A.A.; Weetall, H.H

    1986-01-01

    This book contains eight selections. The titles are: Cytogenetics of the Leukemias and Lymphomas; Cytogenetics of Solid Tumors: Renal Cell Carcinoma, Malignant Melanoma, Retinoblastoma, and Wilms' Tumor; Elucidation of a Normal Function for a Human Proto-Oncogene; Detection of HSV-2 Genes and Gene Products in Cervical Neoplasia; Papillomaviruses in Anogennital Neoplasms; Human Epstein-Barr Virus and Cancer; Hepatitis B Virus and Hepatocellular Carcinoma; and Kaposi's Sarcoma: Acquired Immunodeficiency Syndrome (AIDS) and Associated Viruses.

  20. [Hypophosphatemic oncogenic osteomalacia].

    PubMed

    Mátyus, J; Szebenyi, B; Rédl, P; Mikita, J; Gáspár, L; Haris, A; Radó, J; Kakuk, G

    2000-12-17

    The first case of oncogen osteomalacia in Hungary is reported, to draw the attention of the medical profession to it and to present the new data about its pathomechanism. Pathological hip fracture caused by hypophosphataemic osteomalacia due to isolated renal phosphate wasting was found in a previously healthy 19 years old sportsman. In spite of daily 1.5 micrograms calcitriol treatment and phosphate supplementation, hypophosphataemia persisted for 13 years and he needed regular indometacin medication for his bone pain. During that time an 1.5 cm gingival tumour was found and radically removed. The serum phosphate level returned to normal in a few hours after the operation (preoperative 0.51, after 2, 4 and 8 hours 0.61, 0.68 and 0.79 mmol/l respectively), and remained normal without calcitriol. The histological examination showed epulis with fibroblast and vascular cell proliferation, which has never been previously reported in connection with oncogenic osteomalacia. The pain resolved after 3 months and the bone density became normal in one year. Oncogenic osteomalacia must be considered in every case presenting with atypical hypophosphataemic osteomalacia. Careful dental examination is needed also in the course of search for the underlying tumour. Every tumour-like growth, even the common epulis, has to be operated radically and serum phosphate monitored in the postoperative period in all such cases. PMID:11196239

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

    PubMed Central

    Laderas, Ted G.; Heiser, Laura M.; Sönmez, Kemal

    2015-01-01

    Tumorigenesis is a multi-step process, involving the acquisition of multiple oncogenic mutations that transform cells, resulting in systemic dysregulation that enables proliferation, invasion, and other cancer hallmarks. The goal of precision medicine is to identify therapeutically-actionable mutations from large-scale omic datasets. 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 the oncogene’s deleterious potential, a new genomic feature that we term “surrogate oncogenes.” Surrogate oncogenes are representatives of these mutated subnetworks that interact with oncogenes. By mapping mutations to a protein–protein interaction network, we determine the significance of the observed distribution using permutation-based methods. For a panel of 38 breast cancer cell lines, we identified a significant number of surrogate oncogenes in known oncogenes such as BRCA1 and ESR1, lending credence to this approach. 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 from a single sample, and therefore has the potential to integrate patient-unique mutations into drug sensitivity predictions, suggesting a new direction in precision medicine and drug development. Additionally, we show the prevalence of significant surrogate oncogenes in multiple cancers from The Cancer Genome Atlas, suggesting that surrogate oncogenes may be a useful genomic feature for guiding pancancer analyses and assigning therapies across many tissue

  2. The oncogenic action of ionizing radiation on rat skin

    SciTech Connect

    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.

  3. Oncogenes: The Passport for Viral Oncolysis Through PKR Inhibition.

    PubMed

    Fernandes, Janaina

    2016-01-01

    The transforming properties of oncogenes are derived from gain-of-function mutations, shifting cell signaling from highly regulated homeostatic to an uncontrolled oncogenic state, with the contribution of the inactivating mutations in tumor suppressor genes P53 and RB, leading to tumor resistance to conventional and target-directed therapy. On the other hand, this scenario fulfills two requirements for oncolytic virus infection in tumor cells: inactivation of tumor suppressors and presence of oncoproteins, also the requirements to engage malignancy. Several of these oncogenes have a negative impact on the main interferon antiviral defense, the double-stranded RNA-activated protein kinase (PKR), which helps viruses to spontaneously target tumor cells instead of normal cells. This review is focused on the negative impact of overexpression of oncogenes on conventional and targeted therapy and their positive impact on viral oncolysis due to their ability to inhibit PKR-induced translation blockage, allowing virion release and cell death. PMID:27486347

  4. Oncogenes: The Passport for Viral Oncolysis Through PKR Inhibition

    PubMed Central

    Fernandes, Janaina

    2016-01-01

    The transforming properties of oncogenes are derived from gain-of-function mutations, shifting cell signaling from highly regulated homeostatic to an uncontrolled oncogenic state, with the contribution of the inactivating mutations in tumor suppressor genes P53 and RB, leading to tumor resistance to conventional and target-directed therapy. On the other hand, this scenario fulfills two requirements for oncolytic virus infection in tumor cells: inactivation of tumor suppressors and presence of oncoproteins, also the requirements to engage malignancy. Several of these oncogenes have a negative impact on the main interferon antiviral defense, the double-stranded RNA-activated protein kinase (PKR), which helps viruses to spontaneously target tumor cells instead of normal cells. This review is focused on the negative impact of overexpression of oncogenes on conventional and targeted therapy and their positive impact on viral oncolysis due to their ability to inhibit PKR-induced translation blockage, allowing virion release and cell death. PMID:27486347

  5. Avalanche multiplication and impact ionization in amorphous selenium photoconductive target

    NASA Astrophysics Data System (ADS)

    Park, Wug-Dong; Tanioka, Kenkichi

    2014-03-01

    The avalanche multiplication factor and the hole ionization coefficient in the amorphous selenium (a-Se) high-gain avalanche rushing amorphous photoconductor (HARP) target depend on the electric field. The phenomenon of avalanche multiplication and impact ionization in the 0.4-µm-thick a-Se HARP target is investigated. The hot carrier energy in the 0.4-µm-thick a-Se HARP target increases linearly as the target voltage increases. The energy relaxation length of hot carriers in the a-Se photoconductor of the 0.4-µm-thick HARP target saturates as the electric field increases. The average energy Eav of a hot carrier and the energy relaxation length λE in the a-Se photoconductor of the 0.4-µm-thick HARP target at 1 × 108 V/m were 0.25 eV and 2.5 nm, respectively. In addition, the hole ionization coefficient β and the avalanche multiplication factor M are derived as a function of the electric field, the average energy of a hot carrier, and the impact ionization energy. The experimental hole ionization coefficient β and the avalanche multiplication factor M in the 0.4-µm-thick a-Se HARP target agree with the theoretical results.

  6. Calculated concrete target damage by multiple rod impact and penetration

    SciTech Connect

    Pincosy, P A; Murphy, M J

    2006-12-29

    The effect of enhanced crater formation has been demonstrated experimentally when multiple and delayed shaped charge jets impact and penetrate concrete. The concept for enhancement utilizes a single follow-on jet at the centerline of holes produced by multiple precursor jets penetrating the surrounding the region. Calculations of the 3D crater enhancement phenomena have been conducted with multiple rods to simulate the steady state portion of the multiple jet penetration process. It is expected that this analysis methodology will be beneficial for optimization of the multiple jet crater enhancement application. We present calculated results using ALE3D where the model uses the standard Gruneisen equation of state combined with a rate dependent strength model including material damage parameters. This study focuses on the concrete material damage model as a representation of the portion of the target that would eventually be ejected creating a large bore-hole. The calculations are compared with the experimental evidence and limitations of the modeling approach are discussed.

  7. Silent assassin: oncogenic ras directs epigenetic inactivation of target genes.

    PubMed

    Cheng, Xiaodong

    2008-01-01

    Oncogenic transformation is associated with genetic changes and epigenetic alterations. A study now shows that oncogenic Ras uses a complex and elaborate epigenetic silencing program to specifically repress the expression of multiple unrelated cancer-suppressing genes through a common pathway. These results suggest that cancer-related epigenetic modifications may arise through a specific and instructive mechanism and that genetic changes and epigenetic alterations are intimately connected and contribute to tumorigenesis cooperatively. PMID:18385037

  8. Oncogenic Ras stimulates Eiger/TNF exocytosis to promote growth

    PubMed Central

    Chabu, Chiswili; Xu, Tian

    2014-01-01

    Oncogenic mutations in Ras deregulate cell death and proliferation to cause cancer in a significant number of patients. Although normal Ras signaling during development has been well elucidated in multiple organisms, it is less clear how oncogenic Ras exerts its effects. Furthermore, cancers with oncogenic Ras mutations are aggressive and generally resistant to targeted therapies or chemotherapy. We identified the exocytosis component Sec15 as a synthetic suppressor of oncogenic Ras in an in vivo Drosophila mosaic screen. We found that oncogenic Ras elevates exocytosis and promotes the export of the pro-apoptotic ligand Eiger (Drosophila TNF). This blocks tumor cell death and stimulates overgrowth by activating the JNK-JAK-STAT non-autonomous proliferation signal from the neighboring wild-type cells. Inhibition of Eiger/TNF exocytosis or interfering with the JNK-JAK-STAT non-autonomous proliferation signaling at various steps suppresses oncogenic Ras-mediated overgrowth. Our findings highlight important cell-intrinsic and cell-extrinsic roles of exocytosis during oncogenic growth and provide a new class of synthetic suppressors for targeted therapy approaches. PMID:25411211

  9. Experimental study on impact disruption of porous asteroids: Effects of oblique impact and multiple collisions on impact strength

    NASA Astrophysics Data System (ADS)

    Yasui, Minami; Takano, Shota; Matsue, Kazuma; Arakawa, Masahiko

    2015-08-01

    Most of asteroids would have pores and a plenty of pre-cracks in their interiors, and the pre-cracks could be formed by multiple impacts at various impact angles. Porosity and pre-cracks are important physical properties controlling the impact strength. Okamoto and Arakawa (2009) did impact experiments of porous gypsum spheres to obtain the impact strength of porous asteroids, but they carried out only single impact experiments on the same target at head-on. In this study, we conducted oblique impact and multiple impacts on porous gypsum and examined the effects of impact angle and pre-cracks on the impact strength.We carried out impact experiments by using the one-stage He gas gun and the two-stage H2 gas gun at Kobe University. The impact velocities were <200 m/s (low-vi) and >3 km/s (high-vi). Targets were porous gypsum spheres with the porosity of 55% and the diameters of 7 or 12 cm. The projectiles were a porous gypsum sphere with the diameter of 2.5 cm at low-vi or a polycarbonate sphere with the diameter of 4.7 cm at high-vi. The impact angle changed from 15° to 90°, and the projectile was impacted on the same target for 2-15 times. The impact phenomena were observed by a high-speed digital video camera to measure the fragment velocities.The oblique impact experiments showed that the impact strength did not depend on the impact angle θ between 45° and 90°, and obtained to be ~2000 J/kg, while it drastically changed at the θ from 15° to 30°. We reanalyzed our results by using the effective energy density defined as Qsin2θ, where Q is the energy density, and found that most of the results were consistent with the results of head-on impacts. The multiple impacts showed that the impact strength of pre-impacted targets was larger than that of intact targets in the case of low-vi. This might be caused by the compaction of the target surface. In the case of high-vi, the impact strength of pre-impacted targets was smaller than that of intact targets. This

  10. Artesunate suppresses tumor growth and induces apoptosis through the modulation of multiple oncogenic cascades in a chronic myeloid leukemia xenograft mouse model.

    PubMed

    Kim, Chulwon; Lee, Jong Hyun; Kim, Sung-Hoon; Sethi, Gautam; Ahn, Kwang Seok

    2015-02-28

    Artesunate (ART), a semi-synthetic derivative of artemisinin, is one of the most commonly used anti-malarial drugs. Also, ART possesses anticancer potential albeit through incompletely understood molecular mechanism(s). Here, the effect of ART on various protein kinases, associated gene products, cellular response, and apoptosis was investigated. The in vivo effect of ART on the growth of human CML xenograft tumors in athymic nu/nu mice was also examined. In our preliminary experiments, we first observed that phosphorylation of p38, ERK, CREB, Chk-2, STAT5, and RSK proteins were suppressed upon ART exposure. Interestingly, ART induced the expression of SOCS-1 protein and depletion of SOCS-1 using siRNA abrogated the STAT5 inhibitory effect of the drug. Also various dephosphorylations caused by ART led to the suppression of various survival gene products and induced apoptosis through caspase-3 activation. Moreover, ART also substantially potentiated the apoptosis induced by chemotherapeutic agents. Finally, when administered intraperitoneally, ART inhibited p38, ERK, STAT5, and CREB activation in tumor tissues and the growth of human CML xenograft tumors in mice without exhibiting any significant adverse effects. Overall, our results suggest that ART exerts its anti-proliferative and pro-apoptotic effects through suppression of multiple signaling cascades in CML both in vitro and in vivo. PMID:25738364

  11. Artesunate suppresses tumor growth and induces apoptosis through the modulation of multiple oncogenic cascades in a chronic myeloid leukemia xenograft mouse model

    PubMed Central

    Kim, Chulwon; Lee, Jong Hyun; Kim, Sung-Hoon; Sethi, Gautam; Ahn, Kwang Seok

    2015-01-01

    Artesunate (ART), a semi-synthetic derivative of artemisinin, is one of the most commonly used anti-malarial drugs. Also, ART possesses anticancer potential albeit through incompletely understood molecular mechanism(s). Here, the effect of ART on various protein kinases, associated gene products, cellular response, and apoptosis was investigated. The in vivo effect of ART on the growth of human CML xenograft tumors in athymic nu/nu mice was also examined. In our preliminary experiments, we first observed that phosphorylation of p38, ERK, CREB, Chk-2, STAT5, and RSK proteins were suppressed upon ART exposure. Interestingly, ART induced the expression of SOCS-1 protein and depletion of SOCS-1 using siRNA abrogated the STAT5 inhibitory effect of the drug. Also various dephosphorylations caused by ART led to the suppression of various survival gene products and induced apoptosis through caspase-3 activation. Moreover, ART also substantially potentiated the apoptosis induced by chemotherapeutic agents. Finally, when administered intraperitoneally, ART inhibited p38, ERK, STAT5, and CREB activation in tumor tissues and the growth of human CML xenograft tumors in mice without exhibiting any significant adverse effects. Overall, our results suggest that ART exerts its anti-proliferative and pro-apoptotic effects through suppression of multiple signaling cascades in CML both in vitro and in vivo. PMID:25738364

  12. Single and multiple impact ignition of new and aged high explosives in the Steven Impact Test

    SciTech Connect

    Chidester, S K; DePiero, A H; Garza, R G; Tarver, C M

    1999-06-01

    Threshold impact velocities for ignition of exothermic reaction were determined for several new and aged HMX-based solid high explosives using three types of projectiles in the Steven Test. Multiple impact threshold velocities were found to be approximately 10% lower in damaged charges that did not react in one or more prior impacts. Projectiles with protrusions that concentrate the friction work in a small volume of explosive reduced the threshold velocities by approximately 30%. Flat projectiles required nearly twice as high velocities for ignition as rounded projectiles. Blast overpressure gauges were used for both pristine and damaged charges to quantitatively measure reaction violence. Reactive flow calculations of single and multiple impacts with various projectiles suggest that the ignition rates double in damaged charges.

  13. Rasch analysis of the Multiple Sclerosis Impact Scale (MSIS-29)

    PubMed Central

    Ramp, Melina; Khan, Fary; Misajon, Rose Anne; Pallant, Julie F

    2009-01-01

    Background Multiple Sclerosis (MS) is a degenerative neurological disease that causes impairments, including spasticity, pain, fatigue, and bladder dysfunction, which negatively impact on quality of life. The Multiple Sclerosis Impact Scale (MSIS-29) is a disease-specific health-related quality of life (HRQoL) instrument, developed using the patient's perspective on disease impact. It consists of two subscales assessing the physical (MSIS-29-PHYS) and psychological (MSIS-29-PSYCH) impact of MS. Although previous studies have found support for the psychometric properties of the MSIS-29 using traditional methods of scale evaluation, the scale has not been subjected to a detailed Rasch analysis. Therefore, the objective of this study was to use Rasch analysis to assess the internal validity of the scale, and its response format, item fit, targeting, internal consistency and dimensionality. Methods Ninety-two persons with definite MS residing in the community were recruited from a tertiary hospital database. Patients completed the MSIS-29 as part of a larger study. Rasch analysis was undertaken to assess the psychometric properties of the MSIS-29. Results Rasch analysis showed overall support for the psychometric properties of the two MSIS-29 subscales, however it was necessary to reduce the response format of the MSIS-29-PHYS to a 3-point response scale. Both subscales were unidimensional, had good internal consistency, and were free from item bias for sex and age. Dimensionality testing indicated it was not appropriate to combine the two subscales to form a total MSIS score. Conclusion In this first study to use Rasch analysis to fully assess the psychometric properties of the MSIS-29 support was found for the two subscales but not for the use of the total scale. Further use of Rasch analysis on the MSIS-29 in larger and broader samples is recommended to confirm these findings. PMID:19545445

  14. Principles of Cancer Therapy: Oncogene and Non-oncogene Addiction

    PubMed Central

    Luo, Ji; Solimini, Nicole L.; Elledge, Stephen J.

    2010-01-01

    Cancer is a complex collection of distinct genetic diseases united by common hallmarks. Here, we expand upon the classic hallmarks to include the stress phenotypes of tumorigenesis. We describe a conceptual framework of how oncogene and non-oncogene addictions contribute to these hallmarks and how they can be exploited through stress sensitization and stress overload to selectively kill cancer cells. In particular, we present evidence for a large class of non-oncogenes that are essential for cancer cell survival and present attractive drug targets. Finally, we discuss the path ahead to therapeutic discovery and provide theoretical considerations for combining orthogonal cancer therapies. PMID:19269363

  15. Principles of cancer therapy: oncogene and non-oncogene addiction.

    PubMed

    Luo, Ji; Solimini, Nicole L; Elledge, Stephen J

    2009-03-01

    Cancer is a complex collection of distinct genetic diseases united by common hallmarks. Here, we expand upon the classic hallmarks to include the stress phenotypes of tumorigenesis. We describe a conceptual framework of how oncogene and non-oncogene addictions contribute to these hallmarks and how they can be exploited through stress sensitization and stress overload to selectively kill cancer cells. In particular, we present evidence for a large class of non-oncogenes that are essential for cancer cell survival and present attractive drug targets. Finally, we discuss the path ahead to therapeutic discovery and provide theoretical considerations for combining orthogonal cancer therapies. PMID:19269363

  16. Impacts of multiple stressors during the establishment of fouling assemblages.

    PubMed

    Saloni, Silvia; Crowe, Tasman P

    2015-02-15

    Limited knowledge of the mechanisms through which multiple stressors affect communities and ecosystems limits capacity to predict their effects. Less clear is how stressors impact early colonization of newly available habitats due to scarcity of studies. The present study tested whether copper and freshwater input affect colonization of hard substrata independently or interactively and assessed differences in community respiration and total biomass among early stage assemblages which developed under different regimes of copper and freshwater input. While copper influenced effectively the colonization of individual species, freshwater effect was weak or null. Apart from a significant effect on total community composition, the interactive effect between stressors was weak and mainly driven by antagonistic interactions between copper and water flow. Total biomass and respiration of the community studied were not affected by stressors. These findings contradict the expectation that changes in community structure are likely to cause changes in functioning. PMID:25563931

  17. The Expected Impact of Multiple Scattering on ATLID Signals

    NASA Astrophysics Data System (ADS)

    Donovan, D. P.

    2016-06-01

    ATLID stands for "ATmospheric LIDar" and is the lidar to be flown on the Earth Clouds and Radiation Explorer (EarthCARE) platform in 2018. ATLID is a High-Spectral Resolution (HSRL) system operating at 355nm with a narrower field-of-view and lower orbit than the CALIPSO lidar. In spite of the smaller footprint multiple-scattering (MS) will have an important impact on ATLID cloud signals and, in some aspects, the accurate treatment of MS will be more important for ATLID than CALIPSO. On the other hand, the relationship between integrated backscatter and integrated MS induced depolarization in water clouds will be similar between ATLID and CALIPSO indicating that a CALIPSO-like strategy for cloud-phase identification can be successfully applied to ATLID.

  18. Inhibition of oncogenic epidermal growth factor receptor kinase triggers release of exosome-like extracellular vesicles and impacts their phosphoprotein and DNA content.

    PubMed

    Montermini, Laura; Meehan, Brian; Garnier, Delphine; Lee, Wan Jin; Lee, Tae Hoon; Guha, Abhijit; Al-Nedawi, Khalid; Rak, Janusz

    2015-10-01

    Cancer cells emit extracellular vesicles (EVs) containing unique molecular signatures. Here, we report that the oncogenic EGF receptor (EGFR) and its inhibitors reprogram phosphoproteomes and cargo of tumor cell-derived EVs. Thus, phosphorylated EGFR (P-EGFR) and several other receptor tyrosine kinases can be detected in EVs purified from plasma of tumor-bearing mice and from conditioned media of cultured cancer cells. Treatment of EGFR-driven tumor cells with second generation EGFR kinase inhibitors (EKIs), including CI-1033 and PF-00299804 but not with anti-EGFR antibody (Cetuximab) or etoposide, triggers a burst in emission of exosome-like EVs containing EGFR, P-EGFR, and genomic DNA (exo-gDNA). The EV release can be attenuated by treatment with inhibitors of exosome biogenesis (GW4869) and caspase pathways (ZVAD). The content of P-EGFR isoforms (Tyr-845, Tyr-1068, and Tyr-1173), ERK, and AKT varies between cells and their corresponding EVs and as a function of EKI treatment. Immunocapture experiments reveal the presence of EGFR and exo-gDNA within the same EV population following EKI treatment. These findings suggest that targeted agents may induce cancer cells to change the EV emission profiles reflective of drug-related therapeutic stress. We suggest that EV-based assays may serve as companion diagnostics for targeted anticancer agents. PMID:26272609

  19. Multiple-Instruction, Multiple-Data Path Computers: Parallel Processing Impact on Flight Simulation Software. Final Report.

    ERIC Educational Resources Information Center

    Lord, Robert E.; And Others

    The purpose of this study was to evaluate the parallel processing impact of multiple-instruction multiple-data path (MIMD) computers on flight simulation software. Basic mathematical functions and arithmetic expressions from typical flight simulation software were selected and run on an MIMD computer to evaluate the improvement in execution time…

  20. Comprehensive analysis of HPV16 integration in OSCC reveals no significant impact of physical status on viral oncogene and virally disrupted human gene expression.

    PubMed

    Olthof, Nadine C; Speel, Ernst-Jan M; Kolligs, Jutta; Haesevoets, Annick; Henfling, Mieke; Ramaekers, Frans C S; Preuss, Simon F; Drebber, Uta; Wieland, Ulrike; Silling, Steffi; Lam, Wan L; Vucic, Emily A; Kremer, Bernd; Klussmann, Jens-P; Huebbers, Christian U

    2014-01-01

    Infection with high-risk human papillomavirus (HPV) type 16 is an independent risk factor for the development of oropharyngeal squamous cell carcinomas (OSCC). However, it is unclear whether viral integration is an essential hallmark in the carcinogenic process of OSCC and whether HPV integration correlates with the level of viral gene transcription and influences the expression of disrupted host genes. We analyzed 75 patients with OSCC. HPV16-positivity was proven by p16(INK4A) immunohistochemistry, PCR and FISH. Viral integration was examined using DIPS- as well as APOT-PCR. Viral E2, E6 and E7 gene expression levels were quantified by quantitative reverse transcriptase (RT-q)PCR. Expression levels of 7 human genes disrupted by the virus were extracted from mRNA expression profiling data of 32 OSCCs. Viral copy numbers were assessed by qPCR in 73 tumors. We identified 37 HPV16-human fusion products indicating viral integration in 29 (39%) OSCC. In the remaining tumors (61%) only episome-derived PCR products were detected. When comparing OSCC with or without an integration-derived fusion product, we did not find significant differences in the mean RNA expression of viral genes E2, E6 and E7 or the viral copy numbers per cell, nor did the RNA expression of the HPV-disrupted genes differ from either group of OSCC. In conclusion, our data do not support the hypothesis that integration affects the levels of viral and/or HPV-disrupted human gene transcripts. Thus constitutive, rather than a high level, of expression of oncogene transcripts appears to be required in HPV-related OSCC. PMID:24586376

  1. [Multiple sclerosis: socioeconomic effects and impact on quality of life].

    PubMed

    Ayuso, Guillermo Izquierdo

    2014-12-01

    Multiple sclerosis (MS) is a disease of the central nervous system (CNS) that affects young adults. Survival is long, more than 35 years, and consequently the disease has a huge socioeconomic impact. The present article discusses the enormous difficulties of carrying out economic assessments in this field but also describes the advances made in research on this topic and the advantages of performing socioeconomic evaluations with increasingly sophisticated tools. We also discuss the need to quantify indirect and intangible costs to translate them into quality of life and subsequently into economic cost, expressed in euros in the case of Spain. The available data indicate that the enormous cost of the disease (1200 million euros per year) is due more to disability-related expenditure than to treatment, which-although expensive-does not represent more than 16-18% of the total expenditure (approximately 200 million euros per year). The increase represented by the cost of MS is not based on higher treatment expenditure but on an increase in the incidence and-especially-the prevalence of the disease. Above all, in the last few years, there has been a considerable rise in the percentage of patients with an indication for treatment. Reflection is therefore needed on the use of drug therapy in MS, since a saving in the most effective products seems to increase the overall cost of MS, while expenditure on these drugs represents a saving in the long-term. PMID:25732943

  2. TP53: an oncogene in disguise

    PubMed Central

    Soussi, T; Wiman, K G

    2015-01-01

    The standard classification used to define the various cancer genes confines tumor protein p53 (TP53) to the role of a tumor suppressor gene. However, it is now an indisputable fact that many p53 mutants act as oncogenic proteins. This statement is based on multiple arguments including the mutation signature of the TP53 gene in human cancer, the various gains-of-function (GOFs) of the different p53 mutants and the heterogeneous phenotypes developed by knock-in mouse strains modeling several human TP53 mutations. In this review, we will shatter the classical and traditional image of tumor protein p53 (TP53) as a tumor suppressor gene by emphasizing its multiple oncogenic properties that make it a potential therapeutic target that should not be underestimated. Analysis of the data generated by the various cancer genome projects highlights the high frequency of TP53 mutations and reveals that several p53 hotspot mutants are the most common oncoprotein variants expressed in several types of tumors. The use of Muller's classical definition of mutations based on quantitative and qualitative consequences on the protein product, such as ‘amorph', ‘hypomorph', ‘hypermorph' ‘neomorph' or ‘antimorph', allows a more meaningful assessment of the consequences of cancer gene modifications, their potential clinical significance, and clearly demonstrates that the TP53 gene is an atypical cancer gene. PMID:26024390

  3. Impact of Software Settings on Multiple-Breath Washout Outcomes

    PubMed Central

    Summermatter, Selina; Singer, Florian; Latzin, Philipp; Yammine, Sophie

    2015-01-01

    Background and Objectives Multiple-breath washout (MBW) is an attractive test to assess ventilation inhomogeneity, a marker of peripheral lung disease. Standardization of MBW is hampered as little data exists on possible measurement bias. We aimed to identify potential sources of measurement bias based on MBW software settings. Methods We used unprocessed data from nitrogen (N2) MBW (Exhalyzer D, Eco Medics AG) applied in 30 children aged 5–18 years: 10 with CF, 10 formerly preterm, and 10 healthy controls. This setup calculates the tracer gas N2 mainly from measured O2 and CO2concentrations. The following software settings for MBW signal processing were changed by at least 5 units or >10% in both directions or completely switched off: (i) environmental conditions, (ii) apparatus dead space, (iii) O2 and CO2 signal correction, and (iv) signal alignment (delay time). Primary outcome was the change in lung clearance index (LCI) compared to LCI calculated with the settings as recommended. A change in LCI exceeding 10% was considered relevant. Results Changes in both environmental and dead space settings resulted in uniform but modest LCI changes and exceeded >10% in only two measurements. Changes in signal alignment and O2 signal correction had the most relevant impact on LCI. Decrease of O2 delay time by 40 ms (7%) lead to a mean LCI increase of 12%, with >10% LCI change in 60% of the children. Increase of O2 delay time by 40 ms resulted in mean LCI decrease of 9% with LCI changing >10% in 43% of the children. Conclusions Accurate LCI results depend crucially on signal processing settings in MBW software. Especially correct signal delay times are possible sources of incorrect LCI measurements. Algorithms of signal processing and signal alignment should thus be optimized to avoid susceptibility of MBW measurements to this significant measurement bias. PMID:26167682

  4. Impact of Multiple Environmental Stresses on Wetland Vegetation Dynamics

    NASA Astrophysics Data System (ADS)

    Muneepeerakul, C. P.; Tamea, S.; Muneepeerakul, R.; Miralles-Wilhelm, F. R.; Rinaldo, A.; Rodriguez-Iturbe, I.

    2009-12-01

    This research quantifies the impacts of climate change on the dynamics of wetland vegetation under the effect of multiple stresses, such as drought, water-logging, shade and nutrients. The effects of these stresses are investigated through a mechanistic model that captures the co-evolving nature between marsh emergent plant species and their resources (water, nitrogen, light, and oxygen). The model explicitly considers the feedback mechanisms between vegetation, light and nitrogen dynamics as well as the specific dynamics of plant leaves, rhizomes, and roots. Each plant species is characterized by three independent traits, namely leaf nitrogen (N) content, specific leaf area, and allometric carbon (C) allocation to rhizome storage, which govern the ability to gain and maintain resources as well as to survive in a particular multi-stressed environment. The modeling of plant growth incorporates C and N into the construction of leaves and roots, whose amount of new biomass is determined by the dynamic plant allocation scheme. Nitrogen is internally recycled between pools of plants, litter, humus, microbes, and mineral N. The N dynamics are modeled using a parallel scheme, with the major modifications being the calculation of the aerobic and anoxic periods and the incorporation of the anaerobic processes. A simple hydrologic model with stochastic rainfall is used to describe the water level dynamics and the soil moisture profile. Soil water balance is evaluated at the daily time scale and includes rainfall, evapotranspiration and lateral flow to/from an external water body, with evapotranspiration loss equal to the potential value, governed by the daily average condition of atmospheric water demand. The resulting feedback dynamics arising from the coupled system of plant-soil-microbe are studied in details and species’ fitnesses in the 3-D trait space are compared across various rainfall patterns with different mean and fluctuations. The model results are then

  5. Impact of multiple births on late and moderate prematurity.

    PubMed

    Refuerzo, Jerrie S

    2012-06-01

    Multiple gestations have an increased risk of pregnancy complications compared with singletons. Delay in childbearing and assisted reproductive techniques have remained common reasons for the increase in multiple gestations over the last few decades. Higher rates of both spontaneous and indicated preterm birth in twins and triplets lead to a significant proportion of the moderate preterm birth and late preterm birth rates. The article is a review of the causes of preterm birth and morbidities associated with these pregnancies. PMID:22364678

  6. Erosion of metals by multiple impacts with water

    NASA Technical Reports Server (NTRS)

    Rudy, S. L.; Thiruvengadam, A.

    1971-01-01

    Investigation determines - relation between impact velocity and minimum number of impacts producing visible erosion, relation between high frequency fatigue stresses and number of cycles to failure, water-hammer stresses relation to high frequency endurance limit, erosion rate as exposure time function, and correlates experimental data with recent theory.

  7. The neural basis of stereotypic impact on multiple social categorization.

    PubMed

    Hehman, Eric; Ingbretsen, Zachary A; Freeman, Jonathan B

    2014-11-01

    Perceivers extract multiple social dimensions from another's face (e.g., race, emotion), and these dimensions can become linked due to stereotypes (e.g., Black individuals → angry). The current research examined the neural basis of detecting and resolving conflicts between top-down stereotypes and bottom-up visual information in person perception. Participants viewed faces congruent and incongruent with stereotypes, via variations in race and emotion, while neural activity was measured using fMRI. Hand movements en route to race/emotion responses were recorded using mouse-tracking to behaviorally index individual differences in stereotypical associations during categorization. The medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC) showed stronger activation to faces that violated stereotypical expectancies at the intersection of multiple social categories (i.e., race and emotion). These regions were highly sensitive to the degree of incongruency, exhibiting linearly increasing responses as race and emotion became stereotypically more incongruent. Further, the ACC exhibited greater functional connectivity with the lateral fusiform cortex, a region implicated in face processing, when viewing stereotypically incongruent (relative to congruent) targets. Finally, participants with stronger behavioral tendencies to link race and emotion stereotypically during categorization showed greater dorsolateral prefrontal cortex activation to stereotypically incongruent targets. Together, the findings provide insight into how conflicting stereotypes at the nexus of multiple social dimensions are resolved at the neural level to accurately perceive other people. PMID:25094016

  8. Prognostic Impact of Cytogenetic Abnormalities in Multiple Myeloma

    PubMed Central

    Jian, Yuan; Chen, Xiaolei; Zhou, Huixing; Zhu, Wanqiu; Liu, Nian; Geng, Chuanying; Chen, Wenming

    2016-01-01

    Abstract The identification of specific cytogenetic abnormalities by interphase fluorescence in situ hybridization (i-FISH) has become a routine procedure for prognostic stratification of multiple myeloma (MM) patients. In this study, the prognostic significance of cytogenetic abnormalities detected by interphase fluorescence in situ hybridization (iFISH) in 229 newly diagnosed multiple myeloma patients was retrospectively analyzed. Results showed that del (17p), t(4;14), and 1q21 gain were adverse predictors of progression-free survival (PFS). Patients who carried these cytogenetic abnormalities were more likely to have more adverse biological parameters and lower response rate. Multivariate analysis showed that del (17p), t(4;14), and 1q21 gain were statistically independent predictors of PFS, whereas del (17p) was also adverse predictor of overall survival. Multiple coexisting cytogenetic abnormalities also had a negative correlation with PFS. Bortezomib-based therapy could improve the rate and depth of response in patients with t(4;14) translocation and 1q21 gain. Autologous stem cell transplantation could improve, but not overcome the adverse prognostic effect of high-risk cytogenetic abnormalities. These results demonstrate that MM patients with iFISH abnormalities, especially del (17p), are more likely to have a poor prognosis. PMID:27175647

  9. Mutational patterns in oncogenes and tumour suppressors.

    PubMed

    Baeissa, Hanadi M; Benstead-Hume, Graeme; Richardson, Christopher J; Pearl, Frances M G

    2016-06-15

    All cancers depend upon mutations in critical genes, which confer a selective advantage to the tumour cell. Knowledge of these mutations is crucial to understanding the biology of cancer initiation and progression, and to the development of targeted therapeutic strategies. The key to understanding the contribution of a disease-associated mutation to the development and progression of cancer, comes from an understanding of the consequences of that mutation on the function of the affected protein, and the impact on the pathways in which that protein is involved. In this paper we examine the mutation patterns observed in oncogenes and tumour suppressors, and discuss different approaches that have been developed to identify driver mutations within cancers that contribute to the disease progress. We also discuss the MOKCa database where we have developed an automatic pipeline that structurally and functionally annotates all proteins from the human proteome that are mutated in cancer. PMID:27284061

  10. Oncogenicity of human N-ras oncogene and proto-oncogene introduced into retroviral vectors

    SciTech Connect

    Souyri, M.; Vigon, I.; Charon, M.; Tambourin, P. )

    1989-09-01

    The N-ras gene is the only member of the ras family which has never been naturally transduced into a retrovirus. In order to study the in vitro and in vivo oncogenicity of N-ras and to compare its pathogenicity to that of H-ras, the authors have inserted an activated or a normal form of human N-ras cDNA into a slightly modified Harvey murine sarcoma virus-derived vector in which the H-ras p21 coding region had been deleted. The resulting constructions were transfected into NIH 3T3 cells. The activated N-ras-containing construct (HSN) induced 10{sup 4} foci per {mu}g of DNA and was found to be as transforming as H-ras was. After infection of the transfected cells by either the ecotropic Moloney murine leukemia virus or the amphotropic 4070A helper viruses, rescued transforming viruses were injected into newborn mice. Both pseudotypes of HSN virus containing activated N-ras induced the typical Harvey disease with similar latency. However, they found that the virus which contained normal N-ras p21 (HSn) was also pathogenic and induced splenomegaly, lymphadenopathies, and sarcoma in mice after a latency of 3 to 7 weeks. In addition, Moloney murine leukemia virus pseudotypes of N-ras caused neurological disorders in 30% of the infected animals. These results differed markedly from those of previous experiments in which the authors had inserted the activated form of N-ras in the pSV(X) vector: the resulting SVN-ras virus was transforming on NIH 3T3 cells but was poorly oncogenic in vivo. Altogether, these data demonstrated unequivocally that N-ras is potentially as oncogenic as H-ras and that such oncogenic effect could depend on the vector environment.

  11. Electron impact multiple ionization cross sections of heavy ions

    NASA Astrophysics Data System (ADS)

    Zeng, Jiaolong; Liu, Pengfei; Dai, Jiayu; Yuan, Jianmin

    2014-05-01

    Cross sections of electron impact ionization are important in modeling both astrophysical and laboratory plasmas. For heavy ions, accurate determination of this microscopic physical quantity is difficult due to the complex atomic structure. At high incident electron energy, inner-shell excitation and ionization processes can occur, which will result in complicated decay including Auger and radiative decay processes. For deep inner-shell excitation and ionization, cascaded Auger processes are very likely. Under conditions of collisional ionization equilibrium, the balance of electron-ion recombination and electron impact single ionization determines the charge state distribution (CSD). Accurate CSD, which in turn determined by accurate cross sections, is very important in a wide regime of spectroscopic diagnostics to infer the physical conditions of plasmas such as the electron temperature, electron density, and elemental abundance. As an illustrative example, the cross sections from the ground configuration of Sn13+ in forming Sn13+, -Sn16+ are reported in detail. The contributions from the electron impact excitation, electron impact ionization and resonant excitation processes are included.

  12. Impacts of Multiple Stressors on Southern New England Salt Marshes

    EPA Science Inventory

    In the Northeastern U.S., salt marsh area is in decline. Low sediment supply combined with regionally high rates of sea level rise mean that future salt marsh survival depends primarily on biomass production and organic matter accumulation, which are impacted by high nutrient lo...

  13. Multiple Year Extension Program Outcomes & Impacts through Evaluation

    ERIC Educational Resources Information Center

    Hachfeld, Gary A.; Bau, David B.; Holcomb, C. Robert; Craig, J. William

    2013-01-01

    Dwindling public funding as well as greater competition for grant dollars create a challenge for Extension. For Extension to remain a financially viable organization, educators have to be able to produce substantive, measurable program outcomes and impacts. Evaluative data can inform program development and delivery, and helps administrators…

  14. An Approach for Addressing the Multiple Testing Problem in Social Policy Impact Evaluations

    ERIC Educational Resources Information Center

    Schochet, Peter Z.

    2009-01-01

    In social policy evaluations, the multiple testing problem occurs due to the many hypothesis tests that are typically conducted across multiple outcomes and subgroups, which can lead to spurious impact findings. This article discusses a framework for addressing this problem that balances Types I and II errors. The framework involves specifying…

  15. Emerging landscape of oncogenic signatures across human cancers

    PubMed Central

    Ciriello, Giovanni; Miller, Martin L; Aksoy, Bülent Arman; Senbabaoglu, Yasin; Schultz, Nikolaus; Sander, Chris

    2014-01-01

    Cancer therapy is challenged by the diversity of molecular implementations of oncogenic processes and by the resulting variation in therapeutic responses. Projects such as The Cancer Genome Atlas (TCGA) provide molecular tumor maps in unprecedented detail. The interpretation of these maps remains a major challenge. Here we distilled thousands of genetic and epigenetic features altered in cancers to ~500 selected functional events (SFEs). Using this simplified description, we derived a hierarchical classification of 3,299 TCGA tumors from 12 cancer types. The top classes are dominated by either mutations (M class) or copy number changes (C class). This distinction is clearest at the extremes of genomic instability, indicating the presence of different oncogenic processes. The full hierarchy shows functional event patterns characteristic of multiple cross-tissue groups of tumors, termed oncogenic signature classes. Targetable functional events in a tumor class are suggestive of class-specific combination therapy. These results may assist in the definition of clinical trials to match actionable oncogenic signatures with personalized therapies. PMID:24071851

  16. The Minority Report: Targeting the Rare Oncogenes in NSCLC

    PubMed Central

    McCoach, Caroline E.

    2014-01-01

    Lung cancer is still responsible for the highest number of cancer deaths worldwide. Despite this fact, significant progress has been made in the treatment of non-small cell lung cancer (NSCLC). Specifically, efforts to identify and treat genetic alterations (gene mutations, gene fusions, gene amplification events, etc.) that result in oncogenic drivers are now standard of care (EGFR and ALK) or an intense area of research. The most prevalent oncogenic drivers have likely already been identified; thus, there is now a focus on subgroups of tumors with less common genetic alterations. Interestingly, as we explore these less common mutations, we are discovering that many occur across other tumor types (i.e., non-lung cancer), further justifying their study. Furthermore, many studies have demonstrated that by searching broadly for multiple genetic alterations in large subsets of patients they are able to identify potentially targetable alterations in the majority of patients. Although individually, the rare oncogenic drivers subgroups may seem to occur too infrequently to justify their exploration, the fact that the majority of patients with NSCLC harbor a potentially actionable driver mutation within their tumors and the fact that different types of cancers often have the same oncogenic driver justifies this approach. PMID:25228144

  17. Brain atrophy in multiple sclerosis: therapeutic, cognitive and clinical impact.

    PubMed

    Rojas, Juan Ignacio; Patrucco, Liliana; Miguez, Jimena; Cristiano, Edgardo

    2016-03-01

    Multiple sclerosis (MS) was always considered as a white matter inflammatory disease. Today, there is an important body of evidence that supports the hypothesis that gray matter involvement and the neurodegenerative mechanism are at least partially independent from inflammation. Gray matter atrophy develops faster than white matter atrophy, and predominates in the initial stages of the disease. The neurodegenerative mechanism creates permanent damage and correlates with physical and cognitive disability. In this review we describe the current available evidence regarding brain atrophy and its consequence in MS patients. PMID:27050854

  18. Multiple ionization of atomic targets by proton impact

    SciTech Connect

    Toburen, L.H.; DuBois, R.D.; Manson S.T.

    1983-04-01

    The authors have combined experimental measurements of multiply charged ion production, doubly differential electron emission cross sections and Auger electron spectra produced in fast-proton noble-gas collisions with theoretical inner and outer shell ionization cross sections in an effort to provide a unified description of the ionization process. A detailed analysis is provided for 1-4 MeV proton ionization of krypton. Measured relative yields of Kr/sup +2/ and Kr/sup +3/ ions are in approximate agreement with the photoionization results of Krause and Carlson. If it is assumed that nearly half of the 3d vacancies created in Kr are filled through multiple (3dNNN) Auger transitions, the M-subshell ionization cross sections that are derived from Auger electron spectra are in good agreement with theoretical calculations. The measured absolute yields of Kr/sup +2/ and Kr/sup +3/ are, however, a factor of 2 smaller than those derived from the decay of inner shell vacancies. This discrepancy leads the authors to believe that multiple ionization in the intial interaction is a significant contribution to the observed yields.

  19. Combining Immunotherapy with Oncogene-Targeted Therapy: A New Road for Melanoma Treatment

    PubMed Central

    Aris, Mariana; Barrio, María Marcela

    2015-01-01

    Cutaneous melanoma arises from the malignant transformation of skin melanocytes; its incidence and mortality have been increasing steadily over the last 50 years, now representing 3% of total tumors. Once melanoma metastasizes, prognosis is somber and therapeutic options are limited. However, the discovery of prevalent BRAF mutations in at least 50% of melanoma tumors led to development of BRAF-inhibitors, and other drugs targeting the MAPK pathway including MEK-inhibitors, are changing this reality. These recently approved treatments for metastatic melanoma have made a significant impact on patient survival; though the results are shadowed by the appearance of drug-resistance. Combination therapies provide a rational strategy to potentiate efficacy and potentially overcome resistance. Undoubtedly, the last decade has also born a renaissance of immunotherapy, and encouraging advances in metastatic melanoma treatment are illuminating the road. Immune checkpoint blockades, such as CTLA-4 antagonist-antibodies, and multiple cancer vaccines are now invaluable arms of anti-tumor therapy. Recent work has brought to light the delicate relationship between tumor biology and the immune system. Host immunity contributes to the anti-tumor activity of oncogene-targeted inhibitors within a complex network of cytokines and chemokines. Therefore, combining immunotherapy with oncogene-targeted drugs may be the key to melanoma control. Here, we review ongoing clinical studies of combination therapies using both oncogene inhibitors and immunotherapeutic strategies in melanoma patients. We will revisit the preclinical evidence that tested sequential and concurrent schemes in suitable animal models and formed the basis for the current trials. Finally, we will discuss potential future directions of the field. PMID:25709607

  20. 3 Dimensional Diagnosis Unravelling Prognosis of Multiple Impacted Teeth – A Case Report

    PubMed Central

    Gopinath, Adusumilli; Reddy, Naveen Admala; Rohra, Mayur G

    2013-01-01

    Impaction of teeth results from the interplay between nature and nurture. Radiographs play an important role in assessment of both the location and the typing of impacted teeth. In general, periapical, occlusal, and/or panoramic radiographs are sufficient for providing the information required by the clinician. Recent advances in diagnostic imaging enables to visualize , diagnose and prognose the treatment outcome of the impacted teeth. This case report discusses the value of cone beam computerized tomography (CBCT) for evaluation of the critical parameters like bone thickness , tooth position and tooth morphology of multiple impacted teeth by 3 dimensional radiography – CBCT. In this report, we present a case of 27-year-old male patient with multiple missing teeth. Radiographs revealed multiple impacted permanent teeth, though medical and family history along with physical examination was not suggestive of any syndromes. Intraoral periapical radiograph, Orthopantomograph, Occlusal radiograph, Cone beam computed tomography were taken for the same patient to determine the exact position of multiple impacted teeth and prognose the treatment plan with the associated factors to impacted teeth. Cone beam computed tomography is an accurate modality to localize and determine the prognosing factors associated with multiple impacted teeth. Three-dimensional volumetric imaging might provide information for improved diagnosis and treatment plans, and ultimately result in more successful treatment outcomes and better care for patients. How to cite this article: Gopinath A, Reddy NA, Rohra MG. 3 Dimensional Diagnosis Unravelling Prognosis of Multiple Impacted Teeth – A Case Report. J Int Oral Health 2013; 5(4):78-83. PMID:24155625

  1. Layered tektites - A multiple impact origin for the Australasian tektites

    NASA Astrophysics Data System (ADS)

    Wasson, J. T.

    1991-02-01

    The mechanisms proposed for the origin of tektites from the Australasian field are examined using neutron activation data for twenty layered tektites and six splash tektites of known and widely separated sites of a field greater than 1140 km in length. Evidence is presented indicating that the layered tektites formed as sheets or pools of melt. It is argued that their distribution across a field greater than 1140 km in length is inconsistent with their formation in a single crater, and that many impact craters are required to account for their distribution across such a large field.

  2. Multiple ionization of atomic targets by proton impact

    SciTech Connect

    Toburen, L.H.; DuBois, R.D.; Manson, S.T.

    1982-10-01

    We have combined experimental measurements of multiply charged ion production, doubly differential electron emission cross sections and Auger electron spectra produced in fast proton noble-gas collisions with theoretical inner and outer shell ionization cross sections in an effort to provide a consistent description of the ionization process. A detailed analysis is provided for 1-4 MeV proton ionization of krypton. Our measured relative yields of Kr/sup +2/ and Kr/sup +3/ ions are in approximate agreement with photoionization results of Krause and Carlson. If we assume nearly half of the 3d vacancies created in Kr are filled through multiple (3 dNNN) Auger transitions, the M-subshell ionization cross sections that we derive from our Auger electron spectra are in good agreement with theoretical calculations. The absolute yields of Kr/sup +2/ and Kr/sup +3/ are, however, a factor of 2 smaller than the calculated values.

  3. The impacts of multiple stressors to model ecological structures

    SciTech Connect

    Landis, W.G.; Kelly, S.A.; Markiewicz, A.J.; Matthews, R.A.; Matthews, G.B.

    1995-12-31

    The basis of the community conditioning hypothesis is that ecological structures are the result of their unique etiology. Systems that have been exposed to a variety of stressors should reflect this history. The authors how conducted a series of microcosm experiments that can compare the effects of multiple stressors upon community dynamics. The microcosm protocols are derived from the Standardized Aquatic Microcosm (SAM) and have Lemma and additional protozoan species. Two multiple stressor experiments have been conducted. In an extended length SAM (ELSAM), two of four treatments were dosed with the turbine fuel JP-8 one week into the experiment. Two treatments were later exposed to the heat stress, one that had received jet fuel and one that had not. Similarly, an ELSAM was conducted with the second stressor being the further addition of JP-8 replacing the heat shock. Biological, physical and chemical data were analyzed with multivariate techniques including nonmetric clustering and association analysis. Space-time worms and phase diagrams were also employed to ascertain the dynamic relationships of variables identified as important by the multivariate techniques. The experiments do not result in a simple additive linear response to the additional stressor. Examination of the relative population dynamics reveal alterations in trajectories that suggest treatment related effects. As in previous single stressor experiments, recovery does not occur even after extended experimental periods. The authors are now attempting to measure the resulting trajectories, changes in similarity vectors and overall dynamics. However, community conditioning does appear to be an important framework in understanding systems with a heterogeneous array of stressors.

  4. (Oncogenic action of ionizing radiation)

    SciTech Connect

    Not Available

    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.

  5. Protein kinase Cι expression and oncogenic signaling mechanisms in cancer.

    PubMed

    Murray, Nicole R; Kalari, Krishna R; Fields, Alan P

    2011-04-01

    Accumulating evidence demonstrates that PKCι is an oncogene and prognostic marker that is frequently targeted for genetic alteration in many major forms of human cancer. Functional data demonstrate that PKCι is required for the transformed phenotype of lung, pancreatic, ovarian, prostate, colon, and brain cancer cells. Future studies will be required to determine whether PKCι is also an oncogene in the many other cancer types that also overexpress PKCι. Studies of PKCι using genetically defined models of tumorigenesis have revealed a critical role for PKCι in multiple stages of tumorigenesis, including tumor initiation, progression, and metastasis. Recent studies in a genetic model of lung adenocarcinoma suggest a role for PKCι in transformation of lung cancer stem cells. These studies have important implications for the therapeutic use of aurothiomalate (ATM), a highly selective PKCι signaling inhibitor currently undergoing clinical evaluation. Significant progress has been made in determining the molecular mechanisms by which PKCι drives the transformed phenotype, particularly the central role played by the oncogenic PKCι-Par6 complex in transformed growth and invasion, and of several PKCι-dependent survival pathways in chemo-resistance. Future studies will be required to determine the composition and dynamics of the PKCι-Par6 complex, and the mechanisms by which oncogenic signaling through this complex is regulated. Likewise, a better understanding of the critical downstream effectors of PKCι in various human tumor types holds promise for identifying novel prognostic and surrogate markers of oncogenic PKCι activity that may be clinically useful in ongoing clinical trials of ATM. PMID:20945390

  6. Gray matter damage in multiple sclerosis: Impact on clinical symptoms.

    PubMed

    van Munster, Caspar E P; Jonkman, Laura E; Weinstein, Henry C; Uitdehaag, Bernard M J; Geurts, Jeroen J G

    2015-09-10

    Traditionally, multiple sclerosis (MS) is considered to be a disease primarily affecting the white matter (WM). However, the development of some clinical symptoms such as cognitive impairment cannot be fully explained by the severity of WM pathology alone. During the past decades it became clear that gray matter (GM) damage of the brain is also of major importance in patients with MS. Thanks to improved magnetic resonance imaging techniques, the in vivo detection of GM pathology became possible, enabling a better understanding of the manifestation of various clinical symptoms, such as cognitive impairment. Using higher field strengths and specific sequences, detection of cortical lesions was increased. However, despite these improvements, visualization of cortical MS lesions remains difficult (only about 30-50% of histopathologically confirmed lesions can be detected at 7 Tesla magnetic resonance imaging (MRI)). Furthermore, more research is needed to understand the exact interplay of cortical lesions, GM atrophy and WM pathology in the development of clinical symptoms. In this review, we summarize the historical background that preceded current research and provide an overview of the current knowledge on clinical consequences of GM pathology in MS in terms of disability, cognitive impairment and other clinically important signs such as epileptic seizures. PMID:26164500

  7. Simulating feedback from nuclear clusters: the impact of multiple sources

    NASA Astrophysics Data System (ADS)

    Bourne, Martin A.; Power, Chris

    2016-02-01

    Nuclear star clusters (NCs) are found to exist in the centres of many galaxies and appear to follow scaling relations similar to those of supermassive black holes. Previous analytical work has suggested that such relations are a consequence of feedback-regulated growth. We explore this idea using high-resolution hydrodynamical simulations, focusing on the validity of the simplifying assumptions made in analytical models. In particular, we investigate feedback emanating from multiple stellar sources rather than from a single source, as is usually assumed, and show that collisions between shells of gas swept up by feedback leads to momentum cancellation and the formation of high-density clumps and filaments. This high-density material is resistant both to expulsion from the galaxy potential and to disruption by feedback; if it falls back on to the NC, we expect the gas to be available for further star formation or for feeding a central black hole. We also note that our results may have implications for the evolution of globular clusters and stellar clusters in high-redshift dark matter haloes.

  8. Eyjabakkajokull Glacial Landsystem, Iceland: Geomorphic Impact of Multiple Surges

    NASA Astrophysics Data System (ADS)

    Ingolfsson, O.; Schomacker, A.; Benediktsson, I.

    2013-12-01

    A new glacial geomorphological map of the Eyjabakkajökull forefield in Iceland is presented. The map covers c. 60 km2 and is based on high-resolution aerial photographs recorded in August 2008 as well as field checking. Landforms are manually registered in a geographical information system (ArcGIS) based on inspection of orthorectified imagery and digital elevation models of the area. We mapped subglacially streamlined landforms such as flutes and drumlins on the till plain, supraglacial landforms such as ice-cored moraine, pitted outwash, and concertina eskers, and ice-marginal landforms such as the large, multi-crested 1890 surge end moraine and smaller single-crested end moraines. The glaciofluvial landforms are represented by outwash plains, minor outwash fans, and sinuous eskers. Extramarginal sediments were also registered and consist mainly of old sediments in wetlands or locally weathered bedrock. Eyjabakkajökull has behaved as a surge-type glacier for 2200 years; hence, the mapped landforms originate from multiple surges. Landforms such as large glaciotectonic end moraines, hummocky moraine, long flutes, crevasse-fill ridges, and concertina eskers are characteristic for surge-type glaciers. The surging glacier landsystem of Eyjabakkajökull serves as a modern analog to the landsystems of terrestrial paleo-ice streams.

  9. Common and overlapping oncogenic pathways contribute to the evolution of acute myeloid leukemias

    PubMed Central

    Kvinlaug, Brynn T; Chan, Wai-In; Bullinger, Lars; Ramaswami, Mukundhan; Sears, Christopher; Foster, Donna; Lazic, Stanley E; Okabe, Rachel; Benner, Axel; Lee, Benjamin H; De Silva, Inusha; Valk, Peter JM; Delwel, Ruud; Armstrong, Scott A; Döhner, Hartmut; Gilliland, D Gary; Huntly, Brian JP

    2011-01-01

    Fusion oncogenes in acute myeloid leukemia (AML) promote self-renewal from committed progenitors, thereby linking transformation and self-renewal pathways. Like most cancers, AML is a genetically and biologically heterogeneous disease, but it is unclear whether transformation results from common or overlapping genetic programs acting downstream of multiple mutations, or by the engagement of unique genetic programs acting cooperatively downstream of individual mutations. This distinction is important, because the involvement of common programs would imply the existence of common molecular targets to treat AML, no matter which fusion oncogenes are involved. Here we demonstrate that the ability to promote self-renewal is a generalized property of leukemia-associated oncogenes. Disparate oncogenes initiated overlapping transformation and self-renewal gene expression programs, the common elements of which were defined in established leukemia stem cells from an animal model as well as from a large cohort of patients with differing AML subtypes, where they strongly predicted pathobiological character. Notably, individual genes commonly activated in these programs could partially phenocopy the self-renewal function of leukemia-associated oncogenes in committed murine progenitors. Further, they could generate AML following expression in murine bone marrow. In summary, our findings reveal the operation of common programs of self-renewal and transformation downstream of leukemia-associated oncogenes, suggesting mechanistically common therapeutic approaches to AML are likely to be possible, regardless of the identity of the driver oncogene involved. PMID:21505102

  10. Estrogen Signaling Multiple Pathways to Impact Gene Transcription

    PubMed Central

    Marino, Maria; Galluzzo, Paola; Ascenzi, Paolo

    2006-01-01

    Steroid hormones exert profound effects on cell growth, development, differentiation, and homeostasis. Their effects are mediated through specific intracellular steroid receptors that act via multiple mechanisms. Among others, the action mechanism starting upon 17β-estradiol (E2) binds to its receptors (ER) is considered a paradigmatic example of how steroid hormones function. Ligand-activated ER dimerizes and translocates in the nucleus where it recognizes specific hormone response elements located in or near promoter DNA regions of target genes. Behind the classical genomic mechanism shared with other steroid hormones, E2 also modulates gene expression by a second indirect mechanism that involves the interaction of ER with other transcription factors which, in turn, bind their cognate DNA elements. In this case, ER modulates the activities of transcription factors such as the activator protein (AP)-1, nuclear factor-κB (NF-κB) and stimulating protein-1 (Sp-1), by stabilizing DNA-protein complexes and/or recruiting co-activators. In addition, E2 binding to ER may also exert rapid actions that start with the activation of a variety of signal transduction pathways (e.g. ERK/MAPK, p38/MAPK, PI3K/AKT, PLC/PKC). The debate about the contribution of different ER-mediated signaling pathways to coordinate the expression of specific sets of genes is still open. This review will focus on the recent knowledge about the mechanism by which ERs regulate the expression of target genes and the emerging field of integration of membrane and nuclear receptor signaling, giving examples of the ways by which the genomic and non-genomic actions of ERs on target genes converge. PMID:18369406

  11. Impact of Multiple Factors on the Degree of Tinnitus Distress

    PubMed Central

    Brüggemann, Petra; Szczepek, Agnieszka J.; Rose, Matthias; McKenna, Laurence; Olze, Heidi; Mazurek, Birgit

    2016-01-01

    Objective: The primary cause of subjective tinnitus is a dysfunction of the auditory system; however, the degree of distress tinnitus causes depends largely on the psychological status of the patient. Our goal was to attempt to associate the grade of tinnitus-related distress with the psychological distress, physical, or psychological discomfort patients experienced, as well as potentially relevant social parameters, through a simultaneous analysis of these factors. Methods: We determined the level of tinnitus-related distress in 531 tinnitus patients using the German version of the tinnitus questionnaire (TQ). In addition, we used the Perceived Stress Questionnaire (PSQ); General Depression Scale Allgemeine Depression Skala (ADS), Berlin Mood Questionnaire (BSF); somatic symptoms inventory (BI), and SF-8 health survey as well as general information collected through a medical history. Results: The TQ score significantly correlated with a score obtained using PSQ, ADS, BSF, BI, and SF-8 alongside psychosocial factors such as age, gender, and marital status. The level of hearing loss and the auditory properties of the specific tinnitus combined with perceived stress and the degree of depressive mood and somatic discomfort of a patient were identified as medium-strong predictors of chronic tinnitus. Social factors such as gender, age, or marital status also had an impact on the degree of tinnitus distress. The results that were obtained were implemented in a specific cortical distress network model. Conclusions: Using a large representative sample of patients with chronic tinnitus permitted a simultaneous statistical measurement of psychometric and audiological parameters in predicting tinnitus distress. We demonstrate that single factors can be distinguished in a manner that explains their causative association and influence on the induction of tinnitus-related distress. PMID:27445776

  12. Doubly differential measurements for multiple ionization of argon by electron impact: Comparison with positron impact and photoionization

    SciTech Connect

    Santos, A.C.F.; Hasan, A.; Yates, T.; DuBois, R.D.

    2003-05-01

    Doubly differential cross sections for single and multiple ionization of Ar have been measured for 500, 750, and 1000 eV electron impact. The cross sections were measured as a function of projectile energy loss and scattering angle. The energy loss range was 0-85% of the initial projectile energy and scattering angles were between {+-}22 deg. The data were put on an absolute scale by normalizing to total ionization cross sections available in the literature and found to be in good agreement with the absolute electron impact cross sections from DuBois and Rudd. For 750 eV impact, a comparison was made between the present electron impact data and positron impact data obtained using the same experimental conditions. The same energy dependence and yields for single ionization were found for both electron and positron impact. On the other hand, the double- and triple-ionization yields are smaller for positron impact as compared to electron impact. Comparisons with photoionization data showed that for outer shell ionization the fractions of double and triple ionization of argon by photon impact are in quite good agreement with the present electron impact data.

  13. Cumulative Impact of HIV and Multiple Concurrent Human Papillomavirus Infections on the Risk of Cervical Dysplasia

    PubMed Central

    Adler, David H.; Wallace, Melissa; Bennie, Thola; Abar, Beau; Meiring, Tracy L.; Williamson, Anna-Lise; Bekker, Linda-Gail

    2016-01-01

    Infection with HIV is known to increase the risk of cervical cancer. In addition, evidence suggests that concurrent infection with multiple human papillomavirus (HPV) genotypes increases the risk of cervical dysplasia more than infection with a single HPV genotype. However, the impact of the combination of HIV coinfection and presence of multiple concurrent HPV infections on the risk of cervical dysplasia is uncertain. We compared the results of HPV testing and Pap smears between HIV-infected and HIV-uninfected young women to assess the cumulative impact of these two conditions. We found that both HIV and the presence of multiple concurrent HPV infections are associated with increased risk of associated Pap smear abnormality and that the impact of these two risk factors may be additive. PMID:26997954

  14. Cumulative Impact of HIV and Multiple Concurrent Human Papillomavirus Infections on the Risk of Cervical Dysplasia.

    PubMed

    Adler, David H; Wallace, Melissa; Bennie, Thola; Abar, Beau; Meiring, Tracy L; Williamson, Anna-Lise; Bekker, Linda-Gail

    2016-01-01

    Infection with HIV is known to increase the risk of cervical cancer. In addition, evidence suggests that concurrent infection with multiple human papillomavirus (HPV) genotypes increases the risk of cervical dysplasia more than infection with a single HPV genotype. However, the impact of the combination of HIV coinfection and presence of multiple concurrent HPV infections on the risk of cervical dysplasia is uncertain. We compared the results of HPV testing and Pap smears between HIV-infected and HIV-uninfected young women to assess the cumulative impact of these two conditions. We found that both HIV and the presence of multiple concurrent HPV infections are associated with increased risk of associated Pap smear abnormality and that the impact of these two risk factors may be additive. PMID:26997954

  15. Oncogenic Activities of Human Papillomaviruses

    PubMed Central

    McLaughlin-Drubin, Margaret E.; Münger, Karl

    2009-01-01

    Infectious etiologies for certain human cancers have long been suggested by epidemiological studies and studies with animals. Important support for this concept came from the discovery by Harald zur Hausen’s group that human cervical carcinoma almost universally contains certain “high-risk” human papillomavirus (HPV) types. Over the years, much has been learned about the carcinogenic activities of high-risk HPVs. These studies have revealed that two viral proteins, E6 and E7, that are consistently expressed in HPV-associated carcinomas, are necessary for induction and maintenance of the transformed phenotype. Hence, HPV-associated tumors are unique amongst human solid tumors in that they are universally caused by exposure to the same, molecularly defined oncogenic agents, and the molecular signal transduction pathways subverted by these viral transforming agents are frequently disrupted in other, non-virus associated human cancers. PMID:19540281

  16. A model for debris clouds produced by impact of hypervelocity projectiles on multiplate structures

    NASA Astrophysics Data System (ADS)

    Zhang, Qingming; Long, Renrong; Huang, Fenglei; Chen, Li; Fu, Yuesheng

    2008-11-01

    Hypervelocity impact of spherical and cylindrical projectiles on multipate shields at velocities between 4 and 6km/s was investigated experimentally. A model was developed to describe the motion of the debris clouds generated. Good agreement was obtained between the experimental and simulation results. The model is capable of predicting damage induced by the impact and can be applied to the optimization and design of multiplate shields.

  17. The Impact of Medical Conditions on the Support of Children with Profound Intellectual and Multiple Disabilities

    ERIC Educational Resources Information Center

    Zijlstra, H. P.; Vlaskamp, C.

    2005-01-01

    Background: The aim of this study was to analyse the impact of medical conditions of children with profound intellectual and multiple disabilities on the professional support they receive in centres for special education. Method: The medical files, the daily records and daily communication records between parents and professionals were reviewed…

  18. The Impact of Taiwan's University Multiple-Channel Entrance Policy on Student Learning Outcomes

    ERIC Educational Resources Information Center

    Hsiao-Fang, Lin

    2012-01-01

    This research explores the impact of Taiwan's university multiple-channel entrance policy on student learning outcomes, using quantitative research to look for differences in the learning experiences of third-year students who were admitted via different methods (examination and placement, application for admission, recommendation and selection,…

  19. The Impact of Learning Multiple Foreign Languages on Using Metacognitive Reading Strategies

    ERIC Educational Resources Information Center

    Razi, Salim

    2008-01-01

    This study aims primarily to investigate the impact of learning multiple foreign languages on the use of metacognitive reading strategies (MRSs) by foreign language teaching (FLT) department students. A number of factors such as gender, hand preference, class, and programme with reference to their belief orientation were also involved in the…

  20. Impact of arthritis and multiple chronic conditions on selected life domains - United States, 2013.

    PubMed

    Qin, Jin; Theis, Kristina A; Barbour, Kamil E; Helmick, Charles G; Baker, Nancy A; Brady, Teresa J

    2015-06-01

    About half of U.S. adults have at least one chronic health condition, and the prevalence of multiple (two or more) chronic conditions increased from 21.8% in 2001 to 25.5% in 2012. Chronic conditions profoundly affect quality of life, are leading causes of death and disability, and account for 86% of total health care spending. Arthritis is a common cause of disability, one of the most common chronic conditions, and is included in prevalent combinations of multiple chronic conditions. To determine the impact of having arthritis alone or as one of multiple chronic conditions on selected important life domains, CDC analyzed data from the 2013 National Health Interview Survey (NHIS). Having one or more chronic conditions was associated with significant and progressively higher prevalences of social participation restriction, serious psychological distress, and work limitations. Adults with arthritis as one of their multiple chronic conditions had higher prevalences of adverse outcomes on all three life domains compared with those with multiple chronic conditions but without arthritis. The high prevalence of arthritis, its common co-occurrence with other chronic conditions, and its significant adverse effect on life domains suggest the importance of considering arthritis in discussions addressing the effect of multiple chronic conditions and interventions needed to reduce that impact among researchers, health care providers, and policy makers. PMID:26042649

  1. Effect of multiple and delayed jet impact and penetration on concrete target borehole diameter

    SciTech Connect

    Murphy, M J; Baum, D W; Kuklo, R M; Simonson, S C

    2001-01-26

    The effect of multiple and delayed jet impact and penetration on the borehole diameter in concrete targets is discussed in this paper. A first-order principle of shaped-charge jet penetration is that target hole volume is proportional to the energy deposited in the target by the jet. This principle is the basis for the relation that target borehole diameter at any depth along the penetration path is proportional to the jet energy deposited in the target at that location. Our current research shows that the 'jet energy per unit hole volume constant' for concrete can be substantially altered by the use of multiple and delayed jet impacts. It has been shown that enhanced entrance crater formation results from the simultaneous impact and penetration of three shaped-charge jets. We now demonstrate that enhanced borehole diameter is also observed by the simultaneous impact and penetration of multiple shaped-charge jets followed by the delayed impact and penetration of a single shaped-charge jet.

  2. Targeting oncogenic Ras signaling in hematologic malignancies

    PubMed Central

    Ward, Ashley F.; Braun, Benjamin S.

    2012-01-01

    Ras proteins are critical nodes in cellular signaling that integrate inputs from activated cell surface receptors and other stimuli to modulate cell fate through a complex network of effector pathways. Oncogenic RAS mutations are found in ∼ 25% of human cancers and are highly prevalent in hematopoietic malignancies. Because of their structural and biochemical properties, oncogenic Ras proteins are exceedingly difficult targets for rational drug discovery, and no mechanism-based therapies exist for cancers with RAS mutations. This article reviews the properties of normal and oncogenic Ras proteins, the prevalence and likely pathogenic role of NRAS, KRAS, and NF1 mutations in hematopoietic malignancies, relevant animal models of these cancers, and implications for drug discovery. Because hematologic malignancies are experimentally tractable, they are especially valuable platforms for addressing the fundamental question of how to reverse the adverse biochemical output of oncogenic Ras in cancer. PMID:22898602

  3. Electron-impact multiple ionization of Ne, Ar, Kr and Xe

    NASA Astrophysics Data System (ADS)

    Montanari, C. C.; Miraglia, J. E.

    2014-05-01

    This work describes the multiple ionization cross sections of rare gases by electron-impact. We pay special attention to the high energy region (0.1-10 keV) where the direct ionization is a minor contribution and the post-collisional electron emission dominates the final target charge state. We report here electron-impact single to sextuple ionization cross sections and total ionization cross sections including direct and post-collisional processes, even in the total values. We use the continuum distorted wave and the first Born approximations adapted to describe light-particle impact, i.e. energy, mass and trajectory corrections are incorporated, the latter by considering the electron-target potential and by using the Abel transformation. Auger-type post-collisional contributions are included in the multinomial expansion through experimental branching ratios after single ionization events. Tabulations of these experimental branching ratios for all the orbitals of the four targets are included. Present results are compared with the large amount of electron-impact experimental data available. We have obtained a good description of the multiple-ionization measurements at high energies, where the post-collisional ionization dominates. At intermediate energies, our theoretical results show the correct tendency, with the electron-impact ionization cross sections being far below the proton-impact ones.

  4. Validity of Korean Versions of the Multiple Sclerosis Impact Scale and the Multiple Sclerosis International Quality of Life Questionnaire

    PubMed Central

    Huh, So-Young; Kim, Su-Hyun; Joung, Ae-Ran; Park, Kibyung; Kim, Woojun; Park, Min Su

    2014-01-01

    Background and Purpose Assessment of the health-related quality of life (HRQoL) is important in clinical evaluations of multiple sclerosis (MS) patients for quantifying the impact of illness and treatment on their daily lives. Although MS-specific HRQoL instruments have been used internationally, there are no data regarding HRQoL instruments specifically designed for patients with MS in Korea. The objective of this study was to determine the reliability and validity of the Korean Multiple Sclerosis Impact Scale (MSIS-29) and the Multiple Sclerosis International Quality of Life (MusiQoL) questionnaire. Methods Fifty-six patients with MS were recruited from June 2009 to February 2010 at the National Cancer Center in Korea. The original English versions of the MSIS-29 scale and the MusiQoL questionnaire were translated into Korean and evaluated for their acceptability, reliability, and validity. Results The patients wereaged 36.5±8.6 years (mean±SD; range, 20-56 years). Their score on the Expanded Disability Status Scale was 2.0±1.9 (mean; range, 0-7.5), and their disease duration was 5.2±4.7 years (mean±SD; range, 1-24 years). The Korean versions of the MSIS-29 and MusiQoL questionnaires showed satisfactory psychometric properties, including construct validity (item-internal consistencies of 0.59-0.95 and 0.59-0.92, respectively; item-discriminant validities of 95-100% and 93.8-100%), internal consistency (Cronbach's alpha coefficients of 0.96-0.97 and 0.77-0.96), reliability (intraclass correlation coefficients of 0.78-0.90 and 0.50-0.93), unidimensionality (Loevinger scalability coefficients of 0.70-0.78 and 0.63-0.90), and acceptability. External validity testing indicated the presence of significant correlations between similar aspects of the two questionnaires. Conclusions The Korean translated versions of the MSIS-29 and MusiQoL questionnaires demonstrated reliability and validity for measuring HRQoL in Korean patients with MS. PMID:24829601

  5. ER functions of oncogenes and tumor suppressors: Modulators of intracellular Ca(2+) signaling.

    PubMed

    Bittremieux, Mart; Parys, Jan B; Pinton, Paolo; Bultynck, Geert

    2016-06-01

    Intracellular Ca(2+) signals that arise from the endoplasmic reticulum (ER), the major intracellular Ca(2+)-storage organelle, impact several mitochondrial functions and dictate cell survival and cell death processes. Furthermore, alterations in Ca(2+) signaling in cancer cells promote survival and establish a high tolerance towards cell stress and damage, so that the on-going oncogenic stress does not result in the activation of cell death. Over the last years, the mechanisms underlying these oncogenic alterations in Ca(2+) signaling have started to emerge. An important aspect of this is the identification of several major oncogenes, including Bcl-2, Bcl-XL, Mcl-1, PKB/Akt, and Ras, and tumor suppressors, such as p53, PTEN, PML, BRCA1, and Beclin 1, as direct and critical regulators of Ca(2+)-transport systems located at the ER membranes, including IP3 receptors and SERCA Ca(2+) pumps. In this way, these proteins execute part of their function by controlling the ER-mitochondrial Ca(2+) fluxes, favoring either survival (oncogenes) or cell death (tumor suppressors). Oncogenic mutations, gene deletions or amplifications alter the expression and/or function of these proteins, thereby changing the delicate balance between oncogenes and tumor suppressors, impacting oncogenesis and favoring malignant cell function and behavior. In this review, we provided an integrated overview of the impact of the major oncogenes and tumor suppressors, often altered in cancer cells, on Ca(2+) signaling from the ER Ca(2+) stores. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen. PMID:26772784

  6. Urinary catheterization may not adversely impact quality of life in multiple sclerosis patients.

    PubMed

    James, Rebecca; Frasure, Heidi E; Mahajan, Sangeeta T

    2014-01-01

    Background. Multiple sclerosis (MS) healthcare providers (HCP) have undergone considerable educational efforts regarding the importance of evaluating and treating pelvic floor disorders, specifically, urinary dysfunction. However, limited data are available to determine the impact of catheterization on patient quality of life (QoL). Objectives. To describe the use of urinary catheterization among MS patients and determine the differences between those who report positive versus negative impact of this treatment on QoL. Methods. Patients were queried as part of the 2010 North American Research Committee On Multiple Sclerosis survey; topics included 1) urinary/bladder, bowel, or sexual problems; 2) current urine leakage; 3) current catheter use; 4) catheterizing and QoL. Results. Respondents with current urine leakage were 5143 (54.7%), of which 1201 reported current catheter use (12.8%). The types of catheters (intermittent self-catheterization and Foley catheter (indwelling and suprapubic)) did not differ significantly. Of the current catheter users, 304 (25.35%) respondents reported catheterization negatively impacting QoL, 629 (52.4%) reported a positive impact on QoL, and 223 (18.6%) reported neutral QoL. Conclusions. A large proportion of catheterized MS patients report negative or positive changes in QoL associated with urinary catheterization. Urinary catheterization does not appear to have a universally negative impact on patient QoL. PMID:25006498

  7. Nonsyndromic Bilateral Multiple Impacted Supernumerary Mandibular Third Molars: A Rare and Unusual Case Report

    PubMed Central

    Reddy, G. Siva Prasad; Reddy, G. V.; Krishna, I. Venkata; Regonda, Shravan Kumar

    2013-01-01

    A supernumerary tooth is that which is present additionally to the normal series and can be found in any region of the dental arch. An impacted tooth is defined as the one which is embedded in the alveolus, so that its eruption is prevented, or the tooth is locked in position by bone or the adjacent teeth. The occurrence of multiple supernumerary teeth in only one patient in the absence of an associated systemic condition or syndrome is considered as a rare phenomenon. The occurrence of supernumerary teeth in the lower molar region is rare. A prevalence of less than 2% of cases occurring in this region has been estimated. Their occurrence presents a clinical problem for orthodontists and oral surgeons. The cause, frequency, complications, and surgical operation of impacted teeth are always interesting subjects for study and research. An impacted tooth can result in caries, pulp disease, periapical and periodontal disease, temporomandibular joint disorder, infection of the fascial space, root resorption of the adjacent tooth, and even oral and maxillofacial tumours. The management of impacted wisdom teeth has changed over the past 20 years from removal of nonsymptomatic third molars to simple observation. The aim of this paper is to present a rare case of bilateral multiple impacted supernumerary mandibular third molars. PMID:23476818

  8. Experimental Impacts into Chondritic Targets. Part 1; Disruption of an L6 Chondrite by Multiple Impacts

    NASA Technical Reports Server (NTRS)

    Cintala, Mark J.; Horz, Friedrich

    2007-01-01

    A fragment of an L6 chondrite (ALH 85017,13) with an initial mass (M(sub 0)) of 464.1 g was the target in a series of experimental impacts in which the largest remaining fragment (M(sub R)) after each shot was impacted by a 3.18-mm ceramic sphere at a nominal speed of 2 km/s. This continued until the mass of the largest remaining piece was less than half the mass of the target presented to that shot (M(sub S)). Two chunks of Bushveldt gabbro with similar initial masses were also impacted under the same conditions until M(sub R) was less than half M(sub 0). The two gabbro targets required a total of 1.51x10(exp 7) and 1.75x10(exp 7) erg/g to attain 0.27 and 0.33 M(sub R)/M(sub 0), respectively; the chondrite, however, was considerably tougher, reaching 0.40 and 0.21 M(sub R)/M(sub 0) only after receiving 2.37x10(exp 7) and 3.10x10(exp 7) erg g-1, respectively. The combined ejecta and spallation products from the gabbro impacts were coarser than those from the chondrite and in sufficient quantities that the new surface areas exceeded those from the meteorite until the fifth shot in the chondrite series, which was the number of impacts required to disrupt each gabbro target (i.e., MR/M0 = 0.5). Unlike the behavior shown in previous regolith-evolution series, neither gabbro target produced an enhancement in the size fraction reflecting the mean size of the crystals composing the rock (about 3 mm), an effect possibly related to the width of the shock pulse. The original chondrite was so fine-grained and fractured, and the variance in its grain-size distribution so large, that effects related to grain-size were relegated to the <63- m fraction. Impacts into ALH 85017 produced abundant, fine-grained debris, but otherwise the slopes of its size distributions were comparable to those from other experiments involving natural and fabricated terrestrial targets. The characteristic slopes of the chondrite's size distributions, however, were notably more constant over the entire

  9. Simultaneous Multiple-Jet Impacts in Concrete-Experiments and Advanced Computational Simulations

    SciTech Connect

    Baum, D.W.; Kuklo, R.M.; Routh, J.W.; Simonson, S.C.

    1999-08-12

    The simultaneous impact of multiple shaped-charge jets on a concrete target has been observed experimentally to lead to the formation of a larger and deeper entrance crater than would be expected from the superposition of the craters of the individual jets. The problem has been modeled with the 3-D simulation code ALE3D, running on massively parallel processors. These calculations indicate that the enlarged damage area is the result of tensile stresses caused by the interactions among the pressure waves simultaneously emanating from the three impact sites. This phenomenon has the potential for enhancing the penetration of a follow-on projectile.

  10. Accounting for multiple sources of uncertainty in impact assessments: The example of the BRACE study

    NASA Astrophysics Data System (ADS)

    O'Neill, B. C.

    2015-12-01

    Assessing climate change impacts often requires the use of multiple scenarios, types of models, and data sources, leading to a large number of potential sources of uncertainty. For example, a single study might require a choice of a forcing scenario, climate model, bias correction and/or downscaling method, societal development scenario, model (typically several) for quantifying elements of societal development such as economic and population growth, biophysical model (such as for crop yields or hydrology), and societal impact model (e.g. economic or health model). Some sources of uncertainty are reduced or eliminated by the framing of the question. For example, it may be useful to ask what an impact outcome would be conditional on a given societal development pathway, forcing scenario, or policy. However many sources of uncertainty remain, and it is rare for all or even most of these sources to be accounted for. I use the example of a recent integrated project on the Benefits of Reduced Anthropogenic Climate changE (BRACE) to explore useful approaches to uncertainty across multiple components of an impact assessment. BRACE comprises 23 papers that assess the differences in impacts between two alternative climate futures: those associated with Representative Concentration Pathways (RCPs) 4.5 and 8.5. It quantifies difference in impacts in terms of extreme events, health, agriculture, tropical cyclones, and sea level rise. Methodologically, it includes climate modeling, statistical analysis, integrated assessment modeling, and sector-specific impact modeling. It employs alternative scenarios of both radiative forcing and societal development, but generally uses a single climate model (CESM), partially accounting for climate uncertainty by drawing heavily on large initial condition ensembles. Strengths and weaknesses of the approach to uncertainty in BRACE are assessed. Options under consideration for improving the approach include the use of perturbed physics

  11. An unusual presentation of generalized aggressive periodontitis with multiple impacted supernumerary teeth

    PubMed Central

    Salman, Arif; Meethil, Archana

    2012-01-01

    Aggressive periodontitis is a rare condition that progresses rapidly but affects only a small percentage of population. Most of the cases are familial. The presence of supernumerary teeth is also rather rare and often familial. Therefore, a concomitant presentation of aggressive periodontitis and supernumerary teeth in an individual has generated a great interest among clinicians. Here, we report a rare nonsyndromic case of generalized aggressive periodontitis with multiple impacted supernumerary teeth. PMID:22904664

  12. A model for multiple-drop-impact erosion of brittle solids

    NASA Technical Reports Server (NTRS)

    Engel, O. G.

    1971-01-01

    A statistical model for the multiple-drop-impact erosion of brittle solids was developed. An equation for calculating the rate of erosion is given. The development is not complete since two quantities that are needed to calculate the rate of erosion with use of the equation must be assessed from experimental data. A partial test of the equation shows that it gives results that are in good agreement with experimental observation.

  13. Oncogene Overdose: Too Much of a Bad Thing for Oncogene-Addicted Cancer Cells

    PubMed Central

    Amin, Amit Dipak; Rajan, Soumya S.; Groysman, Matthew J.; Pongtornpipat, Praechompoo; Schatz, Jonathan H.

    2015-01-01

    Acquired resistance to targeted inhibitors remains a major, and inevitable, obstacle in the treatment of oncogene-addicted cancers. Newer-generation inhibitors may help overcome resistance mutations, and inhibitor combinations can target parallel pathways, but durable benefit to patients remains elusive in most clinical scenarios. Now, recent studies suggest a third approach may be available in some cases—exploitation of oncogene overexpression that may arise to promote resistance. Here, we discuss the importance of maintaining oncogenic signaling at “just-right” levels in cells, with too much signaling, or oncogene overdose, being potentially as detrimental as too little. This is highlighted in particular by recent studies of mutant-BRAF in melanoma and the fusion kinase nucleophosmin–anaplastic lymphoma kinase (NPM–ALK) in anaplastic large cell lymphoma. Oncogene overdose may be exploitable to prolong tumor control through intermittent dosing in some cases, and studies of acute lymphoid leukemias suggest that it may be specifically pharmacologically inducible. PMID:26688666

  14. The RET oncogene in papillary thyroid carcinoma.

    PubMed

    Prescott, Jason D; Zeiger, Martha A

    2015-07-01

    Papillary thyroid carcinoma (PTC) is the most common form of thyroid cancer, accounting for greater than 80% of cases. Surgical resection, with or without postoperative radioiodine therapy, remains the standard of care for patients with PTC, and the prognosis is generally excellent with appropriate treatment. Despite this, significant numbers of patients will not respond to maximal surgical and medical therapy and ultimately will die from the disease. This mortality reflects an incomplete understanding of the oncogenic mechanisms that initiate, drive, and promote PTC. Nonetheless, significant insights into the pathologic subcellular events underlying PTC have been discovered over the last 2 decades, and this remains an area of significant research interest. Chromosomal rearrangements resulting in the expression of fusion proteins that involve the rearranged during transfection (RET) proto-oncogene were the first oncogenic events to be identified in PTC. Members of this fusion protein family (the RET/PTC family) appear to play an oncogenic role in approximately 20% of PTCs. Herein, the authors review the current understanding of the clinicopathologic role of RET/PTC fusion proteins in PTC development and progression and the molecular mechanisms by which RET/PTCs exert their oncogenic effects on the thyroid epithelium. PMID:25731779

  15. Perceived Impact of Spasticity Is Associated with Spatial and Temporal Parameters of Gait in Multiple Sclerosis

    PubMed Central

    Balantrapu, Swathi; Sandroff, Brian M.; Sosnoff, Jacob J.; Motl, Robert W.

    2012-01-01

    Background. Spasticity is prevalent and disabling in persons with multiple sclerosis (MS), and the development of the Multiple Sclerosis Spasticity Scale-88 (MSSS-88) provides an opportunity for examining the perceived impact of spasticity and its association with gait in this population. Purpose. This study examined the association between the perceived impact of spasticity and spatio-temporal parameters of gait in persons with MS. Methods. The sample included 44 adults with MS who completed the MSSS-88 and 4 walking trials on a 26-foot GAITRiteTM electronic walkway for measurement of spatio-temporal components of gait including velocity, cadence, base of support, step time, single support, double support, and swing phase. Results. The overall MSSS-88 score was significantly associated with velocity (r = −0.371), cadence (r = −0.306), base of support (r = 0.357), step time (r = 0.305), single leg support (r = −0.388), double leg support (r = 0.379), and swing phase (r = −0.386). Conclusions. The perceived impact of spasticity coincides with alterations of the spatio-temporal parameters of gait in MS. This indicates that subsequent interventions might target a decrease in spasticity or its perceived impact as an approach for improving mobility in MS. PMID:22462022

  16. The impact of embedding multiple modes of representation on student construction of chemistry knowledge

    NASA Astrophysics Data System (ADS)

    McDermott, Mark Andrew

    2009-12-01

    This study was designed to examine the impact of embedding multiple modes of representing science information on student conceptual understanding in science. Multiple representations refer to utilizing charts, graphs, diagrams, and other types of representations to communicate scientific information. This study investigated the impact of encouraging students to embed or integrate the multiple modes with text in end of unit writing-to-learn activities. A quasi-experimental design with four separate sites consisting of intact chemistry classes taught by different teachers at each site was utilized. At each site, approximately half of the classes were designated treatment classes and students in these classes participated in activities designed to encourage strategies to embed multiple modes within text in student writing. The control classes did not participate in these activities. All classes participated in identical end of unit writing tasks in which they were required to use at least one mode other than text, followed by identical end of unit assessments. This progression was then repeated for a second consecutive unit of study. Analysis of quantitative data indicated that in several cases, treatment classes significantly outperformed control classes both on measures of embeddedness in writing and on end of unit assessment measures. In addition, analysis at the level of individual students indicated significant positive correlations in many cases between measures of student embeddedness in writing and student performance on end of unit assessments. Three factors emerged as critical in increasing the likelihood of benefit for students from these types of activities. First, the level of teacher implementation and emphasis on the embeddedness lessons was linked to the possibility of conceptual benefit. Secondly, students participating in two consecutive lessons appeared to receive greater benefit during the second unit, inferring a cumulative benefit. Finally

  17. Epigenetic Pathways of Oncogenic Viruses: Therapeutic Promises.

    PubMed

    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. PMID:26754591

  18. Metabolic alterations accompanying oncogene-induced senescence

    PubMed Central

    Aird, Katherine M; Zhang, Rugang

    2014-01-01

    Senescence is defined as a stable cell growth arrest. Oncogene-induced senescence (OIS) occurs in normal primary human cells after activation of an oncogene in the absence of other cooperating oncogenic stimuli. OIS is therefore considered a bona fide tumor suppression mechanism in vivo. Indeed, overcoming OIS-associated stable cell growth arrest can lead to tumorigenesis. Although cells that have undergone OIS do not replicate their DNA, they remain metabolically active. A number of recent studies report significant changes in cellular metabolism during OIS, including alterations in nucleotide, glucose, and mitochondrial metabolism and autophagy. These alterations may be necessary for stable senescence-associated cell growth arrest, and overcoming these shifts in metabolism may lead to tumorigenesis. This review highlights what is currently known about alterations in cellular metabolism during OIS and the implication of OIS-associated metabolic changes in cellular transformation and the development of cancer therapeutic strategies. PMID:27308349

  19. Penetration and induced damage evolution of concrete and granite when subjected to multiple projectile impacts

    NASA Astrophysics Data System (ADS)

    Gomez, Jason Thomas

    An experimental study was conducted to investigate the penetration process of multiple impacts into concrete targets. The concrete targets were subjected to repeated constant velocity impacts with an ogive nose projectile. The penetration and crater formation data were consistent with single impact penetration data from previous studies conducted at Sandia National Laboratories. In order to predict the depth of the multiple impact penetration, a single impact penetration model, developed by M. Forrestal at Sandia National Laboratories, was extended to account for the degradation of the target strength with each subsequent impact. The degradation of the target was determined empirically and included in the model as a strength-modifying factor. To further understand the multiple impact penetration process, a study was conducted to look at both the static and dynamic properties of concrete and granite as a function of induced damage. Both static and dynamic compression experiments were performed on concrete and granite specimens with various levels of induced damage. The static compressive strength of both materials decreased with increasing levels of damage due to the induced damage causing the activation and propagation of failure cracks in the specimens. In contrast, the dynamic compressive strength remained unchanged with increasing damage due to the inability of the fracture process zone to develop and relieve the strain energy before complete specimen failure. A series of dynamic and static tensile-splitting experiments were performed on concrete and granite specimens to investigate the effect of induced damage on their tensile strength. The experiments showed that the static splitting strength was highly dependent on the orientation of the induced damage with regard to the applied loading, however the dynamic tensile strength decreased with increasing damage with no apparent dependency on the random damage orientation. Photoelastic experiments have shown that

  20. Evaluation of the response of aluminum alloys to single and multiple particle impacts

    SciTech Connect

    Keiser, J.R.; Rao, M.; Notre Dame Univ., IN )

    1989-01-01

    Samples of annealed 1100 aluminum and 7075-T6 aluminum were eroded to steady-state conditions in a multiple particle erosion system. The samples were sectioned through the eroded areas, and a mechanical properties microprobe was used to measure the hardness of the material. The oblique multiple particle impacts produced a rippled surface with the hardness at the top of the wave crests approximately equal to that in the valleys. However, the total depth of hardening was significantly greater in material below the wave crests and was a function of the material for both wave crests and valleys. The depth of hardened material below the wave crest was about equal to the height of the wave plus the depth of hardening below the valley. 23 refs., 5 figs.

  1. Stochastic responses of a viscoelastic-impact system under additive and multiplicative random excitations

    NASA Astrophysics Data System (ADS)

    Zhao, Xiangrong; Xu, Wei; Yang, Yongge; Wang, Xiying

    2016-06-01

    This paper deals with the stochastic responses of a viscoelastic-impact system under additive and multiplicative random excitations. The viscoelastic force is replaced by a combination of stiffness and damping terms. The non-smooth transformation of the state variables is utilized to transform the original system to a new system without the impact term. The stochastic averaging method is applied to yield the stationary probability density functions. The validity of the analytical method is verified by comparing the analytical results with the numerical results. It is invaluable to note that the restitution coefficient, the viscoelastic parameters and the damping coefficients can induce the occurrence of stochastic P-bifurcation. Furthermore, the joint stationary probability density functions with three peaks are explored.

  2. Impact experiments into multiple-mesh targets: Concept development of a lightweight collisional bumper

    NASA Technical Reports Server (NTRS)

    Hoerz, Friedrich; Cintala, Mark J.; Bernhard, Ronald P.; Cardenas, Frank; Davidson, William; Haynes, Gerald; See, Thomas H.; Winkler, Jerry; Gray, Barry

    1993-01-01

    The utility of multiple-mesh targets as potential lightweight shields to protect spacecraft in low-Earth orbit against collisional damage is explored. Earlier studies revealed that single meshes comminute hypervelocity impactors with efficiencies comparable to contiguous targets. Multiple interaction of projectile fragments with any number of meshes should lead to increased comminution, deceleration, and dispersion of the projectile, such that all debris exiting the mesh stack possesses low specific energies (ergs/sq cm) that would readily be tolerated by many flight systems. The study is conceptually exploring the sensitivity of major variables such as impact velocity, the specific areal mass (g/sq cm) of the total mesh stack (SM), and the separation distance (S) between individual meshes. Most experiments employed five or ten meshes with total SM typically less than 0.5 the specific mass of the impactor, and silicate glass impactors rather than metal projectiles. While projectile comminution increases with increasing impact velocity due to progressively higher shock stresses, encounters with multiple-meshes at low velocity (1-2 km/s) already lead to significant disruption of the glass impactors, with the resulting fragments being additionally decelerated and dispersed by subsequent meshes, and, unlike most contiguous single-plate bumpers, leading to respectable performance at low velocity. Total specific bumper mass must be the subject of careful trade-off studies; relatively massive bumpers will generate too much debris being dislodged from the bumper itself, while exceptionally lightweight designs will not cause sufficient comminution, deceleration, or dispersion of the impactor. Separation distance was found to be a crucial design parameter, as it controls the dispersion of the fragment cloud. Substantial mass savings could result if maximum separation distances were employed. The total mass of debris dislodged by multiple-mesh stacks is modestly smaller than

  3. Oncogenic viruses and hepatocellular carcinoma.

    PubMed

    Ben Ari, Ziv; Weitzman, Ella; Safran, Michal

    2015-05-01

    About 80% of hepatocellular carcinoma (HCC) is caused by hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections especially in the setting of established cirrhosis or advanced fibrosis, making HCC prevention a major goal of antiviral therapy. HCC tumors are highly complex and heterogeneous resulting from the aberrant function of multiple molecular pathways. The roles of HCV or HBV in promoting HCC development are still either directly or indirectly are still speculative, but the evidence for both effects is compelling. In patients with chronic hepatitis viral infection, cirrhosis is not a prerequisite for tumorigenesis. PMID:25921667

  4. Impacts of Climate Extremes on Gross Primary Productivity at Multiple Spatial Scales

    NASA Astrophysics Data System (ADS)

    Kim, Soyoun; Ryu, Youngryel; Jiang, Chongya

    2016-04-01

    Climate extreme events have made significant impacts on terrestrial carbon cycles. Recent studies on detection and attribution of climate extreme events and their impact on carbon cycles used coarse spatial resolution data such as 0.5 degree. The coarse resolution data might miss important climate extremes and their impacts on GPP. To fill this research gap, we use a new global GPP product derived from a process-based model, the Breathing Earth System Simulator (BESS). The BESS takes full advantages of MODIS/AVHRR land and atmosphere products, providing global GPP product in 1 km resolution from 2000 to 2015 and 1/12 degree resolution from 1982 to 1999. We first integrate the BESS GPP products to 0.5 degree (1982-2015) and apply the method of Zscheischler et al. (2013). To test the impacts of spatial resolutions on detecting extreme events, we enhance spatial resolutions of the BESS GPP from 0.5 degree to 0.25, 0.125, and 1/12 degrees and quantify the variations of areas which experienced climate extremes. We subsequently investigate hotspot regions where the extremes occur using fine resolution GPP data at 1/12 degree (1982-2015), then analyze the causes of the extreme events that substantially decreased GPP by using precipitation, air temperature, and frost. This study could improve the understanding of the relationship between climate extremes and the carbon cycle at multiple spatial scales.

  5. Combined Inactivation of MYC and K-Ras Oncogenes Reverses Tumorigenesis in Lung Adenocarcinomas and Lymphomas

    PubMed Central

    Koh, Shan; Komatsubara, Kim; Chen, Joy; Horng, George; Bellovin, David I.; Giuriato, Sylvie; Wang, Craig S.; Whitsett, Jeffrey A.; Felsher, Dean W.

    2008-01-01

    Background Conditional transgenic models have established that tumors require sustained oncogene activation for tumor maintenance, exhibiting the phenomenon known as “oncogene-addiction.” However, most cancers are caused by multiple genetic events making it difficult to determine which oncogenes or combination of oncogenes will be the most effective targets for their treatment. Methodology/Principal Findings To examine how the MYC and K-rasG12D oncogenes cooperate for the initiation and maintenance of tumorigenesis, we generated double conditional transgenic tumor models of lung adenocarcinoma and lymphoma. The ability of MYC and K-rasG12D to cooperate for tumorigenesis and the ability of the inactivation of these oncogenes to result in tumor regression depended upon the specific tissue context. MYC-, K-rasG12D- or MYC/K-rasG12D-induced lymphomas exhibited sustained regression upon the inactivation of either or both oncogenes. However, in marked contrast, MYC-induced lung tumors failed to regress completely upon oncogene inactivation; whereas K-rasG12D-induced lung tumors regressed completely. Importantly, the combined inactivation of both MYC and K-rasG12D resulted more frequently in complete lung tumor regression. To account for the different roles of MYC and K-rasG12D in maintenance of lung tumors, we found that the down-stream mediators of K-rasG12D signaling, Stat3 and Stat5, are dephosphorylated following conditional K-rasG12D but not MYC inactivation. In contrast, Stat3 becomes dephosphorylated in lymphoma cells upon inactivation of MYC and/or K-rasG12D. Interestingly, MYC-induced lung tumors that failed to regress upon MYC inactivation were found to have persistent Stat3 and Stat5 phosphorylation. Conclusions/Significance Taken together, our findings point to the importance of the K-Ras and associated down-stream Stat effector pathways in the initiation and maintenance of lymphomas and lung tumors. We suggest that combined targeting of oncogenic

  6. Variations in Multiple Birth Rates and Impact on Perinatal Outcomes in Europe

    PubMed Central

    Heino, Anna; Gissler, Mika; Hindori-Mohangoo, Ashna D.; Blondel, Béatrice; Klungsøyr, Kari; Verdenik, Ivan; Mierzejewska, Ewa; Velebil, Petr; Sól Ólafsdóttir, Helga; Macfarlane, Alison; Zeitlin, Jennifer

    2016-01-01

    Objective Infants from multiple pregnancies have higher rates of preterm birth, stillbirth and neonatal death and differences in multiple birth rates (MBR) exist between countries. We aimed to describe differences in MBR in Europe and to investigate the impact of these differences on adverse perinatal outcomes at a population level. Methods We used national aggregate birth data on multiple pregnancies, maternal age, gestational age (GA), stillbirth and neonatal death collected in the Euro-Peristat project (29 countries in 2010, N = 5 074 643 births). We also used European Society of Human Reproduction and Embryology (ESHRE) data on assisted conception and single embryo transfer (SET). The impact of MBR on outcomes was studied using meta-analysis techniques with random-effects models to derive pooled risk ratios (pRR) overall and for four groups of country defined by their MBR. We computed population attributable risks (PAR) for these groups. Results In 2010, the average MBR was 16.8 per 1000 women giving birth, ranging from 9.1 (Romania) to 26.5 (Cyprus). Compared to singletons, multiples had a nine-fold increased risk (pRR 9.4, 95% Cl 9.1–9.8) of preterm birth (<37 weeks GA), an almost 12-fold increased risk (pRR 11.7, 95% CI 11.0–12.4) of very preterm birth (<32 weeks GA). Pooled RR were 2.4 (95% Cl 1.5–3.6) for fetal mortality at or after 28 weeks GA and 7.0 (95% Cl 6.1–8.0) for neonatal mortality. PAR of neonatal death and very preterm birth were higher in countries with high MBR compared to low MBR (17.1% (95% CI 13.8–20.2) versus 9.8% (95% Cl 9.6–11.0) for neonatal death and 29.6% (96% CI 28.5–30.6) versus 17.5% (95% CI 15.7–18.3) for very preterm births, respectively). Conclusions Wide variations in MBR and their impact on population outcomes imply that efforts by countries to reduce MBR could improve perinatal outcomes, enabling better long-term child health. PMID:26930069

  7. Impact of Natalizumab on Ambulatory Improvement in Secondary Progressive and Disabled Relapsing-Remitting Multiple Sclerosis

    PubMed Central

    Cadavid, Diego; Jurgensen, Stephanie; Lee, Sophia

    2013-01-01

    Background There is an unmet need for disease-modifying therapies to improve ambulatory function in disabled subjects with multiple sclerosis. Objectives: Assess the effects of natalizumab on ambulatory function in disabled subjects with relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS). Methods We retrospectively reviewed ambulatory function as measured by timed 25-foot walk (T25FW) in clinical trial subjects with an Expanded Disability Status Scale score ≥3.5, including RRMS subjects from the phase 3 AFFIRM and SENTINEL trials, relapsing SPMS subjects from the phase 2 MS231 study, and nonrelapsing SPMS subjects from the phase 1b DELIVER study. For comparison, SPMS subjects from the intramuscular interferon beta-1a (IM IFNβ-1a) IMPACT study were also analyzed. Improvement in ambulation was measured using T25FW responder status; response was defined as faster walking times over shorter (6–9-month) or longer (24–30-month) treatment periods relative to subjects’ best predose walking times. Results There were two to four times more T25FW responders among disabled MS subjects in the natalizumab arms than in the placebo or IM IFNβ-1a arms. Responders walked 25 feet an average of 24%–45% faster than nonresponders. Conclusion Natalizumab improves ambulatory function in disabled RRMS subjects and may have efficacy in disabled SPMS subjects. Confirmation of the latter finding in a prospective SPMS study is warranted. PMID:23308186

  8. Impact of natalizumab on patient-reported outcomes in multiple sclerosis: a longitudinal study

    PubMed Central

    2012-01-01

    Background Natalizumab (Tysabri, Biogen Idec and Elan Pharmaceuticals) significantly reduces the relapse rate and disability progression, and improves health-related quality of life (HRQoL), in patients with relapsing-remitting multiple sclerosis. We investigated the impact of natalizumab on patient-reported outcomes (PROs) in a real-world setting. Methods PRO data were collected from patients enrolled in a longitudinal real-world study using validated measures administered as surveys before the patients initiated natalizumab treatment and after the 3rd, 6th, and 12th monthly infusion. HRQoL, ability to carry out daily activities, disability level, and impact on cognitive functioning and fatigue were assessed. Results A total of 333 patients completed 12 months of assessments. After 12 months of natalizumab treatment, 69% to 88% of patients reported a positive outcome (either an improvement or no further decline) in all PRO measures assessed. Significant improvements in general and disease-specific HRQoL were observed after three infusions, both with physical (p < .01) and psychological (p < .001) measures, and were sustained after 12 infusions (all p < .001). The impact of multiple sclerosis on cognitive functioning and fatigue was significantly reduced (both p < .001 after 3 and 12 infusions). Conclusions PRO measures were improved with natalizumab in a real-world setting. The improvements were observed as early as after 3 months and sustained over a 12-month period. The improvements in PROs show that, in clinical practice, the clinical benefits of natalizumab are translated into patient-reported benefits. PMID:23270428

  9. Impact of comorbidity on fatigue management intervention outcomes among people with multiple sclerosis: an exploratory investigation.

    PubMed

    Finlayson, Marcia; Preissner, Katharine; Cho, Chi

    2013-01-01

    This exploratory secondary analysis examined whether the presence of six chronic health conditions moderated the effectiveness of a teleconference-delivered fatigue self-management education program for people with multiple sclerosis (MS). The longitudinal data used were from a randomized controlled trial involving 181 community-dwelling adults with MS. The primary outcome was fatigue impact, as measured by the Fatigue Impact Scale (FIS). Mixed-effects analysis of variance (ANOVA) models were used to determine the best-fitting model. Just under 65% (n = 112) of participants had at least one comorbid condition. Only diabetes and arthritis moderated all three FIS subscales over time. People with diabetes were slower to show improvement after intervention than people without diabetes. People with arthritis made much more dramatic initial gains compared with people without arthritis but had difficulty maintaining those gains over time. The results point to the need for greater attention to the impact of comorbidities on rehabilitation interventions. These exploratory findings suggest that fatigue self-management education protocols may need to be customized to people who are trying to incorporate MS fatigue self-management behaviors while simultaneously managing diabetes or arthritis. PMID:24453759

  10. An Integrated Modeling Framework for Assessment of Impacts of Multiple Global Changes on Terrestrial Productivity

    NASA Astrophysics Data System (ADS)

    Wittig, V.; Yang, X.; Jain, A.

    2008-12-01

    Independent changes in atmospheric carbon dioxide, tropospheric ozone, nitrogen deposition and climate change directly impact terrestrial productivity. Less well understood are the interactive effects of these globally changing factors on terrestrial productivity and the resultant impact on rising atmospheric carbon dioxide concentrations. This study uses the Integrated Science Assessment Model (ISAM) to quantify the impacts of these multiple global changes on terrestrial productivity and further, to project how these changes feedback on atmospheric carbon dioxide concentrations via respiratory carbon fluxes. The ISAM is modified to include a mechanistic model of leaf photosynthesis including the sensitivity of leaf photosynthesis to tropospheric ozone. Leaf-level photosynthetic carbon gain is scaled to the canopy with a sun-shade microclimate model to estimate the gross primary productivity of major biomes comprised of representative plant functional types. The modified carbon cycle in ISAM is coupled to a detailed model of the terrestrial nitrogen cycle therefore providing the integrated modeling framework required to assess the interactive effects of rising carbon dioxide, tropospheric ozone, nitrogen deposition and climate change on global productivity.

  11. Function of oncogenes in cancer development: a changing paradigm

    PubMed Central

    Vicente-Dueñas, Carolina; Romero-Camarero, Isabel; Cobaleda, Cesar; Sánchez-García, Isidro

    2013-01-01

    Tumour-associated oncogenes induce unscheduled proliferation as well as genomic and chromosomal instability. According to current models, therapeutic strategies that block oncogene activity are likely to selectively target tumour cells. However, recent evidences have revealed that oncogenes are only essential for the proliferation of some specific tumour cell types, but not all. Indeed, the latest studies of the interactions between the oncogene and its target cell have shown that oncogenes contribute to cancer development not only by inducing proliferation but also by developmental reprogramming of the epigenome. This provides the first evidence that tumorigenesis can be initiated by stem cell reprogramming, and uncovers a new role for oncogenes in the origin of cancer. Here we analyse these evidences and propose an updated model of oncogene function that can explain the full range of genotype–phenotype associations found in human cancer. Finally, we discuss how this vision opens new avenues for developing novel anti-cancer interventions. PMID:23632857

  12. Oncogenic and Therapeutic Targeting of PTEN Loss in Bone Malignancies.

    PubMed

    Xi, Yongming; Chen, Yan

    2015-09-01

    Being a tumor suppressor, PTEN functions as a dual-specificity protein and phospholipid phosphatase and regulates a variety of cellular processes and signal transduction pathways. Loss of PTEN function has been detected frequently in different forms of cancers, such as breast, prostate and lung cancer, gastric and colon cancer, skin cancer, as well as endometrial carcinoma. In this review, we provide a summary of PTEN and its role in bone malignancies including bone metastases, multiple myeloma, and osteosarcoma, etc. We highlight the importance of PTEN loss leading to activation of the oncogenic PI3K/Akt/mTOR pathway in tumorigenesis and progression, which can be attributed to both genetic and non-genetic alterations involving gene mutation, loss of heterozygosity, promoter hypermethylation, and microRNA mediated negative regulation. We also discuss the emerging therapeutic applications targeting PTEN loss for the treatment of these bone malignant diseases. PMID:25773992

  13. Structure of mutant human oncogene protein determined

    SciTech Connect

    Baum, R.

    1989-01-16

    The protein encoded by a mutant human oncogene differs only slightly in structure from the native protein that initiates normal cell division, a finding that may complicate efforts to develop inhibitors of the mutant protein. Previously, the x-ray structure of the protein encoded by the normal c-Ha-ras gene, a protein believed to signal cells to start or stop dividing through its interaction with guanosine triphosphate (GTP), was reported. The structure of the protein encoded by a transforming c-Ha-ras oncogene, in which a valine codon replaces the normal glycine codon at position 12 in the gene, has now been determined. The differences in the structures of the mutant and normal proteins are located primarily in a loop that interacts with the /beta/-phosphate of a bound guanosine diphosphate (GDP) molecule.

  14. Impact of radial and angular sampling on multiple shells acquisition in diffusion MRI.

    PubMed

    Merlet, Sylvain; Caruyer, Emmanuel; Deriche, Rachid

    2011-01-01

    We evaluate the impact of radial and angular sampling on multiple shells (MS) acquisition in diffusion MRI. The validation of our results is based on a new and efficient method to accurately reconstruct the Ensemble Average Propagator (EAP) in term of the Spherical Polar Fourier (SPF) basis from very few diffusion weighted magnetic resonance images (DW-MRI). This approach nicely exploits the duality between SPF and a closely related basis in which one can respectively represent the EAP and the diffusion signal using the same coefficients. We efficiently combine this relation to the recent acquisition and reconstruction technique called Compressed Sensing (CS). Based on results of multi-tensors models reconstruction, we show how to construct a robust acquisition scheme for both neural fibre orientation detection and attenuation signal/EAP reconstruction. PMID:21995020

  15. Impact of anticipatory processing versus distraction on multiple indices of anxiety in socially anxious individuals.

    PubMed

    Wong, Quincy J J; Moulds, Michelle L

    2011-10-01

    In models of social phobia, anticipatory processing before a social-evaluative event is a key maintaining factor for the disorder. This study investigated the impact of anticipatory processing versus distraction before a social-evaluative task on affective (self-reported anxiety), psychophysiological (skin conductance), cognitive (self-reported maladaptive self-beliefs) and behavioural (in-situation performance) responses of participants. High and low socially anxious undergraduates were randomly allocated to either an anticipatory processing or distraction condition, and then completed an impromptu speech task. Relative to distraction, anticipatory processing increased self-reported anxiety in all participants, and increased skin conductance and the strength of conditional and high standard beliefs in the high (but not low) socially anxious participants. Unconditional beliefs were not affected. For high socially anxious individuals, anticipatory processing was also indirectly associated with poorer speech performance by increasing self-reported anxiety. Anticipatory processing appears to have multiple adverse effects in socially anxious individuals. PMID:21821231

  16. Oncogenes in Cell Survival and Cell Death

    PubMed Central

    Shortt, Jake; Johnstone, Ricky W.

    2012-01-01

    The transforming effects of proto-oncogenes such as MYC that mediate unrestrained cell proliferation are countered by “intrinsic tumor suppressor mechanisms” that most often trigger apoptosis. Therefore, cooperating genetic or epigenetic effects to suppress apoptosis (e.g., overexpression of BCL2) are required to enable the dual transforming processes of unbridled cell proliferation and robust suppression of apoptosis. Certain oncogenes such as BCR-ABL are capable of concomitantly mediating the inhibition of apoptosis and driving cell proliferation and therefore are less reliant on cooperating lesions for transformation. Accordingly, direct targeting of BCR-ABL through agents such as imatinib have profound antitumor effects. Other oncoproteins such as MYC rely on the anti-apoptotic effects of cooperating oncoproteins such as BCL2 to facilitate tumorigenesis. In these circumstances, where the primary oncogenic driver (e.g., MYC) cannot yet be therapeutically targeted, inhibition of the activity of the cooperating antiapoptotic protein (e.g., BCL2) can be exploited for therapeutic benefit. PMID:23209150

  17. TARGETING ONCOGENIC BRAF IN HUMAN CANCER

    PubMed Central

    Pratilas, Christine; Xing, Feng; Solit, David

    2012-01-01

    MAPK pathway activation is a frequent event in human cancer and is often the result of activating mutations in the BRAF and RAS oncogenes. BRAF missense kinase domain mutations, the vast majority of which are V600E, occur in approximately 8% of human tumors. These mutations, which are non-overlapping in distribution with RAS mutations, are observed most frequently in melanoma but also in tumors arising in the colon, thyroid, lung and other sites. Supporting its classification as an oncogene, V600EBRAF stimulates ERK signaling, induces proliferation and is capable of promoting transformation. Given the frequent occurrence of BRAF mutations in human cancer and the continued requirement for BRAF activity in the tumors in which it is mutated, efforts are underway to develop targeted inhibitors of BRAF and its downstream effectors. These agents offer the possibility of greater efficacy and less toxicity than the systemic therapies currently available for tumors driven by activating mutations in the MAPK pathway. Early clinical results with the BRAF-selective inhibitors PLX4032 and GSK2118436 suggest that this strategy will prove successful in a select group of patients whose tumors are driven by oncogenic BRAF. PMID:21818706

  18. RNA helicase A activity is inhibited by oncogenic transcription factor EWS-FLI1

    PubMed Central

    Erkizan, Hayriye Verda; Schneider, Jeffrey A.; Sajwan, Kamal; Graham, Garrett T.; Griffin, Brittany; Chasovskikh, Sergey; Youbi, Sarah E.; Kallarakal, Abraham; Chruszcz, Maksymilian; Padmanabhan, Radhakrishnan; Casey, John L.; Üren, Aykut; Toretsky, Jeffrey A.

    2015-01-01

    RNA helicases impact RNA structure and metabolism from transcription through translation, in part through protein interactions with transcription factors. However, there is limited knowledge on the role of transcription factor influence upon helicase activity. RNA helicase A (RHA) is a DExH-box RNA helicase that plays multiple roles in cellular biology, some functions requiring its activity as a helicase while others as a protein scaffold. The oncogenic transcription factor EWS-FLI1 requires RHA to enable Ewing sarcoma (ES) oncogenesis and growth; a small molecule, YK-4-279 disrupts this complex in cells. Our current study investigates the effect of EWS-FLI1 upon RHA helicase activity. We found that EWS-FLI1 reduces RHA helicase activity in a dose-dependent manner without affecting intrinsic ATPase activity; however, the RHA kinetics indicated a complex model. Using separated enantiomers, only (S)-YK-4-279 reverses the EWS-FLI1 inhibition of RHA helicase activity. We report a novel RNA binding property of EWS-FLI1 leading us to discover that YK-4-279 inhibition of RHA binding to EWS-FLI1 altered the RNA binding profile of both proteins. We conclude that EWS-FLI1 modulates RHA helicase activity causing changes in overall transcriptome processing. These findings could lead to both enhanced understanding of oncogenesis and provide targets for therapy. PMID:25564528

  19. Role of "oncogenic nexus" of CIP2A in breast oncogenesis: how does it work?

    PubMed

    De, Pradip; Carlson, Jennifer H; Leyland-Jones, Brian; Dey, Nandini

    2015-01-01

    The CIP2A gene is an oncogene associated with solid and hematologic malignancies [1]. CIP2A protein is an oncoprotein and a potential cancer therapy target [2]. Literature shows that CIP2A inhibits the tumor suppressor protein PP2A [3] which downregulates phophorylation of AKT, a hallmark of cancers [4] and stabilizes the proto-oncogene, c-MYC in tumor cells [5], the comprehensive action of CIP2A and its functional interaction(s) with other oncoproteins and tumor suppressors is not clearly established. Recently we tried to put forward a contextual mode-of-action of CIP2A protein in a review which proposed that CIP2A influences oncogenesis via an "oncogenic nexus" [1]. In this review we critically evaluated the potential relevance of the mode-of-action of the "oncogenic nexus" of CIP2A in breast carcinogenesis and appraised the role of this nexus in different PAM50 luminal A, PAM50 luminal B, PAM50 HER2-enriched and PAM50 basal BC. This review has a novel approach. Here we have not only compiled and discussed the latest developments in this field but also presented data obtained from c-BioPortal and STRING10 in order to substantiate our view regarding the mode-of-action of the "oncogenic nexus" of CIP2A. We functionally correlated alterations of genes pertaining to the "oncogenic nexus" of CIP2A with protein-protein interactions between the different components of the nexus including (1) subunits of PP2A, (2) multiple transcription factors including MYC oncogene and (3) components of the PI3K-mTOR and the MAPK-ERK oncogenic pathways. Using these proteins as "input" to STRING10 we studied the association, Action view, at the highest Confidence level. OncoPrints (c-BioPortal) showed alterations (%) of regulatory subunits genes of PP2A (PPP2R1A and PPP2R1B) along with alterations of CIP2A in breast invasive carcinoma (TCGA, Nature 2012 & TCGA, Provisional). Similar genetic alterations of PP2A were also observed in samples of breast tumors at our Avera Research

  20. Perceived Impact of a Self-Management Program for Fatigue in Multiple Sclerosis

    PubMed Central

    Wilkinson, Amanda; Snowdon, Jessie

    2016-01-01

    Background: Fatigue in multiple sclerosis (MS) is reported to be one of its most debilitating symptoms, affecting personal, family, and community participation. Despite a high incidence of MS in New Zealand, there was no cohesive approach to support people with MS to manage their fatigue. This prompted the development of Minimise Fatigue, Maximise Life: Creating Balance with Multiple Sclerosis (MFML), a group-based, 6-week fatigue self-management program. This study explored the perceived impact of MFML for participants who attended the program. Methods: We undertook semistructured individual telephone interviews 1 (n = 23) and 3 (n = 11) months after delivery of the program. Data were analyzed for themes. Results: Two themes emerged from the data: achieving behavior change to manage fatigue and whole of life effects. These themes represent participants' perceived benefits of the program. Conclusions: This study provides evidence that the MFML fatigue self-management program positively affected the lives of participants. The findings suggest that participants had begun to successfully develop and integrate self-management skills into their everyday lives. This affected the individual personally and also their participation in family and community life. This study adds to the current knowledge and understanding of the positive effect that delivery of a fatigue self-management intervention can have for people with MS. PMID:26917995

  1. The impact of relative intensity noise on the signal in multiple reference optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Neuhaus, Kai; Subhash, Hrebesh; Alexandrov, Sergey; Dsouza, Roshan; Hogan, Josh; Wilson, Carol; Leahy, Martin; Slepneva, Svetlana; Huyet, Guillaume

    2016-03-01

    Multiple reference optical coherence tomography (MR-OCT) applies a unique low-cost solution to enhance the scanning depth of standard time domain OCT by inserting an partial mirror into the reference arm of the interferometric system. This novel approach achieves multiple reflections for different layers and depths of an sample with minimal effort of engineering and provides an excellent platform for low-cost OCT systems based on well understood production methods for micro-mechanical systems such as CD/DVD pick-up systems. The direct integration of a superluminescent light-emitting diode (SLED) is a preferable solution to reduce the form- factor of an MR-OCT system. Such direct integration exposes the light source to environmental conditions that can increase fluctuations in heat dissipation and vibrations and affect the noise characteristics of the output spectrum. This work describes the impact of relative intensity noise (RIN) on the quality of the interference signal of MR-OCT related to a variety of environmental conditions, such as temperature.

  2. The impact of multiple endpoint dependency on Q and I(2) in meta-analysis.

    PubMed

    Thompson, Christopher Glen; Becker, Betsy Jane

    2014-09-01

    A common assumption in meta-analysis is that effect sizes are independent. When correlated effect sizes are analyzed using traditional univariate techniques, this assumption is violated. This research assesses the impact of dependence arising from treatment-control studies with multiple endpoints on homogeneity measures Q and I(2) in scenarios using the unbiased standardized-mean-difference effect size. Univariate and multivariate meta-analysis methods are examined. Conditions included different overall outcome effects, study sample sizes, numbers of studies, between-outcomes correlations, dependency structures, and ways of computing the correlation. The univariate approach used typical fixed-effects analyses whereas the multivariate approach used generalized least-squares (GLS) estimates of a fixed-effects model, weighted by the inverse variance-covariance matrix. Increased dependence among effect sizes led to increased Type I error rates from univariate models. When effect sizes were strongly dependent, error rates were drastically higher than nominal levels regardless of study sample size and number of studies. In contrast, using GLS estimation to account for multiple-endpoint dependency maintained error rates within nominal levels. Conversely, mean I(2) values were not greatly affected by increased amounts of dependency. Last, we point out that the between-outcomes correlation should be estimated as a pooled within-groups correlation rather than using a full-sample estimator that does not consider treatment/control group membership. PMID:26052849

  3. The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib

    PubMed Central

    Yeung, David T. O.; Yeoman, Alexandra L.; Altamura, Haley K.; Jamison, Bronte A.; Field, Chani R.; Hodgson, J. Graeme; Lustgarten, Stephanie; Rivera, Victor M.; Hughes, Timothy P.; Branford, Susan

    2016-01-01

    The third-generation tyrosine kinase inhibitor (TKI) ponatinib shows activity against all common BCR-ABL1 single mutants, including the highly resistant BCR-ABL1-T315I mutant, improving outcome for patients with refractory chronic myeloid leukemia (CML). However, responses are variable, and causal baseline factors have not been well-studied. The type and number of low-level BCR-ABL1 mutations present after imatinib resistance has prognostic significance for subsequent treatment with nilotinib or dasatinib as second-line therapy. We therefore investigated the impact of low-level mutations detected by sensitive mass-spectrometry before ponatinib initiation (baseline) on treatment response in 363 TKI-resistant patients enrolled in the PONATINIB for Chronic Myeloid Leukemia Evaluation and Ph+ Acute Lymphoblastic Leukemia trial, including 231 patients in chronic phase (CP-CML). Low-level mutations were detected in 53 patients (15%, including low-level T315I in 14 patients); most, however, did not undergo clonal expansion during ponatinib treatment and, moreover, no specific individual mutations were associated with inferior outcome. We demonstrate however, that the number of mutations detectable by mass spectrometry after TKI resistance is associated with response to ponatinib treatment and could be used to refine the therapeutic approach. Although CP-CML patients with T315I (63/231, 27%) had superior responses overall, those with multiple mutations detectable by mass spectrometry (20, 32%) had substantially inferior responses compared with those with T315I as the sole mutation detected (43, 68%). In contrast, for CP-CML patients without T315I, the inferior responses previously observed with nilotinib/dasatinib therapy for imatinib-resistant patients with multiple mutations were not seen with ponatinib treatment, suggesting that ponatinib may prove to be particularly advantageous for patients with multiple mutations detectable by mass spectrometry after TKI resistance

  4. The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib.

    PubMed

    Parker, Wendy T; Yeung, David T O; Yeoman, Alexandra L; Altamura, Haley K; Jamison, Bronte A; Field, Chani R; Hodgson, J Graeme; Lustgarten, Stephanie; Rivera, Victor M; Hughes, Timothy P; Branford, Susan

    2016-04-14

    The third-generation tyrosine kinase inhibitor (TKI) ponatinib shows activity against all common BCR-ABL1 single mutants, including the highly resistant BCR-ABL1-T315I mutant, improving outcome for patients with refractory chronic myeloid leukemia (CML). However, responses are variable, and causal baseline factors have not been well-studied. The type and number of low-level BCR-ABL1 mutations present after imatinib resistance has prognostic significance for subsequent treatment with nilotinib or dasatinib as second-line therapy. We therefore investigated the impact of low-level mutations detected by sensitive mass-spectrometry before ponatinib initiation (baseline) on treatment response in 363 TKI-resistant patients enrolled in the PONATINIB for Chronic Myeloid Leukemia Evaluation and Ph(+)Acute Lymphoblastic Leukemia trial, including 231 patients in chronic phase (CP-CML). Low-level mutations were detected in 53 patients (15%, including low-level T315I in 14 patients); most, however, did not undergo clonal expansion during ponatinib treatment and, moreover, no specific individual mutations were associated with inferior outcome. We demonstrate however, that the number of mutations detectable by mass spectrometry after TKI resistance is associated with response to ponatinib treatment and could be used to refine the therapeutic approach. Although CP-CML patients with T315I (63/231, 27%) had superior responses overall, those with multiple mutations detectable by mass spectrometry (20, 32%) had substantially inferior responses compared with those with T315I as the sole mutation detected (43, 68%). In contrast, for CP-CML patients without T315I, the inferior responses previously observed with nilotinib/dasatinib therapy for imatinib-resistant patients with multiple mutations were not seen with ponatinib treatment, suggesting that ponatinib may prove to be particularly advantageous for patients with multiple mutations detectable by mass spectrometry after TKI resistance

  5. Predictive performance of microarray gene signatures: impact of tumor heterogeneity and multiple mechanisms of drug resistance

    PubMed Central

    A’Hern, Roger; Bidard, Francois-Clement; Lemetre, Christophe; Swanton, Charles; Shen, Ronglai; Reis-Filho, Jorge S.

    2014-01-01

    Gene signatures have failed to predict responses to breast cancer therapy in patients to date. In this study, we used bioinformatic methods to explore the hypothesis that the existence of multiple drug resistance mechanisms in different patients may limit the power of gene signatures to predict responses to therapy. Additionally, we explored whether sub-stratification of resistant cases could improve performance. Gene expression profiles from 1,550 breast cancers analyzed with the same microarray platform were retrieved from publicly available sources. Gene expression changes were introduced in cases defined as sensitive or resistant to a hypothetical therapy. In the resistant group, up to five different mechanisms of drug resistance causing distinct or overlapping gene expression changes were generated bioinformatically, and their impact on sensitivity, specificity and predictive values of the signatures was investigated. We found that increasing the number of resistance mechanisms corresponding to different gene expression changes weakened the performance of the predictive signatures generated, even if the resistance-induced changes in gene expression were sufficiently strong and informative. Performance was also affected by cohort composition and the proportion of sensitive versus resistant cases or resistant cases that were mechanistically distinct. It was possible to improve response prediction by sub-stratifying chemotherapy-resistant cases from actual datasets (non-bioinformatically-perturbed datasets), and by using outliers to model multiple resistance mechanisms. Our work supports the hypothesis that the presence of multiple resistance mechanisms to a given therapy in patients limits the ability of gene signatures to make clinically-useful predictions. PMID:24706696

  6. Model of multiple exposure to contaminants in monitoring the environmental impact on population health.

    PubMed

    Kliment, V

    1996-12-01

    The model study is focused on possibilities of comprehensive evaluation of the multiple exposure of humans to selected inorganic contaminants (arsenic, cadmium, lead, zinc) monitored within the subsystems of the monitoring the environmental impact on population health (inhalation and ingestion exposure from air, drinking water and foodstuffs and biological monitoring). The mean daily intake of contaminants of average adults is assessed using the monitoring and literature data. The exposure balance showed that the total intake of individual contaminants studied did not exceed the limit values given by the exposure standards (acceptable daily intake). The highest value of exposure reaching 28% of the limit was reported for cadmium. The prevailing pathway of exposure is ingestion of foodstuffs: more than 95% in all contaminants under study. Information on the intake of contaminants is used as input in a linear multicompartmental model describing their kinetics and retention in the human organism. The results of the model computation are compared with the laboratory data obtained in the biological monitoring of adult urine. The model and monitoring sets of results were found to conform well for cadmium and zinc. For arsenic and lead the model values are roughly one order of magnitude lower than the monitored ones which should be considered as acceptable for the model studies of this type. The model study of contaminant monitoring data processing and evaluation suggests further applications of health risk assessment representing one of the basic outputs of monitoring the environmental impact on population health. PMID:8997533

  7. Accepting multiple simultaneous liver offers does not negatively impact transplant outcomes.

    PubMed

    Eldeen, Firas Zahr; Mourad, Moustafa Mabrouk; Bhandari, Mayank; Roll, Garrett; Gunson, Bridget; Mergental, Hynek; Bramhall, Simon; Isaac, John; Muiesan, Paolo; Mirza, Darius F; Perera, M Thamara P R

    2016-02-01

    Impact of performing multiple liver transplants (LT) in a short period of time is unknown. Consecutively performed LT potentially increase complication rates through team fatigue and overutilization of resources and increase ischemia time. We analyzed the impact of undertaking consecutive LT (Consecutive liver transplant, CLT; LT preceded by another transplant performed not more than 12 h before, both transplants grouped together) on outcomes. Of 1702 LT performed, 314 (18.4%) were CLT. Outcome data was compared with solitary LT (SLT; not more than one LT in 12-h period). Recipient, donor, and graft characteristics were evenly matched between SLT and CLT; second LT of CLT group utilized younger donors grafts with longer cold ischemic times (P = 0.015). Implantation and operative time were significantly lower in CLT recipients on intergroup analysis (P = 0.0001 and 0.002, respectively). Early hepatic artery thrombosis (E-HAT) was higher in CLT versus SLT (P = 0.038), despite absolute number of E-HAT being low in all groups. Intragroup analysis demonstrated a trend toward more frequent E-HAT in first LT, compared to subsequent transplants; however, difference did not reach statistical significance (P = 0.135). In era of organ scarcity, CLT performed at high-volume center is safe and allows pragmatic utilization of organs, potentially reducing number of discarded grafts and reducing waiting list mortality. PMID:26463509

  8. A new climate era in the sub-Arctic: Accelerating climate changes and multiple impacts

    NASA Astrophysics Data System (ADS)

    Callaghan, Terry V.; Bergholm, Fredrik; Christensen, Torben R.; Jonasson, Christer; Kokfelt, Ulla; Johansson, Margareta

    2010-07-01

    Climate warming in the Swedish sub-Arctic since 2000 has reached a level at which statistical analysis shows for the first time that current warming has exceeded that in the late 1930's and early 1940's, and has significantly crossed the 0°C mean annual temperature threshold which causes many cryospheric and ecological impacts. The accelerating temperature increase trend has driven similar trends in the century-long increase in snow thickness, loss of lake ice, increases in active layer thickness, lake water TOC (total organic carbon) concentrations and the assemblages of diatoms, and changes in tree-line location and plant community structure. Some of these impacts were not evident in the first warm period of the 20th Century. Changes in climate are associated with reduced temperature variability, particularly loss of cold winters and cool summers, and an increase in extreme precipitation events that cause mountain slope instability and infrastructure failure. The long term records of multiple, local environmental factors compiled here for the first time provide detailed information for adaptation strategy development while dramatic changes in an environment particularly vulnerable to climate change highlight the need to adopt global mitigation strategies.

  9. Impacts of Variability and Uncertainty in Solar Photovoltaic Generation at Multiple Timescales

    SciTech Connect

    Ela, E.; Diakov, V.; Ibanez, E.; Heaney, M.

    2013-05-01

    The characteristics of variability and uncertainty of PV solar power have been studied extensively. These characteristics can create challenges for system operators who must ensure a balance between generation and demand while obeying power system constraints at the lowest possible cost. A number of studies have looked at the impact of wind power plants, and some recent studies have also included solar PV. The simulations that are used in these studies, however, are typically fixed to one time resolution. This makes it difficult to analyze the variability across several timescales. In this study, we use a simulation tool that has the ability to evaluate both the economic and reliability impacts of PV variability and uncertainty at multiple timescales. This information should help system operators better prepare for increases of PV on their systems and develop improved mitigation strategies to better integrate PV with enhanced reliability. Another goal of this study is to understand how different mitigation strategies and methods can improve the integration of solar power more reliably and efficiently.

  10. Prognostic impact of immunophenotypic complete response in patients with multiple myeloma achieving better than complete response.

    PubMed

    Fukumoto, Kota; Fujisawa, Manabu; Suehara, Yasuto; Narita, Ken-Taro; Usui, Yoshiaki; Takeuchi, Masami; Matsue, Kosei

    2016-08-01

    To investigate the impact of immunophenotypic complete response [iCR, ≤10(-4) multiple myeloma (MM) cells defined by multicolor flow cytometry (MFC)] on survival in patients with MM, we retrospectively analyzed 78 patients that obtained conventional CR at our hospital. Survivals were landmarked at achievement of CR. The rate of stringent CR (sCR) among patients with CR was 88%, and iCR for CR and sCR patients were 44% and 49%, respectively. Achievement of iCR was associated with significantly longer disease-free survival (DFS) not only in CR patients (p = 0.009) but also in sCR patients (p = 0.002), while sCR attainment per se did not have statistically significant impact on DFS (p = 0.06) or overall survival (OS) (p = 0.587). Univariate and multivariate analyses indicated that attainment of iCR was independently associated with longer 2-year DFS in addition to creatinine (≤2.0 mg/dL) and maintenance therapy. This study highlights the importance of pursuing iCR even in patients with sCR. PMID:26764045

  11. Surgical management of multiple supernumerary teeth and an impacted maxillary permanent central incisor.

    PubMed

    Rallan, Mandeep; Rallan, Neelakshi Singh; Goswami, Mousumi; Rawat, Kamini

    2013-01-01

    Hyperdontia is the condition of having supernumerary teeth, or teeth which appear in addition to the regular number of teeth. It is a developmental anomaly and has been argued to arise from multiple aetiologies. The most common site is the maxillary incisor region; but the prevalence of more than three teeth supernumerary tooth is less than 1%. A case of 13 year male patient is reported with a multiple impacted supernumerary tooth in maxillary anterior region hindering the eruption of right permanent central incisor. The supernumerary tooth was treated via surgical approach followed by an interim prosthesis for permanent central incisor which later on erupted in due course of time. Background Supernumerary teeth may be defined as any teeth or tooth substance in excess of the usual configuration of 20 deciduous and 32 permanent teeth. The presence of supernumerary teeth in the premaxillary region often poses unique diagnostic and managerial concerns for the practitioner. Rarely is the surplus number compensated by an absence or deficiency of other teeth. Therefore, the dysfunctional nature of supernumerary teeth and their ability to create a variety of pathological disturbances in the normal eruption and position of adjacent teeth warrants their early detection and prudent management. Approximately 76-86% of cases represent single-tooth hyperdontia, with two supernumerary teeth noted in 12-23% and three or more extra teeth noted in less than 1% of cases. Multiple supernumerary teeth are also associated with many syndromes like cleidocranial dysplasia and Gardner’s syndrome etc. However, it is rare to find multiple supernumeraries in individuals with no other associated disease or syndrome. In such cases, the maxillary anterior region is the common site of occurrence. The exact aetiology is not clearly understood. The supernumerary teeth result from any disturbance in the initiation and proliferation stages of odontogenesis. There are several theories regarding the

  12. Power of PTEN/AKT: Molecular switch between tumor suppressors and oncogenes

    PubMed Central

    XIE, YINGQIU; NAIZABEKOV, SANZHAR; CHEN, ZHANLIN; TOKAY, TURSONJAN

    2016-01-01

    An increasing amount of evidence has shown that tumor suppressors can become oncogenes, or vice versa, but the mechanism behind this is unclear. Recent findings have suggested that phosphatase and tensin homolog (PTEN) is one of the powerful switches for the conversion between tumor suppressors and oncogenes. PTEN regulates a number of cellular processes, including cell death and proliferation, through the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Furthermore, a number of studies have suggested that PTEN deletions may alter various functions of certain tumor suppressor and oncogenic proteins. The aim of the present review was to analyze specific cases driven by PTEN loss/AKT activation, including aberrant signaling pathways and novel drug targets for clinical application in personalized medicine. The findings illustrate how PTEN loss and/or AKT activation switches MDM2-dependent p53 downregulation, and induces conversion between oncogene and tumor suppressor in enhancer of zeste homolog 2, BTB domain-containing 7A, alternative reading frame 2, p27 and breast cancer 1, early onset, through multiple mechanisms. This review highlights the genetic basis of complex drug targets and provides insights into the rationale of precision cancer therapy. PMID:27347153

  13. Activation of proto-oncogenes by disruption of chromosome neighborhoods.

    PubMed

    Hnisz, Denes; Weintraub, Abraham S; Day, Daniel S; Valton, Anne-Laure; Bak, Rasmus O; Li, Charles H; Goldmann, Johanna; Lajoie, Bryan R; Fan, Zi Peng; Sigova, Alla A; Reddy, Jessica; Borges-Rivera, Diego; Lee, Tong Ihn; Jaenisch, Rudolf; Porteus, Matthew H; Dekker, Job; Young, Richard A

    2016-03-25

    Oncogenes are activated through well-known chromosomal alterations such as gene fusion, translocation, and focal amplification. In light of recent evidence that the control of key genes depends on chromosome structures called insulated neighborhoods, we investigated whether proto-oncogenes occur within these structures and whether oncogene activation can occur via disruption of insulated neighborhood boundaries in cancer cells. We mapped insulated neighborhoods in T cell acute lymphoblastic leukemia (T-ALL) and found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes. Perturbation of such boundaries in nonmalignant cells was sufficient to activate proto-oncogenes. Mutations affecting chromosome neighborhood boundaries were found in many types of cancer. Thus, oncogene activation can occur via genetic alterations that disrupt insulated neighborhoods in malignant cells. PMID:26940867

  14. Impact of optical hard limiter on the performance of an optical overlapped-code division multiple access system

    NASA Astrophysics Data System (ADS)

    Inaty, Elie; Raad, Robert; Tablieh, Nicole

    2011-08-01

    Throughout this paper, a closed form expression of the multiple access interference (MAI) limited bit error rate (BER) is provided for the multiwavelength optical code-division multiple-access system when the system is working above the nominal transmission rate limit imposed by the passive encoding-decoding operation. This system is known in literature as the optical overlapped code division multiple access (OV-CDMA) system. A unified analytical framework is presented emphasizing the impact of optical hard limiter (OHL) on the BER performance of such a system. Results show that the performance of the OV-CDMA system may be highly improved when using OHL preprocessing at the receiver side.

  15. Impact of Melatonin on Motor, Cognitive and Neuroimaging Indices in Patients with Multiple Sclerosis.

    PubMed

    Roostaei, Tina; Sahraian, Mohammad Ali; Hajeaghaee, Sara; Gholipour, Taha; Togha, Mansoureh; Siroos, Bahaadin; Mansouri, Sepideh; Mohammadshirazi, Zahra; Aghazadeh Alasti, Maryam; Harirchian, Mohammad Hossein

    2015-12-01

    A series of preclinical and clinical studies have shown the immunomodulatory effect of  melatonin, especially in the state of chronic inflammation. A double-blind, randomized, parallel-group, placebo-controlled clinical trial was designed to study the tolerability and efficacy of supplemental therapy with melatonin (3 mg/day) in comparison to placebo in relapsing-remitting MS (RRMS) patients receiving once weekly interferon beta. Patients were followed up for 12 months. Primary outcomes consisted of the number of relapses, change in Extended Disability Status Scale (EDSS), and the number and volume of new T2 and gadolinium-enhancing brain lesions. Secondary outcomes included change in performance on Multiple Sclerosis Functional Composite (MSFC) as well as change in fatigue and depression. The outcomes were evaluated every three months. Twenty-six patients (13 in each group) were recruited in the study. All participants, except for one patient in the placebo group, completed the study. No patient reported serious adverse events. There was no significant difference either in primary or secondary outcomes between melatonin and placebo arm. However, a trend for beneficial effect was observed for melatonin on change in MSFC performance and the cognitive subscore of the Modified Fatigue Impact Scale (p=0.05 and 0.006, respectively, not corrected for multiple comparisons). We found no significant effect for treatment with melatonin on measures of clinical and functional disability and development of brain lesions in our small sample-size study. Studies with higher statistical power and longer follow up are needed to further evaluate the potential immunomodulatory effect of melatonin in RRMS treatment. PMID:26725556

  16. Impact of Groundwater Flow and Energy Load on Multiple Borehole Heat Exchangers.

    PubMed

    Dehkordi, S Emad; Schincariol, Robert A; Olofsson, Bo

    2015-01-01

    The effect of array configuration, that is, number, layout, and spacing, on the performance of multiple borehole heat exchangers (BHEs) is generally known under the assumption of fully conductive transport. The effect of groundwater flow on BHE performance is also well established, but most commonly for single BHEs. In multiple-BHE systems the effect of groundwater advection can be more complicated due to the induced thermal interference between the boreholes. To ascertain the influence of groundwater flow and borehole arrangement, this study investigates single- and multi-BHE systems of various configurations. Moreover, the influence of energy load balance is also examined. The results from corresponding cases with and without groundwater flow as well as balanced and unbalanced energy loads are cross-compared. The groundwater flux value, 10(-7) m/s, is chosen based on the findings of previous studies on groundwater flow interaction with BHEs and thermal response tests. It is observed that multi-BHE systems with balanced loads are less sensitive to array configuration attributes and groundwater flow, in the long-term. Conversely, multi-BHE systems with unbalanced loads are influenced by borehole array configuration as well as groundwater flow; these effects become more pronounced with time, unlike when the load is balanced. Groundwater flow has more influence on stabilizing loop temperatures, compared to array characteristics. Although borehole thermal energy storage (BTES) systems have a balanced energy load function, preliminary investigation on their efficiency shows a negative impact by groundwater which is due to their dependency on high temperature gradients between the boreholes and surroundings. PMID:25227154

  17. Melanoma: oncogenic drivers and the immune system

    PubMed Central

    Karachaliou, Niki; Pilotto, Sara; Teixidó, Cristina; Viteri, Santiago; González-Cao, María; Riso, Aldo; Morales-Espinosa, Daniela; Molina, Miguel Angel; Chaib, Imane; Santarpia, Mariacarmela; Richardet, Eduardo; Bria, Emilio

    2015-01-01

    Advances and in-depth understanding of the biology of melanoma over the past 30 years have contributed to a change in the consideration of melanoma as one of the most therapy-resistant malignancies. The finding that oncogenic BRAF mutations drive tumor growth in up to 50% of melanomas led to a molecular therapy revolution for unresectable and metastatic disease. Moving beyond BRAF, inactivation of immune regulatory checkpoints that limit T cell responses to melanoma has provided targets for cancer immunotherapy. In this review, we discuss the molecular biology of melanoma and we focus on the recent advances of molecularly targeted and immunotherapeutic approaches. PMID:26605311

  18. Hedgehog Cholesterolysis: Specialized Gatekeeper to Oncogenic Signaling.

    PubMed

    Callahan, Brian P; Wang, Chunyu

    2015-01-01

    Discussions of therapeutic suppression of hedgehog (Hh) signaling almost exclusively focus on receptor antagonism; however, hedgehog's biosynthesis represents a unique and potentially targetable aspect of this oncogenic signaling pathway. Here, we review a key biosynthetic step called cholesterolysis from the perspectives of structure/function and small molecule inhibition. Cholesterolysis, also called cholesteroylation, generates cholesterol-modified Hh ligand via autoprocessing of a hedgehog precursor protein. Post-translational modification by cholesterol appears to be restricted to proteins in the hedgehog family. The transformation is essential for Hh biological activity and upstream of signaling events. Despite its decisive role in generating ligand, cholesterolysis remains conspicuously unexplored as a therapeutic target. PMID:26473928

  19. Oncogenic role of nucleophosmin/B23.

    PubMed

    Yung, Benjamin Yat Ming

    2007-01-01

    Nucleophosmin/B23 was first identified as a nucleolar protein expressed at higher levels in cancer cells compared to normal cells. Nucleophosmin/B23 has long been thus thought to have a role in tumor formation. With our efforts and others in the last 15 years, nucleophosmin/B23 has proven to have an oncogenic role. In this review, we provide evidence suggesting that nucleophosmin/B23 may be a crucial gene in regulation of cancer growth and discuss how nucleophosmin/B23 can contribute to tumorigenesis. PMID:17939258

  20. Evaluation of Factors Affecting Vaccine Efficacy of Recombinant Marek's Disease Virus Lacking the Meq Oncogene in Chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have previously reported that deletion of Meq gene from oncogenic rMd5 virus rendered it apathogenic for chickens. Here we examined multiple factors affecting Marek’s disease (MD) vaccine efficacy of this non-pathogenic recombinant Meq null rMd5 virus (rMd5deltaMeq). These factors included host g...

  1. Adverse Prognostic Impact of Bone Marrow Microvessel Density in Multiple Myeloma

    PubMed Central

    Lee, Nuri; Lee, Hyewon; Moon, Soo Young; Sohn, Ji Yeon; Hwang, Sang Mee; Yoon, Ok Jin; Youn, Hye Sun

    2015-01-01

    Background Angiogenesis is important for the proliferation and survival of multiple myeloma (MM) cells. Bone marrow (BM) microvessel density (MVD) is a useful marker of angiogenesis and is determined by immunohistochemical staining with anti-CD34 antibody. This study investigated the prognostic impact of MVD and demonstrated the relationship between MVD and previously mentioned prognostic factors in patients with MM. Methods The study included 107 patients with MM. MVD was assessed at initial diagnosis in a blinded manner by two hematopathologists who examined three CD34-positive hot spots per patient and counted the number of vessels in BM samples. Patients were divided into three groups according to MVD tertiles. Cumulative progression-free survival (PFS) and overall survival (OS) curves, calculated by using Kaplan-Meier method, were compared among the three groups. Prognostic impact of MVD was assessed by calculating Cox proportional hazard ratio (HR). Results Median MVDs in the three groups were 16.8, 33.9, and 54.7. MVDs were correlated with other prognostic factors, including β2-microglobulin concentration, plasma cell percentage in the BM, and cancer stage according to the International Staging System. Multivariate Cox regression analysis showed that high MVD was an independent predictor of PFS (HR=2.57; 95% confidence interval, 1.22-5.42; P=0.013). PFS was significantly lower in the high MVD group than in the low MVD group (P=0.025). However, no difference was observed in the OS (P=0.428). Conclusions Increased BM MVD is a marker of poor prognosis in patients newly diagnosed with MM. BM MVD should be assessed at the initial diagnosis of MM. PMID:26354343

  2. Chronic, low concentration exposure to pharmaceuticals impacts multiple organ systems in zebrafish.

    PubMed

    Galus, Michal; Kirischian, Nina; Higgins, Sarah; Purdy, James; Chow, Justin; Rangaranjan, Sahaana; Li, Hongxia; Metcalfe, Chris; Wilson, Joanna Y

    2013-05-15

    Pharmaceuticals are found in both receiving and drinking water due to their persistent release in waste-water effluents, raising concerns for environmental and human health. Chronic, aqueous exposure of zebrafish (Danio rerio) to environmentally relevant concentrations of acetaminophen (ACE), venlafaxaine (VEN) (10μgL(-1)), carbamazepine (CBZ) and gemfibrozil (GEM) (0.5 and 10μgL(-1)) decreased reproductive output. Atretic oocytes and altered ovarian histology were seen in female zebrafish exposed to CBZ and GEM, suggesting a direct effect on oocyte development that may account for the reduced fecundity. Apoptosis within the theca and granulosa cells was identified in exposed female zebrafish with atretic oocytes by TUNEL positive staining. The incidence of follicular apoptosis was nearly 2-fold higher in exposed females than the controls. All compounds significantly altered kidney proximal tubule morphology but there was no difference in the incidence of apoptotic cells within the kidney between control and exposed in either males or females. Liver histology was altered by ACE and GEM exposure. Parental exposure to pharmaceuticals did not increase developmental abnormalities, hatching success, or mortality in embryos. Yet, direct exposure of embryos to ACE increased developmental abnormalities and mortality; exposure to 0.5μgL(-1) of all pharmaceuticals increased mortality. CBZ decreased plasma 11-ketotestosterone concentrations in males and females. Overall, these data suggest that low concentration, chronic exposure of fish to pharmaceuticals impacts fish development as well as multiple organ systems in adult fish, leading to effects on reproduction and histology of liver and kidney. These results are significant in understanding the consequences of chronic, low concentration pharmaceutical exposure to fish and suggest that exposed populations are at risk of negative impacts to reproduction and health. PMID:23375851

  3. Impact of Exercise on Innate Immunity in Multiple Sclerosis Progression and Symptomatology

    PubMed Central

    Barry, Alison; Cronin, Owen; Ryan, Aisling M.; Sweeney, Brian; Yap, Siew M.; O'Toole, Orna; Allen, Andrew P.; Clarke, Gerard; O'Halloran, Ken D.; Downer, Eric J.

    2016-01-01

    Multiple Sclerosis (MS), an idiopathic progressive immune-mediated neurological disorder of the central nervous system (CNS), is characterized by recurrent episodes of inflammatory demyelination and consequent axonal deterioration. It accounts for functional deterioration and lasting disability among young adults. A body of literature demonstrates that physical activity counteracts fatigue and depression and may improve overall quality of life in MS patients. Furthermore, much data indicates that exercise ameliorates chronic neuroinflammation and its related pathologies by tipping cytokine profiles toward an anti-inflammatory signature. Recent data has focused on the direct impact of exercise training on the innate immune system by targeting toll-like receptors (TLRs), signaling pattern recognition receptors that govern the innate immune response, shedding light on the physiological role of TLRs in health and disease. Indeed, TLRs continue to emerge as players in the neuroinflammatory processes underpinning MS. This review will highlight evidence that physical activity and exercise are potential immunomodulatory therapies, targeting innate signaling mechanism(s) to modulate MS symptom development and progression. PMID:27313534

  4. Impact of Exercise on Innate Immunity in Multiple Sclerosis Progression and Symptomatology.

    PubMed

    Barry, Alison; Cronin, Owen; Ryan, Aisling M; Sweeney, Brian; Yap, Siew M; O'Toole, Orna; Allen, Andrew P; Clarke, Gerard; O'Halloran, Ken D; Downer, Eric J

    2016-01-01

    Multiple Sclerosis (MS), an idiopathic progressive immune-mediated neurological disorder of the central nervous system (CNS), is characterized by recurrent episodes of inflammatory demyelination and consequent axonal deterioration. It accounts for functional deterioration and lasting disability among young adults. A body of literature demonstrates that physical activity counteracts fatigue and depression and may improve overall quality of life in MS patients. Furthermore, much data indicates that exercise ameliorates chronic neuroinflammation and its related pathologies by tipping cytokine profiles toward an anti-inflammatory signature. Recent data has focused on the direct impact of exercise training on the innate immune system by targeting toll-like receptors (TLRs), signaling pattern recognition receptors that govern the innate immune response, shedding light on the physiological role of TLRs in health and disease. Indeed, TLRs continue to emerge as players in the neuroinflammatory processes underpinning MS. This review will highlight evidence that physical activity and exercise are potential immunomodulatory therapies, targeting innate signaling mechanism(s) to modulate MS symptom development and progression. PMID:27313534

  5. Impact of extended-release dalfampridine on walking ability in patients with multiple sclerosis

    PubMed Central

    Hayes, Keith C

    2011-01-01

    Dalfampridine extended release (ER) 10 mg is an oral tablet form of the potassium (K+) channel-blocking compounded dalfampridine, also known as fampridine, and chemically 4-aminopyridine or 4-AP, which received regulatory approval in the United States for the treatment of walking in patients with multiple sclerosis (MS) in January 2010. Two pivotal Phase 3 clinical trials demonstrated significant improvements in walking in patients with the four primary forms of MS following administration of dalfampridine ER tablets 10 mg twice daily. The drug is thought to act by restoring conduction in focally demyelinated axons and by enhancing neurotransmission, thereby leading to improved neurological function. This review describes how dalfampridine represents a new pharmacotherapeutic approach to the clinical management of mobility impairment. It describes the mechanism of action and chemistry of dalfampridine ER, its pharmacokinetics, tolerability, and side effects, and the outcomes of multicenter trials showing its efficacy in improving walking speed. Clinician and patient global assessments, as well as patient self-assessment of the impact of MS on their gait disability, confirm clinically relevant benefit from the therapy. Patients tolerate the drug well and their improvement in terms of household and community ambulation, inferred from analysis of pooled data from several studies, is likely to translate into benefits in the performance of instrumental activities of daily living and a reduction in the neuropsychiatric burden of disease. PMID:21573085

  6. R Squared Shrinkage in Multiple Regression Research: An Empirical Evaluation of Use and Impact of Adjusted Effect Formulae.

    ERIC Educational Resources Information Center

    Thatcher, Greg W.; Henson, Robin K.

    This study examined research in training and development to determine effect size reporting practices. It focused on the reporting of corrected effect sizes in research articles using multiple regression analyses. When possible, researchers calculated corrected effect sizes and determine if the associated shrinkage could have impacted researcher…

  7. The Impact of Multiple Intelligences-Based Instruction on Developing Speaking Skills of the Pre-Service Teachers of English

    ERIC Educational Resources Information Center

    Salem, Ashraf Atta M. S.

    2013-01-01

    The current study investigates the impact of multiple intelligences-based Instruction on developing speaking skills of the pre-service teachers of English. Therefore, the problem of the current study can be stated in the lack of speaking skills of the pre-service teachers of English in Hurgada faculty of Education, South Valley University. To…

  8. Teaching Multiple Modes of Representation in Middle-School Science Classrooms: Impact on Student Learning and Multimodal Use

    ERIC Educational Resources Information Center

    Nixon, Ryan S.; Smith, Leigh K.; Wimmer, Jennifer J.

    2015-01-01

    This quasi-experimental study investigated how explicit instruction about multiple modes of representation (MMR) impacted grades 7 (n = 61) and 8 (n = 141) students' learning and multimodal use on end-of-unit assessments. Half of each teacher's (n = 3) students received an intervention consisting of explicit instruction on MMR in science…

  9. The Impact of Embedding Multiple Modes of Representation within Writing Tasks on High School Students' Chemistry Understanding

    ERIC Educational Resources Information Center

    McDermott, Mark A.; Hand, Brian

    2013-01-01

    This study investigated the impact on chemistry learning of the degree to which students embedded or integrated multiple modes of representation in end of unit writing-to-learn activities. A multi-case study approach utilizing quasi-experimental methodology involving intact high school chemistry classes taught by two different teachers was…

  10. The Gender Mix among Staff in Schools for Pupils with Severe and Profound Multiple Learning Difficulties and Its Impact.

    ERIC Educational Resources Information Center

    Goss, Phil

    2003-01-01

    This paper reports on several studies of gender mix among staff in ten schools for students with severe, profound and/or multiple disabilities. Headteachers' perceptions of the impact of women's dominance in these positions are explored, and a series of proposals for future recruitment and staff development is put forth. (Contains seven…

  11. Assessing the Impact of Faking on Binary Personality Measures: An IRT-Based Multiple-Group Factor Analytic Procedure

    ERIC Educational Resources Information Center

    Ferrando, Pere J.; Anguiano-Carrasco, Cristina

    2009-01-01

    This article proposes a model-based multiple-group procedure for assessing the impact of faking on personality measures and the scores derived from these measures. The assessment is at the item level and the base model, which is intended for binary items, can be parameterized both as an Item Response Theory (IRT) model and as an Item…

  12. Targeting oncogenes to improve breast cancer chemotherapy.

    PubMed

    Christensen, Laura A; Finch, Rick A; Booker, Adam J; Vasquez, Karen M

    2006-04-15

    Despite recent advances in treatment, breast cancer remains a serious health threat for women. Traditional chemotherapies are limited by a lack of specificity for tumor cells and the cell cycle dependence of many chemotherapeutic agents. Here we report a novel strategy to help overcome these limitations. Using triplex-forming oligonucleotides (TFOs) to direct DNA damage site-specifically to oncogenes overexpressed in human breast cancer cells, we show that the effectiveness of the anticancer nucleoside analogue gemcitabine can be improved significantly. TFOs targeted to the promoter region of c-myc directly inhibited gene expression by approximately 40%. When used in combination, specific TFOs increased the incorporation of gemcitabine at the targeted site approximately 4-fold, presumably due to induction of replication-independent DNA synthesis. Cells treated with TFOs and gemcitabine in combination showed a reduction in both cell survival and capacity for anchorage-independent growth (approximately 19% of untreated cells). This combination affected the tumorigenic potential of these cancer cells to a significantly greater extent than either treatment alone. This novel strategy may be used to increase the range of effectiveness of antitumor nucleosides in any tumor which overexpresses a targetable oncogene. Multifaceted chemotherapeutic approaches such as this, coupled with triplex-directed gene targeting, may lead to more than incremental improvements in nonsurgical treatment of breast tumors. PMID:16618728

  13. Single and multiple objective biomass-to-biofuel supply chain optimization considering environmental impacts

    NASA Astrophysics Data System (ADS)

    Valles Sosa, Claudia Evangelina

    respond to these new challenges, the Modified Multiple Objective Evolutionary Algorithm for the design optimization of a biomass to bio-refinery logistic system that considers the simultaneous maximization of the total profit and the minimization of three environmental impacts is presented. Sustainability balances economic, social and environmental goals and objectives. There exist several works in the literature that have considered economic and environmental objectives for the presented supply chain problem. However, there is a lack of research performed in the social aspect of a sustainable logistics system. This work proposes a methodology to integrate social aspect assessment, based on employment creation. Finally, most of the assessment methodologies considered in the literature only contemplate deterministic values, when in realistic situations uncertainties in the supply chain are present. In this work, Value-at-Risk, an advanced risk measure commonly used in portfolio optimization is included to consider the uncertainties in biofuel prices, among the others.

  14. 40 CFR 798.3320 - Combined chronic toxicity/oncogenicity.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 32 2014-07-01 2014-07-01 false Combined chronic toxicity/oncogenicity. 798.3320 Section 798.3320 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Chronic Exposure § 798.3320 Combined chronic toxicity/oncogenicity....

  15. The Impact of Ambulance and Patient Diversion on Crowdedness of Multiple Emergency Departments in a Region

    PubMed Central

    Kao, Chung-Yao; Yang, Jhen-Ci; Lin, Chih-Hao

    2015-01-01

    Emergency department (ED) overcrowding threatens healthcare quality. Ambulance diversion (AD) may relieve ED overcrowding; however, diverting patients from an overcrowded ED will load neighboring EDs with more patients and may result in regional overcrowding. The purpose of this study was to evaluate the impact of different diversion strategies on the crowdedness of multiple EDs in a region. The importance of regional coordination was also explored. A queuing model for patient flow was utilized to develop a computer program for simulating AD among EDs in a region. Key parameters, including patient arrival rates, percentages of patients of different acuity levels, percentage of patients transported by ambulance, and total resources of EDs, were assigned based on real data. The crowdedness indices of each ED and the regional crowdedness index were assessed to evaluate the effectiveness of various AD strategies. Diverting patients equally to all other EDs in a region is better than diverting patients only to EDs with more resources. The effect of diverting all ambulance-transported patients is similar to that of diverting only low-acuity patients. To minimize regional crowdedness, ambulatory patients should be sent to proper EDs when AD is initiated. Based on a queuing model with parameters calibrated by real data, patient flows of EDs in a region were simulated by a computer program. From a regional point of view, randomly diverting ambulatory patients provides almost no benefit. With regards to minimizing the crowdedness of the whole region, the most promising strategy is to divert all patients equally to all other EDs that are not already crowded. This result implies that communication and coordination among regional hospitals are crucial to relieve overall crowdedness. A regional coordination center may prioritize AD strategies to optimize ED utility. PMID:26659589

  16. The Impact of Ambulance and Patient Diversion on Crowdedness of Multiple Emergency Departments in a Region.

    PubMed

    Kao, Chung-Yao; Yang, Jhen-Ci; Lin, Chih-Hao

    2015-01-01

    Emergency department (ED) overcrowding threatens healthcare quality. Ambulance diversion (AD) may relieve ED overcrowding; however, diverting patients from an overcrowded ED will load neighboring EDs with more patients and may result in regional overcrowding. The purpose of this study was to evaluate the impact of different diversion strategies on the crowdedness of multiple EDs in a region. The importance of regional coordination was also explored. A queuing model for patient flow was utilized to develop a computer program for simulating AD among EDs in a region. Key parameters, including patient arrival rates, percentages of patients of different acuity levels, percentage of patients transported by ambulance, and total resources of EDs, were assigned based on real data. The crowdedness indices of each ED and the regional crowdedness index were assessed to evaluate the effectiveness of various AD strategies. Diverting patients equally to all other EDs in a region is better than diverting patients only to EDs with more resources. The effect of diverting all ambulance-transported patients is similar to that of diverting only low-acuity patients. To minimize regional crowdedness, ambulatory patients should be sent to proper EDs when AD is initiated. Based on a queuing model with parameters calibrated by real data, patient flows of EDs in a region were simulated by a computer program. From a regional point of view, randomly diverting ambulatory patients provides almost no benefit. With regards to minimizing the crowdedness of the whole region, the most promising strategy is to divert all patients equally to all other EDs that are not already crowded. This result implies that communication and coordination among regional hospitals are crucial to relieve overall crowdedness. A regional coordination center may prioritize AD strategies to optimize ED utility. PMID:26659589

  17. Impact of Pharmacotherapy on Cognitive Dysfunction in Patients with Multiple Sclerosis.

    PubMed

    Roy, Shumita; Benedict, Ralph H B; Drake, Allison S; Weinstock-Guttman, Bianca

    2016-03-01

    Cognitive impairment is a common symptom of multiple sclerosis (MS), adversely impacting many spheres of daily functioning. Yet the effectiveness of pharmacological interventions for cognitive impairment in MS is unclear. Clinicians and patients alike would benefit from formal guidelines regarding effective management of cognitive symptoms. We reviewed the background on the measurement, pathophysiology and risk factors for cognitive dysfunction in MS, and then examined the published clinical trials of pharmacotherapy, including both disease-modifying treatments (DMTs) and symptom-management therapies (SMTs). Our review of DMTs revealed only a single well-designed, randomized, controlled trial where intramuscular interferon (IFN)-β1a, administered once weekly, was compared with placebo. The results showed significant benefits in terms of cognitive processing speed and memory. Less convincing but promising data have shown the potential benefits of IFN-β1b and natalizumab. The literature on SMTs is replete with placebo-controlled, single-centre studies, with a failure to replicate initially promising results. The results for SMTs such as acetylcholinesterase inhibitors and psychostimulants are mixed. Some encouraging data show promise but not to a threshold of indication for standard clinical use. Numerous methodological factors hamper research in this area. Acknowledging the lack of firm conclusions, we argue that all DMTs are likely to benefit cognition and that, if otherwise safe, SMTs with some empirical support may be attempted at the discretion of the treating clinician. We offer some guidance on the assessment and monitoring of cognitive function to inform off-license treatment of cognitive impairment in MS patients. PMID:26884145

  18. A One-Day Dental Faculty Workshop in Writing Multiple-Choice Questions: An Impact Evaluation.

    PubMed

    AlFaris, Eiad; Naeem, Naghma; Irfan, Farhana; Qureshi, Riaz; Saad, Hussain; Al Sadhan, Ra'ed; Abdulghani, Hamza Mohammad; Van der Vleuten, Cees

    2015-11-01

    Long training workshops on the writing of exam questions have been shown to be effective; however, the effectiveness of short workshops needs to be demonstrated. The aim of this study was to evaluate the impact of a one-day, seven-hour faculty development workshop at the College of Dentistry, King Saud University, Saudi Arabia, on the quality of multiple-choice questions (MCQs). Kirkpatrick's four-level evaluation model was used. Participants' satisfaction (Kirkpatrick's Level 1) was evaluated with a post-workshop questionnaire. A quasi-experimental, randomized separate sample, pretest-posttest design was used to assess the learning effect (Kirkpatrick's Level 2). To evaluate transfer of learning to practice (Kirkpatrick's Level 3), MCQs created by ten faculty members as a result of the training were assessed. To assess Kirkpatrick's Level 4 regarding institutional change, interviews with three key leaders of the school were conducted, coded, and analyzed. A total of 72 course directors were invited to and attended some part of the workshop; all 52 who attended the entire workshop completed the satisfaction form; and 22 of the 36 participants in the experimental group completed the posttest. The results showed that all 52 participants were highly satisfied with the workshop, and significant positive changes were found in the faculty members' knowledge and the quality of their MCQs with effect sizes of 0.7 and 0.28, respectively. At the institutional level, the interviews demonstrated positive structural changes in the school's assessment system. Overall, this one-day item-writing faculty workshop resulted in positive changes at all four of Kirkpatrick's levels; these effects suggest that even a short training session can improve a dental school's assessment of its students. PMID:26522635

  19. SU-E-T-428: Dosimetric Impact of Multileaf Collimator Leaf Width On Single and multiple Isocenter Stereotactic IMRT Treatment Plans for multiple Brain Tumors

    SciTech Connect

    Giem, J; Algan, O; Ahmad, S; Ali, I; Young, J; Hossain, S

    2014-06-01

    Purpose: To assess the impacts that multileaf collimator (MLC) leaf width has on the dose conformity and normal brain tissue doses of single and multiple isocenter stereotactic IMRT (SRT) plans for multiple intracranial tumors. Methods: Fourteen patients with 2–3 targets were studied retrospectively. Patients treated with multiple isocenter treatment plans using 9 to 12 non-coplanar beams per lesion underwent repeat planning using single isocenter and 10 to 12 non-coplanar beams with 2.5mm, 3mm and 5mm MLC leaf widths. Brainlab iPlan treatment planning system for delivery with the 2.5mm MLC served as reference. Identical contour sets and dose-volume constraints were applied. The prescribed dose to each target was 25 Gy to be delivered over 5 fractions with a minimum of 99% dose to cover ≥ 95% of the target volume. Results: The lesions and normal brains ranged in size from 0.11 to 51.67cc (median, 2.75cc) and 1090 to 1641cc (median, 1401cc), respectively. The Paddick conformity index for single and multiple isocenter (2.5mm vs. 3mm and 5mm MLCs) was (0.79±0.08 vs. 0.79±0.07 and 0.77±0.08) and (0.79±0.09 vs. 0.77±0.09 and 0.76±0.08), respectively. The average normal brain volumes receiving 15 Gy for single and multiple isocenter (2.5mm vs. 3mm and 5mm MLCs) were (3.65% vs. 3.95% and 4.09%) and (2.89% vs. 2.91% and 2.92%), respectively. Conclusion: The average dose conformity observed for the different leaf width for single and multiple isocenter plans were similar, throughout. However, the average normal brain volumes receiving 2.5 to 15 Gy were consistently lower for the 2.5mm MLC leaf width, especially for single isocenter plans. The clinical consequences of these integral normal brain tissue doses are still unknown, but employing the use of the 2.5mm MLC option is desirable at sparing normal brain tissue for both single and multiple isocenter cases.

  20. Hedgehog Cholesterolysis: Specialized Gatekeeper to Oncogenic Signaling

    PubMed Central

    Callahan, Brian P.; Wang, Chunyu

    2015-01-01

    Discussions of therapeutic suppression of hedgehog (Hh) signaling almost exclusively focus on receptor antagonism; however, hedgehog’s biosynthesis represents a unique and potentially targetable aspect of this oncogenic signaling pathway. Here, we review a key biosynthetic step called cholesterolysis from the perspectives of structure/function and small molecule inhibition. Cholesterolysis, also called cholesteroylation, generates cholesterol-modified Hh ligand via autoprocessing of a hedgehog precursor protein. Post-translational modification by cholesterol appears to be restricted to proteins in the hedgehog family. The transformation is essential for Hh biological activity and upstream of signaling events. Despite its decisive role in generating ligand, cholesterolysis remains conspicuously unexplored as a therapeutic target. PMID:26473928

  1. TGIF function in oncogenic Wnt signaling.

    PubMed

    Razzaque, Mohammed S; Atfi, Azeddine

    2016-04-01

    Transforming growth-interacting factor (TGIF) has been implicated in the pathogenesis of many types of human cancer, but the underlying mechanisms remained mostly enigmatic. Our recent study has revealed that TGIF functions as a mediator of oncogenic Wnt/β-catenin signaling. We found that TGIF can interact with and sequesters Axin1 and Axin2 into the nucleus, thereby culminating in disassembly of the β-catenin-destruction complex and attendant accumulation of β-catenin in the nucleus, where it activates expression of Wnt target genes, including TGIF itself. We have provided proof-of-concept evidences that high levels of TGIF expression correlate with poor prognosis in patients with triple negative breast cancer (TNBC), and that TGIF empowers Wnt-driven mammary tumorigenesis in vivo. Here, we will briefly summarize how TGIF influences Wnt signaling to promote tumorigenesis. PMID:26522669

  2. Impact of prosthodontic treatment on the oral health related quality of life in a maxillectomy patient with multiple impairments.

    PubMed

    Faheemuddin, Muhammad; Yazdanie, Nazia; Nawaz, Muhammad Sohaib

    2014-01-01

    Oral Health Related Quality of Life is an important component in the treatment of a patient. Patients with multiple impairments have a compromised quality of life, which is further worsened by ablative maxillary surgery. A properly made oral prosthesis aids in the daily life functions and therefore, has a positive impact on the quality of life of the patient. This article discusses a case in which prosthodontic treatment improved the Oral Health Related Quality of Life in a maxillectomy patient having multiple impairments. PMID:25603688

  3. Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element.

    PubMed

    Mansour, Marc R; Abraham, Brian J; Anders, Lars; Berezovskaya, Alla; Gutierrez, Alejandro; Durbin, Adam D; Etchin, Julia; Lawton, Lee; Sallan, Stephen E; Silverman, Lewis B; Loh, Mignon L; Hunger, Stephen P; Sanda, Takaomi; Young, Richard A; Look, A Thomas

    2014-12-12

    In certain human cancers, the expression of critical oncogenes is driven from large regulatory elements, called super-enhancers, that recruit much of the cell's transcriptional apparatus and are defined by extensive acetylation of histone H3 lysine 27 (H3K27ac). In a subset of T-cell acute lymphoblastic leukemia (T-ALL) cases, we found that heterozygous somatic mutations are acquired that introduce binding motifs for the MYB transcription factor in a precise noncoding site, which creates a super-enhancer upstream of the TAL1 oncogene. MYB binds to this new site and recruits its H3K27 acetylase-binding partner CBP, as well as core components of a major leukemogenic transcriptional complex that contains RUNX1, GATA-3, and TAL1 itself. Additionally, most endogenous super-enhancers found in T-ALL cells are occupied by MYB and CBP, which suggests a general role for MYB in super-enhancer initiation. Thus, this study identifies a genetic mechanism responsible for the generation of oncogenic super-enhancers in malignant cells. PMID:25394790

  4. Impact of psychotherapy on insomnia symptoms in patients with depression and multiple sclerosis.

    PubMed

    Baron, Kelly Glazer; Corden, Marya; Jin, Ling; Mohr, David C

    2011-04-01

    The purpose of the study was to evaluate the prevalence of insomnia in multiple sclerosis patients with comorbid depression, associations between psychological symptoms, multiple sclerosis symptoms and insomnia, and to test effects of a 16-week protocol-based psychotherapy intervention for depression on insomnia symptoms. Participants with multiple sclerosis and depression (n = 127) were randomized to telephone administered cognitive behavioral therapy and telephone administered supportive emotion-focused therapy. Multiple sclerosis functional limitation was measured at baseline. Depression, insomnia, anxiety and quality of life were evaluated at pre treatment, mid treatment (8 weeks), and post treatment (16 weeks). Prevalence of insomnia ≥3 times per week was 78% at pre treatment and 43% at post treatment. Insomnia at baseline was associated with depression, multiple sclerosis related mood symptoms and anxiety. Middle of the night awakenings were associated with swallowing and speech problems. Improvements in insomnia were associated with improvement in depression and anxiety. Participants with residual insomnia were more likely to have major depressive disorder, greater multiple sclerosis severity, elevated anxiety and lower mental components of quality of life. Results demonstrate rates of insomnia in patients with comorbid multiple sclerosis and depression are higher than those reported in the general multiple sclerosis population and additional insomnia treatment is indicated beyond the treatment of comorbid psychological disorders. PMID:20809354

  5. Evidence for Multiple Holocene Marine Impact Events: Ejecta in a Bog Core

    NASA Astrophysics Data System (ADS)

    Abbott, D. H.; Courty, M.; Breger, D.; Costa, S.; Gerard-Little, P.; Burckle, L.; Pekar, S.

    2006-12-01

    In a core from Tamarack Pond (a former bog) in the Hudson Highlands of New York, we found two layers containing marine microfossils. Because carbon rich sediments can be bioturbated over 20 cm depths, we give the layer thicknesses as 20 cm. The first layer is at 332-354 cm depth. It contains a radiolarian with a splashed on coating of Fe-Cr-Ni metal. It also contains a benthonic foraminiferal fossil. The second layer is at 432-454 cm depth. The second layer contains a degraded radiolarian fossil, a silicate with a splashed on coating of Fe-Cr-Ni metal, a carbon rich spherule containing Fe-Cr-Ni metal, and a grain of titanomagnetite with multiple craters. It also contains organic matter with Sn in it. As Tamarack Pond is quite far from the ocean, the marine fossils in the cores are unlikely to be windblown debris of Holocene age. A benthonic foraminifera is particularly unlikely to be blown by the wind. This conclusion is strengthened by the observation that the splashed on coating of Fe-Cr-Ni metal occurs in chondritic relative abundances with Fe>Cr>Ni. In grains with a thick layer of splashed metal, the Ni is sufficiently abundant to produce 3 distinct Ni peaks in the X-ray analysis. Such a high abundance of Ni coupled with chondritic relative abundances suggests that the Fe-Cr- Ni splash is derived from the vaporization of an extraterrestrial impactor. If we assume that the sedimentation rate of the Tamarack Pond core is the same as that of a previously dated core from nearby Sutherland Pond, the two layers have an uncorrected C-14 age of around 900-1200 B.C. for the layer at 332-354 cm and 2100 to 2400 B.C. for the layer at 432-454 cm. Both ages have a rough correspondence with times of climate downturn recorded in tree ring data (1159 and 2354 B.C.). These climate downturns cannot be explained by volcanic eruptions and are proposed to be cosmogenic in origin[1]. The older layer also corresponds in components to a previously studied circa 2350 B.C. impact ejecta

  6. Characterization of dissolved organic matter in drinking water sources impacted by multiple tributaries.

    PubMed

    Rosario-Ortiz, Fernando L; Snyder, Shane A; Suffet, I H

    2007-10-01

    The characterization of dissolved organic matter (DOM) in drinking water sources is important as this material contributes to the formation of disinfection by-products (DBPs) and affects how water treatment unit operations are optimized. Drinking water utilities often draw water from sources impacted by multiple tributaries, with possible shifts in DOM concentrations and reactivity over time, depending on specific environmental conditions. In this study, results are presented on the characterization of DOM under varying ambient conditions from the four main tributaries of Lake Mead, a large reservoir in the southwest United States. The tributaries include the Las Vegas Wash (LVW), Muddy River (MR), Virgin River (VR) and the upper Colorado River (UCR). One additional sample was collected at the outflow of the reservoir (lower Colorado River (LCR)). The DOM was characterized by both bulk parameters (specific ultraviolet absorbance (SUVA)) and specific physicochemical properties, i.e. size, polarity and fluorescence. The analyses were performed emphasizing limited changes in its natural configuration by eliminating analytical preparation steps, excluding sample filtration (0.45 microm filter). Results indicate that each tributary had a different molecular weight distribution, as well as fluorescence properties, which helped in the identification of the relative source of DOM (allochthonous versus autochthonous). The largest apparent molecular weight distribution was observed for DOM samples collected at the MR site, which is fed mostly by groundwater seepage. The smallest apparent molecular weight was observed for DOM collected at the LCR site, suggesting that retention in the reservoir resulted in a decrease in molecular weight as a probable result of photo oxidation and microbial processes. Fluorescence analysis aided the differentiation of DOM by clearly identifying waters that were affected by microbial activity (LVW, UCR, and LCR), either by wastewater influence

  7. Activation of ras oncogenes preceding the onset of neoplasia

    SciTech Connect

    Kumar, R.; Barbacid, M. ); Sukumar, S. )

    1990-06-01

    The identification of ras oncogenes in human and animal cancers including precancerous lesions indicates that these genes participate in the early stages of neoplastic development. Yet, these observations do not define the timing of ras oncogene activation in the multistep process of carcinogenesis. To ascertain the timing of ras oncogene activation, an animal model system was devised that involves the induction of mammary carcinomas in rats exposed at birth to the carcinogen nitrosomethylurea. High-resolution restriction fragment length polymorphism analysis of polymerase chain reaction-amplified ras sequences revealed the presence of both H-ras and K-ras oncogenes in normal mammary glands 2 weeks after carcinogen treatment and at least 2 months before the onset of neoplasia. These ras oncogenes can remain latent within the mammary gland until exposure to estrogens, demonstrating that activation of ras oncogenes can precede the onset of neoplasia and suggesting that normal physiological proliferative processes such as estrogen-induced mammary gland development may lead to neoplasia if the targeted cells harbor latent ras oncogenes.

  8. Cyclin K and cyclin D1b are oncogenic in myeloma cells

    PubMed Central

    2010-01-01

    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. PMID:20459741

  9. Noncanonical Roles of the Immune System in Eliciting Oncogene Addiction

    PubMed Central

    Casey, Stephanie C.; Bellovin, David I.; Felsher, Dean W.

    2013-01-01

    Summary Cancer is highly complex. The magnitude of this complexity makes it highly surprising that even the brief suppression of an oncogene can sometimes result in rapid and sustained tumor regression illustrating that cancers can be “oncogene addicted” [1-10]. The essential implication is that oncogenes may not only fuel the initiation of tumorigenesis, but in some cases necessarily their surfeit of activation is paramaount to maintain a neoplastic state [11]. Oncogene suppression acutely restores normal physiological programs that effectively overrides secondary genetic events and a cancer collapses [12,13]. Oncogene addiction is mediated both through both tumor intrinsic cell-autonomous mechanisms including proliferative arrest, apoptosis, differentiation and cellular senescence [1,2,4,12] but also host-dependent mechanisms that interact with these tumor intrinsic programs [14,15]. Notably, oncogene inactivation elicits a host immune response that involves specific immune effectors and cytokines that facilitate a remodeling of the tumor microenvironment including the shut down of angiogenesis and the induction of cellular senescence of tumor cells [16]. Hence, immune effectors are critically involved in tumor initiation and prevention [17-19] and progression [20], but also appear to be essential to tumor regression upon oncogene inactivation [21-23]. The understanding how the inactivation of an oncogene elicits a systemic signal in the host that prompts a deconstruction of a tumor could have important implications. The combination of oncogene-targeted therapy together with immunomodulatory therapy may be ideal for the development of both a robust tumor intrinsic as well as immunological effectively leading to sustained tumor regression. PMID:23571026

  10. The Impact of Disability on the Career Development of People with Multiple Sclerosis.

    ERIC Educational Resources Information Center

    Salomone, Paul R.; O'Connell, Kathryn R.

    1998-01-01

    Interviews with 12 people with multiple sclerosis explored the meaning of career and work in their lives and the implications of living with a disability, as well as barriers they faced, particularly environmental barriers and societal attitudes. (SK)

  11. The Impact of Conservation Management on the Community Composition of Multiple Organism Groups in Eutrophic Interconnected Man-Made Ponds.

    PubMed

    Lemmens, Pieter; Mergeay, Joachim; Van Wichelen, Jeroen; De Meester, Luc; Declerck, Steven A J

    2015-01-01

    Ponds throughout the world are subjected to a variety of management measures for purposes of biodiversity conservation. Current conservation efforts typically comprise a combination of multiple measures that directly and indirectly impact a wide range of organism groups. Knowledge of the relative impact of individual measures on different taxonomic groups is important for the development of effective conservation programs. We conducted a field study of 28 man-made ponds, representing four management types differing in the frequency of periodic pond drainage and the intensity of fish stock management. We disentangled the relative importance of direct and indirect effects of pond management measures on the community composition of phytoplankton, zooplankton, aquatic macro-invertebrates, submerged and emergent vascular plants. With the exception of phytoplankton, pond management had strong effects on the community composition of all investigated biota. Whether management affected communities directly or indirectly through its impact on fish communities or local environmental conditions in the pond varied between organism groups. Overall, the impact of pond drainage regime and fish community characteristics on the community composition of target organism groups were more important than local environmental conditions. The majority of taxa were negatively associated with fish density, whereas multiple emergent plant species and several taxa of aquatic macro-invertebrates were positively affected by increased drainage frequency. The effects of fish community and drainage tended to be largely independent. The present study indicates that pond drainage is an important element for biodiversity conservation in eutrophicated shallow and interconnected man-made ponds. PMID:26422390

  12. The Impact of Conservation Management on the Community Composition of Multiple Organism Groups in Eutrophic Interconnected Man-Made Ponds

    PubMed Central

    Lemmens, Pieter; Mergeay, Joachim; Van Wichelen, Jeroen; De Meester, Luc; Declerck, Steven A. J.

    2015-01-01

    Ponds throughout the world are subjected to a variety of management measures for purposes of biodiversity conservation. Current conservation efforts typically comprise a combination of multiple measures that directly and indirectly impact a wide range of organism groups. Knowledge of the relative impact of individual measures on different taxonomic groups is important for the development of effective conservation programs. We conducted a field study of 28 man-made ponds, representing four management types differing in the frequency of periodic pond drainage and the intensity of fish stock management. We disentangled the relative importance of direct and indirect effects of pond management measures on the community composition of phytoplankton, zooplankton, aquatic macro-invertebrates, submerged and emergent vascular plants. With the exception of phytoplankton, pond management had strong effects on the community composition of all investigated biota. Whether management affected communities directly or indirectly through its impact on fish communities or local environmental conditions in the pond varied between organism groups. Overall, the impact of pond drainage regime and fish community characteristics on the community composition of target organism groups were more important than local environmental conditions. The majority of taxa were negatively associated with fish density, whereas multiple emergent plant species and several taxa of aquatic macro-invertebrates were positively affected by increased drainage frequency. The effects of fish community and drainage tended to be largely independent. The present study indicates that pond drainage is an important element for biodiversity conservation in eutrophicated shallow and interconnected man-made ponds. PMID:26422390

  13. Impact of Proactive Case Management by Multiple Sclerosis Specialist Nurses on Use of Unscheduled Care and Emergency Presentation in Multiple Sclerosis

    PubMed Central

    Quinn, Debbie; Bowen, Amy

    2015-01-01

    Background: Multiple sclerosis (MS) affects approximately 100,000 people in the United Kingdom, with rising emergency admissions to the hospital. The multiple sclerosis specialist nurse plays a pivotal role in managing MS care in the United Kingdom, and there is anecdotal evidence that this role can help avoid emergency presentations and unnecessary hospital admissions. Methods: A retrospective service evaluation took place in one established MS nursing service. The impact of the introduction of proactive nurse-led management and a rapid response service on rates of emergency presentation, hospital admission, and bed use was examined. The primary intervention was the introduction of extra nursing hours (6 hours per week) and the reallocation of some routine administrative duties, which allowed the service to move to a proactive management model aimed at avoiding the need for unplanned care. In addition, a care pathway was implemented in the emergency department for patients with MS who did present. Results: Reduction in utilization was from a mean of 2700 bed-days per year (2002–2006) to a mean of 198 bed-days per year (2007–2013). Conclusions: During a 10-year period, moving from reactive management to proactive management demonstrated an increase in complex specialist nursing interventions and led to a decrease in emergency presentation and bed use at the local acute-care center. PMID:26300701

  14. Coeval ages of Australasian, Central American and Western Canadian tektites reveal multiple impacts 790 ka ago

    NASA Astrophysics Data System (ADS)

    Schwarz, Winfried H.; Trieloff, Mario; Bollinger, Klemens; Gantert, Niklas; Fernandes, Vera A.; Meyer, Hans-Peter; Povenmire, Hal; Jessberger, Elmar K.; Guglielmino, Massimo; Koeberl, Christian

    2016-04-01

    High resolution 40Ar-39Ar step heating dating of australites and indochinites, representing a large area of the Australasian strewn field, and more recently discovered tektite-like glasses from Central America (Belize) and Western Canada, were carried out. Precise plateau ages were obtained in all cases, yielding indistinguishable ages of 789 ± 9 ka for four australites, 783 ± 5 ka for four indochinites, 783 ± 17 ka for one Western Canadian and 769 ± 16 ka for one Belize impact glass. Concerning major elements and REEs, australites and the Western Canadian impact glass are indistinguishable. If the Western Canadian sample was transported by impact ejection and belongs to the Australasian strewn field, this implies extremely far ballistic transport of 9000 km distance, assuming a source crater in southern Asia. The distinct major element and REE composition of the Belize impact glass suggests formation in another separate impact event. We conclude that the Australasian/Western Canadian impact glasses formed 785 ± 7 ka ago in a single event and Belize impact glass in a separate event 769 ± 16 ka ago. The two impact events forming these two strewn fields occurred remarkably closely related in time, i.e., separated by <30 ka.

  15. Lysyl oxidase activity regulates oncogenic stress response and tumorigenesis.

    PubMed

    Wiel, C; Augert, A; Vincent, D F; Gitenay, D; Vindrieux, D; Le Calvé, B; Arfi, V; Lallet-Daher, H; Reynaud, C; Treilleux, I; Bartholin, L; Lelievre, E; Bernard, D

    2013-01-01

    Cellular senescence, a stable proliferation arrest, is induced in response to various stresses. Oncogenic stress-induced senescence (OIS) results in blocked proliferation and constitutes a fail-safe program counteracting tumorigenesis. The events that enable a tumor in a benign senescent state to escape from OIS and become malignant are largely unknown. We show that lysyl oxidase activity contributes to the decision to maintain senescence. Indeed, in human epithelial cell the constitutive expression of the LOX or LOXL2 protein favored OIS escape, whereas inhibition of lysyl oxidase activity was found to stabilize OIS. The relevance of these in vitro observations is supported by in vivo findings: in a transgenic mouse model of aggressive pancreatic ductal adenocarcinoma (PDAC), increasing lysyl oxidase activity accelerates senescence escape, whereas inhibition of lysyl oxidase activity was found to stabilize senescence, delay tumorigenesis, and increase survival. Mechanistically, we show that lysyl oxidase activity favors the escape of senescence by regulating the focal-adhesion kinase. Altogether, our results demonstrate that lysyl oxidase activity participates in primary tumor growth by directly impacting the senescence stability. PMID:24113189

  16. Oncogenic Potential of Hepatitis C Virus Proteins

    PubMed Central

    Banerjee, Arup; Ray, Ratna B.; Ray, Ranjit

    2010-01-01

    Chronic hepatitis C virus (HCV) infection is a major risk factor for liver disease progression, and may lead to cirrhosis and hepatocellular carcinoma (HCC). The HCV genome contains a single-stranded positive sense RNA with a cytoplasmic lifecycle. HCV proteins interact with many host-cell factors and are involved in a wide range of activities, including cell cycle regulation, transcriptional regulation, cell proliferation, apoptosis, lipid metabolism, and cell growth promotion. Increasing experimental evidences suggest that HCV contributes to HCC by modulating pathways that may promote malignant transformation of hepatocytes. At least four of the 10 HCV gene products, namely core, NS3, NS5A and NS5B play roles in several potentially oncogenic pathways. Induction of both endoplasmic reticulum (ER) stress and oxidative stress by HCV proteins may also contribute to hepatocyte growth promotion. The current review identifies important functions of the viral proteins connecting HCV infections and potential for development of HCC. However, most of the putative transforming potentials of the HCV proteins have been defined in artificial cellular systems, and need to be established relevant to infection and disease models. The new insight into the mechanisms for HCV mediated disease progression may offer novel therapeutic targets for one of the most devastating human malignancies in the world today. PMID:21994721

  17. Oncogene-dependent apoptosis is mediated by caspase-9

    PubMed Central

    Fearnhead, Howard O.; Rodriguez, Joe; Govek, Eve-Ellen; Guo, Wenjun; Kobayashi, Ryuji; Hannon, Greg; Lazebnik, Yuri A.

    1998-01-01

    Understanding how oncogenic transformation sensitizes cells to apoptosis may provide a strategy to kill tumor cells selectively. We previously developed a cell-free system that recapitulates oncogene dependent apoptosis as reflected by activation of caspases, the core of the apoptotic machinery. Here, we show that this activation requires a previously identified apoptosis-promoting complex consisting of caspase-9, APAF-1, and cytochrome c. As predicted by the in vitro system, preventing caspase-9 activation blocked drug-induced apoptosis in cells sensitized by E1A, an adenoviral oncogene. Oncogenes, such as E1A, appear to facilitate caspase-9 activation by several mechanisms, including the control of cytochrome c release from the mitochondria. PMID:9811857

  18. ERBB2 oncogenicity: ERBIN helps to perform the job

    PubMed Central

    Mei, Lin; Borg, Jean-Paul

    2015-01-01

    ERBB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) is an oncogenic tyrosine kinase receptor that is overexpressed in breast cancer. Antibodies and inhibitors targeting ERBB2 are currently available, although therapeutic failures remain frequent. We discuss here recent data showing that the scaffold protein ERBB2IP (ERBB2 interacting protein, best known as ERBIN) regulates ERBB2 stability and may represent a future therapeutic target. PMID:27308480

  19. Know thy neighbor: stromal cells can contribute oncogenic signals

    NASA Technical Reports Server (NTRS)

    Tlsty, T. D.; Hein, P. W.

    2001-01-01

    Although the stroma within carcinogenic lesions is known to be supportive and responsive to tumors, new data increasingly show that the stroma also has a more active, oncogenic role in tumorigenesis. Stromal cells and their products can transform adjacent tissues in the absence of pre-existing tumor cells by inciting phenotypic and genomic changes in the epithelial cells. The oncogenic action of distinctive stromal components has been demonstrated through a variety of approaches, which provide clues about the cellular pathways involved.

  20. Role of “oncogenic nexus” of CIP2A in breast oncogenesis: how does it work?

    PubMed Central

    De, Pradip; Carlson, Jennifer H; Leyland-Jones, Brian; Dey, Nandini

    2015-01-01

    The CIP2A gene is an oncogene associated with solid and hematologic malignancies [1]. CIP2A protein is an oncoprotein and a potential cancer therapy target [2]. Literature shows that CIP2A inhibits the tumor suppressor protein PP2A [3] which downregulates phophorylation of AKT, a hallmark of cancers [4] and stabilizes the proto-oncogene, c-MYC in tumor cells [5], the comprehensive action of CIP2A and its functional interaction(s) with other oncoproteins and tumor suppressors is not clearly established. Recently we tried to put forward a contextual mode-of-action of CIP2A protein in a review which proposed that CIP2A influences oncogenesis via an “oncogenic nexus” [1]. In this review we critically evaluated the potential relevance of the mode-of-action of the “oncogenic nexus” of CIP2A in breast carcinogenesis and appraised the role of this nexus in different PAM50 luminal A, PAM50 luminal B, PAM50 HER2-enriched and PAM50 basal BC. This review has a novel approach. Here we have not only compiled and discussed the latest developments in this field but also presented data obtained from c-BioPortal and STRING10 in order to substantiate our view regarding the mode-of-action of the “oncogenic nexus” of CIP2A. We functionally correlated alterations of genes pertaining to the “oncogenic nexus” of CIP2A with protein-protein interactions between the different components of the nexus including (1) subunits of PP2A, (2) multiple transcription factors including MYC oncogene and (3) components of the PI3K-mTOR and the MAPK-ERK oncogenic pathways. Using these proteins as “input” to STRING10 we studied the association, Action view, at the highest Confidence level. OncoPrints (c-BioPortal) showed alterations (%) of regulatory subunits genes of PP2A (PPP2R1A and PPP2R1B) along with alterations of CIP2A in breast invasive carcinoma (TCGA, Nature 2012 & TCGA, Provisional). Similar genetic alterations of PP2A were also observed in samples of breast tumors at our

  1. A Record of the Sequence and Intensity of Multiple Impacts in the NWA 7298 H Chondrite

    NASA Astrophysics Data System (ADS)

    Friedrich, J. M.; Weisberg, M. K.; Rivers, M. L.

    2013-09-01

    We demonstrate evidence for the sequence and intensity of at least three distinct impact events affecting NWA 7298. These observations yield new opportunities for investigating the dynamic collisional evolution of asteroids.

  2. Identification of Tumor Suppressors and Oncogenes from Genomic and Epigenetic Features in Ovarian Cancer

    PubMed Central

    Wrzeszczynski, Kazimierz O.; Varadan, Vinay; Byrnes, James; Lum, Elena; Kamalakaran, Sitharthan; Levine, Douglas A.; Dimitrova, Nevenka; Zhang, Michael Q.; Lucito, Robert

    2011-01-01

    The identification of genetic and epigenetic alterations from primary tumor cells has become a common method to identify genes critical to the development and progression of cancer. We seek to identify those genetic and epigenetic aberrations that have the most impact on gene function within the tumor. First, we perform a bioinformatic analysis of copy number variation (CNV) and DNA methylation covering the genetic landscape of ovarian cancer tumor cells. We separately examined CNV and DNA methylation for 42 primary serous ovarian cancer samples using MOMA-ROMA assays and 379 tumor samples analyzed by The Cancer Genome Atlas. We have identified 346 genes with significant deletions or amplifications among the tumor samples. Utilizing associated gene expression data we predict 156 genes with altered copy number and correlated changes in expression. Among these genes CCNE1, POP4, UQCRB, PHF20L1 and C19orf2 were identified within both data sets. We were specifically interested in copy number variation as our base genomic property in the prediction of tumor suppressors and oncogenes in the altered ovarian tumor. We therefore identify changes in DNA methylation and expression for all amplified and deleted genes. We statistically define tumor suppressor and oncogenic features for these modalities and perform a correlation analysis with expression. We predicted 611 potential oncogenes and tumor suppressors candidates by integrating these data types. Genes with a strong correlation for methylation dependent expression changes exhibited at varying copy number aberrations include CDCA8, ATAD2, CDKN2A, RAB25, AURKA, BOP1 and EIF2C3. We provide copy number variation and DNA methylation analysis for over 11,500 individual genes covering the genetic landscape of ovarian cancer tumors. We show the extent of genomic and epigenetic alterations for known tumor suppressors and oncogenes and also use these defined features to identify potential ovarian cancer gene candidates. PMID

  3. Enhanced plasticity of bulk metallic glass in different aspect ratios via laser shock peening with multiple impacts

    NASA Astrophysics Data System (ADS)

    Fu, Jie; Zhu, Yunhu; Zheng, Chao; Liu, Ren; Ji, Zhong

    2016-09-01

    In this study laser shock peening (LSP) with multiple laser impacts was used to improve the mechanical properties especially the plasticity of Zr35Ti30Cu8.25Be26.75 bulk metallic glass (BMG) pillars in two aspect ratios (1:1 and 2:1). It was found that, with increasing laser impacts up to 5, the compression plastic strain of BMG pillar with aspect ratio of 1:1 increased from 0 to 1.48% and the compression strength increased significantly from 1569 MPa to 1721 MPa. With further laser impacts beyond 5, the changes in the plasticity and the compression strength were observed to be insignificant. Considering the effect of sample geometry at the same laser impacts, it could be concluded that the BMG pillars with smaller aspect ratio of 1:1 had better mechanical properties than that of the lager BMG pillars with aspect ratio of 2:1. Besides, the elastic strain limit of BMG pillars with LSP was not only independent of the laser impacts, but also irrelevant to the aspect ratio. At last, we discussed the reason for the increase of plasticity in view of the creation of excess free volume during LSP.

  4. Acquisition of Alphabet Knowledge in Kindergarten: Impact of Multiple Means of Representation

    ERIC Educational Resources Information Center

    Evans, La'Tondra; Stone, Karen

    2011-01-01

    Learning the alphabet is essential to learning how to read. This study focuses on teaching Kindergarten students the alphabet using multiple means of representation. The 24 Kindergarten students in this study have been exposed to activities that reflect their learning styles, interaction among various group settings, and they have been allowed to…

  5. Exploring the Impact of Classified Staff Interactions on Student Retention: A Multiple Case Study Approach

    ERIC Educational Resources Information Center

    Schmitt, Mary Ann; Duggan, Molly H.

    2011-01-01

    This multiple case study explored classified staff interactions with students as a possible strategy for increasing student success. Individual interviews, observations, and a focus group with support staff were used to investigate their interactions with students, their view of these interactions, and their expectations of students. Findings…

  6. The Impact of Parental Multiple Sclerosis on the Adjustment of Children and Adolescents.

    ERIC Educational Resources Information Center

    De Judicibus, Margaret A.; McCabe, Marita P.

    2004-01-01

    Thirty-one parents with multiple sclerosis (MS) participated in a study to investigate the adjustment of their children, 24 boys and 24 girls aged 4 to 16 years. The majority of parents believed that their illness had an effect on their children. The perception of parents regarding their children's problems in the areas of emotions, concentration,…

  7. Quality of Life in Patients with Multiple Sclerosis: The Impact of Depression, Fatigue, and Disability

    ERIC Educational Resources Information Center

    Goksel Karatepe, Altlnay; Kaya, Taciser; Gunaydn, Rezzan; Demirhan, Aylin; Ce, Plnar; Gedizlioglu, Muhtesem

    2011-01-01

    Aim: The aim of this study was to assess the quality of life (QoL) in patients with multiple sclerosis (MS), and to evaluate its association with disability and psychosocial factors especially depression and fatigue. Methods: Demographic characteristics, education level, disease severity, and disease duration were documented for each patient. QoL,…

  8. Development and Field Test of the Multiple Intelligences Learning Instruction Congruency Impact Scale

    ERIC Educational Resources Information Center

    Peifer, Nancy

    2012-01-01

    The purpose of this study was to contribute to the academic discussion regarding the validity of Multiple Intelligences (MI) theory through focusing on the validity of an important construct embedded in the theory, that of congruence between instructional style and preferred MI style for optimal learning. Currently there is insufficient empirical…

  9. Exploring the Impact of Sports Participation on Multiple Intelligence Development of High School Female Students

    ERIC Educational Resources Information Center

    Kul, Marat

    2015-01-01

    After Gardner had introduced the Multiple Intelligence (MI) theory, many researchers tried to find out the possibilities of applying this theory in the education domain. Moreover, the effects of different kinds of athletic applications on intelligence development within the framework of this theory have also been under investigation. This study…

  10. Exploring the Impact of Classified Staff Interactions on the Student Experience: A Multiple Case Study Approach

    ERIC Educational Resources Information Center

    Schmitt, Mary Ann

    2011-01-01

    This qualitative multiple case study explored front-line classified staff interactions with students as a possible strategy for increasing student success. The study was based on the premise that too few students stay at a community college long enough to achieve their academic goals. Therefore, college leaders must identify new strategies to…

  11. Comparing multiple exciton generation in quantum dots to impact ionization in bulk semiconductors: implications for enhancement of solar energy conversion.

    PubMed

    Beard, Matthew C; Midgett, Aaron G; Hanna, Mark C; Luther, Joseph M; Hughes, Barbara K; Nozik, Arthur J

    2010-08-11

    Multiple exciton generation (MEG) in quantum dots (QDs) and impact ionization (II) in bulk semiconductors are processes that describe producing more than one electron-hole pair per absorbed photon. We derive expressions for the proper way to compare MEG in QDs with II in bulk semiconductors and argue that there are important differences in the photophysics between bulk semiconductors and QDs. Our analysis demonstrates that the fundamental unit of energy required to produce each electron-hole pair in a given QD is the band gap energy. We find that the efficiency of the multiplication process increases by at least 2 in PbSe QDs compared to bulk PbSe, while the competition between cooling and multiplication favors multiplication by a factor of 3 in QDs. We also demonstrate that power conversion efficiencies in QD solar cells exhibiting MEG can greatly exceed conversion efficiencies of their bulk counterparts, especially if the MEG threshold energy can be reduced toward twice the QD band gap energy, which requires a further increase in the MEG efficiency. Finally, we discuss the research challenges associated with achieving the maximum benefit of MEG in solar energy conversion since we show the threshold and efficiency are mathematically related. PMID:20698615

  12. Comparing Multiple Exciton Generation in Quantum Dots To Impact Ionization in Bulk Semiconductors: Implications for Enhancement of Solar Energy Conversion

    SciTech Connect

    Beard, Matthew C.; Midgett, Aaron G.; Hanna, Mark C.; Luther, Joseph M.; Hughes, Barbara K.; Nozik, Arthur J.

    2010-07-26

    Multiple exciton generation (MEG) in quantum dots (QDs) and impact ionization (II) in bulk semiconductors are processes that describe producing more than one electron-hole pair per absorbed photon. We derive expressions for the proper way to compare MEG in QDs with II in bulk semiconductors and argue that there are important differences in the photophysics between bulk semiconductors and QDs. Our analysis demonstrates that the fundamental unit of energy required to produce each electron-hole pair in a given QD is the band gap energy. We find that the efficiency of the multiplication process increases by at least 2 in PbSe QDs compared to bulk PbSe, while the competition between cooling and multiplication favors multiplication by a factor of 3 in QDs. We also demonstrate that power conversion efficiencies in QD solar cells exhibiting MEG can greatly exceed conversion efficiencies of their bulk counterparts, especially if the MEG threshold energy can be reduced toward twice the QD band gap energy, which requires a further increase in the MEG efficiency. Finally, we discuss the research challenges associated with achieving the maximum benefit of MEG in solar energy conversion since we show the threshold and efficiency are mathematically related.

  13. Impact of the Body Mass on Complications and Outcome in Multiple Trauma Patients: What Does the Weight Weigh?

    PubMed Central

    Andruszkow, Hagen; Mommsen, Philipp; Zeckey, Christian; Frink, Michael

    2013-01-01

    Obesity is known as an independent risk factor for various morbidities. The influence of an increased body mass index (BMI) on morbidity and mortality in critically injured patients has been investigated with conflicting results. To verify the impact of weight disorders in multiple traumatized patients, 586 patients with an injury severity score >16 points treated at a level I trauma center between 2005 and 2011 were differentiated according to the BMI and analyzed regarding morbidity and outcome. Plasma levels of interleukin- (IL-) 6 and C-reactive protein (CRP) were measured during clinical course to evaluate the inflammatory response to the “double hit” of weight disorders and multiple trauma. In brief, obesity was the highest risk factor for development of a multiple organ dysfunction syndrome (MODS) (OR 4.209, 95%-CI 1.515–11.692) besides injury severity (OR 1.054, 95%-CI 1.020–1.089) and APACHE II score (OR 1.059, 95%-CI 1.001–1.121). In obese patients as compared to those with overweight, normal weight, and underweight, the highest levels of CRP were continuously present while increased systemic IL-6 levels were found until day 4. In conclusion, an altered posttraumatic inflammatory response in obese patients seems to determine the risk for multiple organ failure after severe trauma. PMID:24023413

  14. Depressive Symptoms Among Grandparents Raising Grandchildren: The Impact of Participation in Multiple Roles

    PubMed Central

    Baker, Lindsey A.; Silverstein, Merril

    2009-01-01

    Using the Health and Retirement Study, this research examines well-being among grandparents raising grandchildren during middle to late life, specifically looking at how other roles in which a grandparent is participating (such as worker, volunteer, parent or caregiver) may influence depressive symptoms among grandparent caregivers. Results indicate that grandparents who have recently begun raising a grandchild experience lower levels of well-being when compared to grandparents who are not raising a grandchild regardless of the grandparent's level of participation in roles beyond that of grandparent caregiver, while grandparents who have been raising a grandchild for longer periods of time seem to benefit from their participation in multiple roles. However, a higher level of participation in outside roles is associated with a decline in well-being among grandparents who stopped raising a grandchild, suggesting that, for these grandparents, participation in multiple roles acted mainly as a stressor, rather than as a resource. PMID:19890447

  15. [A long-term follow-up case of multiple impacted teeth associated with large follicular cyst in maxilla].

    PubMed

    Hirose, K; Suzuki, S; Kuroda, T

    2000-06-01

    Longitudinal record of a case of multiple impacted teeth associated with large follicular cyst in the right maxilla was presented. The patient was an 8-year-10-month-old girl whose chief complaint was delayed eruption of the right upper incisor. Clinical examination revealed a large follicular cyst in the right maxillary sinus, which greatly displaced teeth germs. Marsupialization followed by orthodontic extrusion successfully brought unerupted teeth into their positions. Greatly displaced upper right canine, which was as high as the floor of the orbit, erupted spontaneously after reduction of the lesion. During the subsequent years, the patient developed crowded dentition and reduced overbite, which needed additional orthodontic treatment with extraction of premolars. The patient was 26-years 8-months old upon completion of treatment. The surgical, orthodontic, and periodontological aspects of the case were reexamined. Marsupialization of dentigerous cysts can preserve impacted teeth, however, the outcome might be affected by several factors such as overall growth of facial bones. PMID:10921246

  16. [Impact of TDZ and NAA on adventitious bud induction and cluster bud multiplication in Tulipa edulis].

    PubMed

    Zhu, Li-Fang; Xu, Chao; Zhu, Zai-Biao; Yang, He-Tong; Guo, Qiao-Sheng; Xu, Hong-jian; Ma, Hong-Jian; Zhao, Gui-Hua

    2014-08-01

    To explore the method of explants directly induced bud and establish the tissue culture system of mutiple shoot by means of direct organogenesis, core bud and daughter bulbs (the top of bud stem expanded to form daughter bulb) of T. edulis were used as explants and treated with thidiazuron (TDZ) and 1-naphthlcetic acid (NAA). The results showed that the optimal medium for bud inducted form core bud and daughter bulb were MS + TDZ 2.0 mg x L(-1) + NAA 4.0 mg x L(-1) and MS +TDZ 2.0 mg x L(-1) + NAA 2.0 mg x L(-1) respectively, both of them had a bud induction rate of 72.92%, 79.22%. The optimal medium for cluster buds multiplication was MS + TDZ 0.2 mg x L(-1) + NAA 0.2 mg x L(-1), and proliferation coefficient was 2.23. After proliferation, cluster buds rooting occurred on MS medium with IBA 1.0 mg x L(-1) and the rooting rate was 52.6%, three to five seedlings in each plant. Using core bud and daughter bulb of T. edulis, the optimum medium for adventitious bud directly inducted from daughter bulb, core bud and cluster bud multiplication were screened out and the tissue culture system of multiple shoot by means of direct organogenesis was established. PMID:25509282

  17. Preparation and impact of multiple (water-in-oil-in-water) emulsions in meat systems.

    PubMed

    Cofrades, S; Antoniou, I; Solas, M T; Herrero, A M; Jiménez-Colmenero, F

    2013-11-01

    The aim of this paper was to prepare and characterise multiple emulsions and assess their utility as pork backfat replacers in meat gel/emulsion model systems. In order to improve the fat content (in quantitative and qualitative terms) pork backfat was replaced by a water-in-oil-in-water emulsion (W1/O/W2) prepared with olive oil (as lipid phase), polyglycerol ester of polyricinoleic acid (PGPR) as a lipophilic emulsifier, and sodium caseinate (SC) and whey protein concentrate (WP) as hydrophilic emulsifiers. The emulsion properties (particle size and distribution, stability, microstructure) and meat model system characteristics (composition, texture, fat and water binding properties, and colour) of the W1/O/W2, as affected by reformulation, were evaluated. Multiple emulsions showed a well-defined monomodal distribution. Freshly prepared multiple emulsions showed good thermal stability (better using SC) with no creaming. The meat systems had good water and fat binding properties irrespective of formulation. The effect on texture by replacement of pork backfat by W1/O/W2 emulsions generally depends on the type of double emulsion (associated with the hydrophilic emulsifier used in its formulation) and the fat level in the meat system. PMID:23768366

  18. Assessing the impacts of nonrandom seed dispersal by multiple frugivore partners on plant recruitment.

    PubMed

    Razafindratsima, Onja H; Dunham, Amy E

    2015-01-01

    Directed dispersal is defined as enhanced dispersal of seeds into suitable microhabitats, resulting in higher recruitment than if seeds were dispersed randomly. While this constitutes one of the main explanations for the adaptive value of frugivore-mediated seed dispersal, the generality of this advantage has received little study, particularly when multiple dispersers are involved. We used probability recruitment models of a long-lived rainforest tree in Madagascar to compare recruitment success under dispersal by multiple frugivores, no dispersal, and random dispersal. Models were parameterized using a three-year recruitment experiment and observational data of dispersal events by three frugivorous lemur species that commonly disperse its seeds. Frugivore-mediated seed dispersal was nonrandom with respect to canopy cover and increased modeled per-seed sapling recruitment fourfold compared to no dispersal. Seeds dispersed by one frugivore, Eulemur rubriventer, had higher modeled recruitment probability than seeds dispersed randomly. However, as a group, our models suggest that seeds dispersed by lemurs would have lower recruitment than if dispersal were random. Results demonstrate the importance of evaluating the contribution of multiple frugivores to plant recruitment for understanding plant population dynamics and the ecological and evolutionary significance of seed dispersal. PMID:26236886

  19. Educational Impact of Graduate Nonprofit Degree Programs: Perspectives of Multiple Stakeholders.

    ERIC Educational Resources Information Center

    Mirabella, Roseanne M.; Wish, Naomi B.

    1999-01-01

    As part of a larger study, focus groups conducted at ten university-based nonprofit-management education programs investigated the impact of the programs on various stakeholders, including faculty, administrators, employers in the nonprofit sector, and alumni. Implications for program goals, targeted skills and competencies, and measurement of…

  20. Effects of multiple. 30-caliber bullet impacts on steel-encased explosives: Experimental Report I

    SciTech Connect

    Honodel, C A

    1984-12-01

    Thirty-one experiments have been performed in a series where typical explosive formulations for weapons were encased in steel vessels and impacted by up to six .30-caliber bullets fired at 1.2-s intervals. We have observed that detonation can occur on the second bullet impact if the high-explosive configuration (detonator, booster, and main charge) is complete and tested at an elevated temperature. So far, shots with some mock parts have exploded (no detonation) after several bullet impacts, where the response to preceeding bullets ranged from no reaction to violent deflagration. When RX-26-AF was substituted for the booster explosive LX-10, there was reduced violence. Conversely, when we completely replaced all the high-explosive components with a solid filling of LX-10, we discovered a charge-size limitation where detonation occurred on the first bullet impact. To help quantify the violence exhibited by these detonations, we purposely detonated one shot and compared the high-speed camera records and recovery samples.

  1. Trend and uncertainty analysis of simulated climate change impacts with multiple GCMs and emission scenarios

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Impacts of climate change on hydrology, soil erosion, and wheat production during 2010-2039 at El Reno in central Oklahoma, USA, were simulated using the Water Erosion Prediction Project (WEPP) model. Projections from four GCMs (CCSR/NIES, CGCM2, CSIRO-Mk2, and HadCM3) under three emissions scenari...

  2. Assessing the Impact of Temperature on Grape Phenolic Metabolism Using Multiple Chromatographic Approaches

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study assessed the impact of fruit temperature on the phenolic metabolism of grape berries (Vitis vinifera L. cv. Merlot) grown under field conditions with controlled exposure to sunlight. Individual cluster temperatures were manipulated in situ. Diurnal temperature fluctuation was damped by ...

  3. Experimental and numerical study of single and multiple impacts of angular particles on ductile metals

    NASA Astrophysics Data System (ADS)

    Takaffoli, Mahdi

    Solid particle erosion occurs when small high speed particles impact surfaces. It can be either destructive such as in the erosion of oil pipelines by corrosion byproducts, or constructive such as in abrasive jet machining processes. Two dimensional finite element (FE) models of single rhomboid particles impact on a copper target were developed using two different techniques to deal with the problem of element distortion: (i) element deletion, and (ii) remeshing. It was found that the chip formation and the material pile-up, two phenomena that cannot be simulated using a previously developed rigid-plastic model, could be simulated using the FE models, resulting in a good agreement with experiments performed using a gas gun. However, remeshing in conjunction with a failure model caused numerical instabilities. The element deletion approach also induced errors in mass loss due to the removal of distorted elements. To address the limitations of the FE approach, smoothed particle hydrodynamics (SPH) which can better accommodate large deformations, was used in the simulation of the impact of single rhomboid particles on an aluminum alloy target. With appropriate constitutive and failure parameters, SPH was demonstrated to be suitable for simulating all of the relevant damage phenomena observed during impact experiments. A new methodology was developed for generating realistic three dimensional particle geometries based on measurements of the size and shape parameter distributions for a sample of 150 microm nominal diameter angular aluminum oxide powder. The FE models of these generated particles were implemented in a SPH/FE model to simulate non-overlapping particle impacts. It was shown that the simulated particles produced distributions of crater and crater lip dimensions that agreed well with those measured from particle blasting experiments. Finally, a numerical model for simulating overlapping impacts of angular particles was developed and compared to experimental

  4. Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase

    PubMed Central

    Moccia, Marialuisa; Liu, Qingsong; Guida, Teresa; Federico, Giorgia; Brescia, Annalisa; Zhao, Zheng; Choi, Hwan Geun; Deng, Xianming; Tan, Li; Wang, Jinhua; Billaud, Marc; Gray, Nathanael S.

    2015-01-01

    Oncogenic mutation of the RET receptor tyrosine kinase is observed in several human malignancies. Here, we describe three novel type II RET tyrosine kinase inhibitors (TKI), ALW-II-41-27, XMD15-44 and HG-6-63-01, that inhibit the cellular activity of oncogenic RET mutants at two digit nanomolar concentration. These three compounds shared a 3-trifluoromethyl-4-methylpiperazinephenyl pharmacophore that stabilizes the ‘DFG-out’ inactive conformation of RET activation loop. They blocked RET-mediated signaling and proliferation with an IC50 in the nM range in fibroblasts transformed by the RET/C634R and RET/M918T oncogenes. They also inhibited autophosphorylation of several additional oncogenic RET-derived point mutants and chimeric oncogenes. At a concentration of 10 nM, ALW-II-41-27, XMD15-44 and HG-6-63-01 inhibited RET kinase and signaling in human thyroid cancer cell lines carrying oncogenic RET alleles; they also inhibited proliferation of cancer, but not non-tumoral Nthy-ori-3-1, thyroid cells, with an IC50 in the nM range. The three compounds were capable of inhibiting the ‘gatekeeper’ V804M mutant which confers substantial resistance to established RET inhibitors. In conclusion, we have identified a type II TKI scaffold, shared by ALW-II-41-27, XMD15-44 and HG-6-63-01, that may be used as novel lead for the development of novel agents for the treatment of cancers harboring oncogenic activation of RET. PMID:26046350

  5. The Impact of Escape Alternative Position Change in Multiple-Choice Test on the Psychometric Properties of a Test and Its Items Parameters

    ERIC Educational Resources Information Center

    Hamadneh, Iyad Mohammed

    2015-01-01

    This study aimed at investigating the impact changing of escape alternative position in multiple-choice test on the psychometric properties of a test and it's items parameters (difficulty, discrimination & guessing), and estimation of examinee ability. To achieve the study objectives, a 4-alternative multiple choice type achievement test…

  6. Impact of Airway Gas Exchange on the Multiple Inert Gas Elimination Technique: Theory

    PubMed Central

    Anderson, Joseph C.; Hlastala, Michael P.

    2011-01-01

    The multiple inert gas elimination technique (MIGET) provides a method for estimating alveolar gas exchange efficiency. Six soluble inert gases are infused into a peripheral vein. Measurements of these gases in breath, arterial blood, and venous blood are interpreted using a mathematical model of alveolar gas exchange (MIGET model) that neglects airway gas exchange. A mathematical model describing airway and alveolar gas exchange predicts that two of these gases, ether and acetone, exchange primarily within the airways. To determine the effect of airway gas exchange on the MIGET, we selected two additional gases, toluene and m-dichlorobenzene, that have the same blood solubility as ether and acetone and minimize airway gas exchange via their low water solubility. The airway-alveolar gas exchange model simulated the exchange of toluene, m-dichlorobenzene, and the six MIGET gases under multiple conditions of alveolar ventilation-to-perfusion, V̇A/Q̇, heterogeneity. We increased the importance of airway gas exchange by changing bronchial blood flow, Q̇br. From these simulations, we calculated the excretion and retention of the eight inert gases and divided the results into two groups: 1) the standard MIGET gases which included acetone and ether and 2) the modified MIGET gases which included toluene and m-dichlorobenzene. The MIGET mathematical model predicted distributions of ventilation and perfusion for each grouping of gases and multiple perturbations of V̇A/Q̇ and Q̇br. Using the modified MIGET gases, MIGET predicted a smaller dead space fraction, greater mean V̇A, greater log(SDVA), and more closely matched the imposed V̇A distribution than that using the standard MIGET gases. Perfusion distributions were relatively unaffected. PMID:20336837

  7. Impact of airway gas exchange on the multiple inert gas elimination technique: theory.

    PubMed

    Anderson, Joseph C; Hlastala, Michael P

    2010-03-01

    The multiple inert gas elimination technique (MIGET) provides a method for estimating alveolar gas exchange efficiency. Six soluble inert gases are infused into a peripheral vein. Measurements of these gases in breath, arterial blood, and venous blood are interpreted using a mathematical model of alveolar gas exchange (MIGET model) that neglects airway gas exchange. A mathematical model describing airway and alveolar gas exchange predicts that two of these gases, ether and acetone, exchange primarily within the airways. To determine the effect of airway gas exchange on the MIGET, we selected two additional gases, toluene and m-dichlorobenzene, that have the same blood solubility as ether and acetone and minimize airway gas exchange via their low water solubility. The airway-alveolar gas exchange model simulated the exchange of toluene, m-dichlorobenzene, and the six MIGET gases under multiple conditions of alveolar ventilation-to-perfusion, VA/Q, heterogeneity. We increased the importance of airway gas exchange by changing bronchial blood flow, Qbr. From these simulations, we calculated the excretion and retention of the eight inert gases and divided the results into two groups: (1) the standard MIGET gases which included acetone and ether and (2) the modified MIGET gases which included toluene and m-dichlorobenzene. The MIGET mathematical model predicted distributions of ventilation and perfusion for each grouping of gases and multiple perturbations of VA/Q and Qbr. Using the modified MIGET gases, MIGET predicted a smaller dead space fraction, greater mean VA, greater log(SDVA), and more closely matched the imposed VA distribution than that using the standard MIGET gases. Perfusion distributions were relatively unaffected. PMID:20336837

  8. Impacts of multiple stressors on ecosystem function: Leaf decomposition in constructed urban wetlands.

    PubMed

    Mackintosh, Teresa J; Davis, Jenny A; Thompson, Ross M

    2016-01-01

    The impact of stormwater on stream biota is well documented, but less is known about the impacts on ecosystem processes, such as the breakdown of organic matter. This study sought to establish whether the degree of urbanisation affected rates of leaf-litter breakdown within constructed wetlands. A litter bag method was used to ascertain rate of decomposition along a gradient of urbanisation (total imperviousness, TI), in constructed wetlands in western and south-eastern Melbourne. A significant positive relationship between TI and breakdown rate was found in the south-eastern wetlands. The significant reduction in rate of invertebrate-mediated breakdown with increasing concentration of certain metals was consistent with other studies. However, overall there was an increase in rate of breakdown. Studies have shown that the effects of heavy metals can be negated if nutrient levels are high. Our results suggest that other parameters besides exposure to contaminants are likely to affect leaf litter breakdown. PMID:26371988

  9. Correction of Multiple Canine Impactions by Mixed Straightwire and Cantilever Mechanics: A Case Report

    PubMed Central

    Iodice, Giorgio; d'Antò, Vincenzo; Riccitiello, Francesco; Pellegrino, Gioacchino; Valletta, Rosa

    2014-01-01

    Background. This case report describes the orthodontic treatment of a woman, aged 17 years, with a permanent dentition, brachyfacial typology, Angle Class I, with full impaction of two canines (13,33), and a severe ectopy of the maxillary left canine. Her main compliant was the position of the ectopic teeth. Methods. Straightwire fixed appliances, together with cantilever mechanics, were used to correct the impaired occlusion and to obtain an ideal torque control. Results and Conclusion. The treatment objectives were achieved in 26 months of treatment. The impactions were fully corrected with an optimal torque. The cantilever mechanics succeeded in obtaining tooth repositioning in a short lapse of time. After treatment, the dental alignment was stable. PMID:25140261

  10. Multiple impacts of epilepsy and contributing factors: findings from an ethnographic study in Vietnam

    PubMed Central

    Aydemir, Nuran; Vu Trung, Dang; Snape, Dee; Baker, Gus A; Jacoby, Ann

    2009-01-01

    We investigated issues related to treatment, impact of epilepsy, attitudes toward epilepsy and disclosure in Vietnam by using in depth interviews with people with epilepsy (PWE) and their family members. We found that although participants prefer Western treatment methods more than traditional ones, they experience problems in accessing different kinds of anti-epileptic drugs (AEDs) and higher-level treatment facilities and with respect to treatment expenses. The impact of epilepsy can be observed in a wide range of daily living activities which include working, education, marriage prospects and family formation. Although both families and society at large do not hold negative attitudes toward epilepsy, most PWE reported a sense of burden to others. Both PWE and family members generally prefer disclosing epilepsy rather than concealing it from others. Our findings strongly suggest a need for different types of AEDs, and supporting information for PWE, family members and general public about epilepsy. PMID:19800851

  11. Preliminary Investigation of Impact on Multiple-Sheet Structures and an Evaluation of the Meteoroid Hazard to Space Vehicles

    NASA Technical Reports Server (NTRS)

    Nysmith, C. Robert; Summers, James L.

    1961-01-01

    Small pyrex glass spheres, representative of stoney meteoroids, were fired into 2024-T3 aluminum alclad multiple-sheet structures at velocities to 11,000 feet per second to evaluate the effectiveness of multisheet hull construction as a means of increasing the resistance of a spacecraft to meteoroid penetrations. The results of these tests indicate that increasing the number of sheets in a structure while keeping the total sheet thickness constant and increasing the spacing between sheets both tend to increase the penetration resistance of a structure of constant weight per unit area. In addition, filling the space between the sheets with a light filler material was found to substantially increase structure penetration resistance with a small increase in weight. An evaluation of the meteoroid hazard to space vehicles is presented in the form of an illustrative-example for two specific lunar mission vehicles, a single-sheet, monocoque hull vehicle and a glass-wool filled, double-sheet hull vehicle. The evaluation is presented in terms of the "best" and the "worst" conditions that might be expected as determined from astronomical and satellite measurements, high-speed impact data, and hypothesized meteoroid structures and compositions. It was observed that the vehicle flight time without penetration can be increased significantly by use of multiple-sheet rather than single-sheet hull construction with no increase in hull weight. Nevertheless, it is evident that a meteoroid hazard exists, even for the vehicle with the selected multiple-sheet hull.

  12. The impact of napping on memory for future-relevant stimuli: Prioritization among multiple salience cues.

    PubMed

    Bennion, Kelly A; Payne, Jessica D; Kensinger, Elizabeth A

    2016-06-01

    Prior research has demonstrated that sleep enhances memory for future-relevant information, including memory for information that is salient due to emotion, reward, or knowledge of a later memory test. Although sleep has been shown to prioritize information with any of these characteristics, the present study investigates the novel question of how sleep prioritizes information when multiple salience cues exist. Participants encoded scenes that were future-relevant based on emotion (emotional vs. neutral), reward (rewarded vs. unrewarded), and instructed learning (intentionally vs. incidentally encoded), preceding a delay consisting of a nap, an equivalent time period spent awake, or a nap followed by wakefulness (to control for effects of interference). Recognition testing revealed that when multiple dimensions of future relevance co-occur, sleep prioritizes top-down, goal-directed cues (instructed learning, and to a lesser degree, reward) over bottom-up, stimulus-driven characteristics (emotion). Further, results showed that these factors interact; the effect of a nap on intentionally encoded information was especially strong for neutral (relative to emotional) information, suggesting that once one cue for future relevance is present, there are diminishing returns with additional cues. Sleep may binarize information based on whether it is future-relevant or not, preferentially consolidating memory for the former category. Potential neural mechanisms underlying these selective effects and the implications of this research for educational and vocational domains are discussed. (PsycINFO Database Record PMID:27214500

  13. Inhibition of ras oncogene: a novel approach to antineoplastic therapy.

    PubMed

    Scharovsky, O G; Rozados, V R; Gervasoni, S I; Matar, P

    2000-01-01

    The most frequently detected oncogene alterations, both in animal and human cancers, are the mutations in the ras oncogene family. These oncogenes are mutated or overexpressed in many human tumors, with a high incidence in tumors of the pancreas, thyroid, colon, lung and certain types of leukemia. Ras is a small guanine nucleotide binding protein that transduces biological information from the cell surface to cytoplasmic components within cells. The signal is transduced to the cell nucleus through second messengers, and it ultimately induces cell division. Oncogenic forms of p21(ras) lead to unregulated, sustained signaling through downstream effectors. The ras family of oncogenes is involved in the development of both primary tumors and metastases making it a good therapeutic target. Several therapeutic approaches to cancer have been developed pointing to reducing the altered gene product or to eliminating its biological function: (1) gene therapy with ribozymes, which are able to break down specific RNA sequences, or with antisense oligonucleotides, (2) immunotherapy through passive or active immunization protocols, and (3) inhibition of p21(ras) farnesylation either by inhibition of farnesyl transferase or synthesis inhibition of farnesyl moieties. PMID:10895051

  14. Oncogenic Ras/Src cooperativity in pancreatic neoplasia

    PubMed Central

    Shields, DJ; Murphy, EA; Desgrosellier, JS; Mielgo, A; Lau, SKM; Barnes, LA; Lesperance, J; Huang, M; Schmedt, C; Tarin, D; Lowy, AM; Cheresh, DA

    2011-01-01

    Pancreas cancer is one of the most lethal malignancies and is characterized by activating mutations of Kras, present in 95% of patients. More than 60% of pancreatic cancers also display increased c-Src activity, which is associated with poor prognosis. Although loss of tumor suppressor function (for example, p16, p53, Smad4) combined with oncogenic Kras signaling has been shown to accelerate pancreatic duct carcinogenesis, it is unclear whether elevated Src activity contributes to Kras-dependent tumorigenesis or is simply a biomarker of disease progression. Here, we demonstrate that in the context of oncogenic Kras, activation of c-Src through deletion of C-terminal Src kinase (CSK) results in the development of invasive pancreatic ductal adenocarcinoma (PDA) by 5–8 weeks. In contrast, deletion of CSK alone fails to induce neoplasia, while oncogenic Kras expression yields PDA at low frequency after a latency of 12 months. Analysis of cell lines derived from Ras/Src-induced PDA’s indicates that oncogenic Ras/Src cooperativity may lead to genomic instability, yet Ras/Src-driven tumor cells remain dependent on Src signaling and as such, Src inhibition suppresses growth of Ras/Src-driven tumors. These findings demonstrate that oncogenic Ras/Src cooperate to accelerate PDA onset and support further studies of Src-directed therapies in pancreatic cancer. PMID:21242978

  15. Oncogenes and RNA splicing of human tumor viruses.

    PubMed

    Ajiro, Masahiko; Zheng, Zhi-Ming

    2014-09-01

    Approximately 10.8% of human cancers are associated with infection by an oncogenic virus. These viruses include human papillomavirus (HPV), Epstein-Barr virus (EBV), Merkel cell polyomavirus (MCV), human T-cell leukemia virus 1 (HTLV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), hepatitis C virus (HCV) and hepatitis B virus (HBV). These oncogenic viruses, with the exception of HCV, require the host RNA splicing machinery in order to exercise their oncogenic activities, a strategy that allows the viruses to efficiently export and stabilize viral RNA and to produce spliced RNA isoforms from a bicistronic or polycistronic RNA transcript for efficient protein translation. Infection with a tumor virus affects the expression of host genes, including host RNA splicing factors, which play a key role in regulating viral RNA splicing of oncogene transcripts. A current prospective focus is to explore how alternative RNA splicing and the expression of viral oncogenes take place in a cell- or tissue-specific manner in virus-induced human carcinogenesis. PMID:26038756

  16. Diversity of mutations in the RET proto-oncogene and its oncogenic mechanism in medullary thyroid cancer.

    PubMed

    Hedayati, Mehdi; Zarif Yeganeh, Marjan; Sheikholeslami, Sara; Afsari, Farinaz

    2016-08-01

    Thyroid cancer is the most common endocrine malignancy and accounts for nearly 1% of all of human cancer. Thyroid cancer has four main histological types: papillary, follicular, medullary, and anaplastic. Papillary, follicular, and anaplastic thyroid carcinomas are derived from follicular thyroid cells, whereas medullary thyroid carcinoma (MTC) originates from the neural crest parafollicular cells or C-cells of the thyroid gland. MTC represents a neuroendocrine tumor and differs considerably from differentiated thyroid carcinoma. MTC is one of the aggressive types of thyroid cancer, which represents 3-10% of all thyroid cancers. It occurs in hereditary (25%) and sporadic (75%) forms. The hereditary form of MTC has an autosomal dominant mode of inheritance. According to the present classification, hereditary MTC is classified as a multiple endocrine neoplasi type 2 A & B (MEN2A & MEN2B) and familial MTC (FMTC). The RET proto-oncogene is located on chromosome 10q11.21. It is composed of 21 exons and encodes a transmembrane receptor tyrosine kinase. RET regulates a complex network of signal transduction pathways during development, survival, proliferation, differentiation, and migration of the enteric nervous system progenitor cells. Gain of function mutations in RET have been well demonstrated in MTC development. Variants of MTC result from different RET mutations, and they have a good genotype-phenotype correlation. Various MTC related mutations have been reported in different exons of the RET gene. We proposed that RET genetic mutations may be different in distinct populations. Therefore, the aim of this study was to find a geographical pattern of RET mutations in different populations. PMID:26678667

  17. The Physics of Protoplanetesimal Dust Agglomerates. V. Multiple Impacts of Dusty Agglomerates at Velocities Above the Fragmentation Threshold

    NASA Astrophysics Data System (ADS)

    Kothe, Stefan; Güttler, Carsten; Blum, Jürgen

    2010-12-01

    In recent years, a number of new experiments have advanced our knowledge on the early growth phases of protoplanetary dust aggregates. Some of these experiments have shown that collisions between porous and compacted agglomerates at velocities above the fragmentation threshold velocity can lead to growth of the compact body, when the porous collision partner fragments upon impact and transfers mass to the compact agglomerate. To obtain a deeper understanding of this potentially important growth process, we performed laboratory and drop tower experiments to study multiple impacts of small, highly porous dust-aggregate projectiles onto sintered dust targets. The projectile and target consisted of 1.5 μm monodisperse, spherical SiO2 monomers with volume filling factors of 0.15 ± 0.01 and 0.45 ± 0.05, respectively. The fragile projectiles were accelerated by a solenoid magnet and combined with a projectile magazine with which 25 impacts onto the same spot on the target could be performed in vacuum. We measured the mass-accretion efficiency and the volume filling factor for different impact velocities between 1.5 and 6.0 m s^{-1}. The experiments at the lowest impact speeds were performed in the Bremen drop tower under microgravity conditions to allow partial mass transfer also for the lowest adhesion case. Within this velocity range, we found a linear increase of the accretion efficiency with increasing velocity. In the laboratory experiments, the accretion efficiency increases from 0.12 to 0.21 in units of the projectile mass. The recorded images of the impacts showed that the mass transfer from the projectile to the target leads to the growth of a conical structure on the target after less than 100 impacts. From the images, we also measured the volume filling factors of the grown structures, which ranged from 0.15 (uncompacted) to 0.40 (significantly compacted) with increasing impact speed. The velocity dependency of the mass-transfer efficiency and the packing

  18. Oncogenic KRAS and BRAF Drive Metabolic Reprogramming in Colorectal Cancer.

    PubMed

    Hutton, Josiah E; Wang, Xiaojing; Zimmerman, Lisa J; Slebos, Robbert J C; Trenary, Irina A; Young, Jamey D; Li, Ming; Liebler, Daniel C

    2016-09-01

    Metabolic reprogramming, in which altered utilization of glucose and glutamine supports rapid growth, is a hallmark of most cancers. Mutations in the oncogenes KRAS and BRAF drive metabolic reprogramming through enhanced glucose uptake, but the broader impact of these mutations on pathways of carbon metabolism is unknown. Global shotgun proteomic analysis of isogenic DLD-1 and RKO colon cancer cell lines expressing mutant and wild type KRAS or BRAF, respectively, failed to identify significant differences (at least 2-fold) in metabolic protein abundance. However, a multiplexed parallel reaction monitoring (PRM) strategy targeting 73 metabolic proteins identified significant protein abundance increases of 1.25-twofold in glycolysis, the nonoxidative pentose phosphate pathway, glutamine metabolism, and the phosphoserine biosynthetic pathway in cells with KRAS G13D mutations or BRAF V600E mutations. These alterations corresponded to mutant KRAS and BRAF-dependent increases in glucose uptake and lactate production. Metabolic reprogramming and glucose conversion to lactate in RKO cells were proportional to levels of BRAF V600E protein. In DLD-1 cells, these effects were independent of the ratio of KRAS G13D to KRAS wild type protein. A study of 8 KRAS wild type and 8 KRAS mutant human colon tumors confirmed the association of increased expression of glycolytic and glutamine metabolic proteins with KRAS mutant status. Metabolic reprogramming is driven largely by modest (<2-fold) alterations in protein expression, which are not readily detected by the global profiling methods most commonly employed in proteomic studies. The results indicate the superiority of more precise, multiplexed, pathway-targeted analyses to study functional proteome systems. Data are available through MassIVE Accession MSV000079486 at ftp://MSV000079486@massive.ucsd.edu. PMID:27340238

  19. Multiple goals and time constraints: perceived impact on physicians' performance of evidence-based behaviours

    PubMed Central

    2009-01-01

    Background Behavioural approaches to knowledge translation inform interventions to improve healthcare. However, such approaches often focus on a single behaviour without considering that health professionals perform multiple behaviours in pursuit of multiple goals in a given clinical context. In resource-limited consultations, performing these other goal-directed behaviours may influence optimal performance of a particular evidence-based behaviour. This study aimed to investigate whether a multiple goal-directed behaviour perspective might inform implementation research beyond single-behaviour approaches. Methods We conducted theory-based semi-structured interviews with 12 general medical practitioners (GPs) in Scotland on their views regarding two focal clinical behaviours--providing physical activity (PA) advice and prescribing to reduce blood pressure (BP) to <140/80 mmHg--in consultations with patients with diabetes and persistent hypertension. Theory-based constructs investigated were: intention and control beliefs from the theory of planned behaviour, and perceived interfering and facilitating influence of other goal-directed behaviours performed in a diabetes consultation. We coded interview content into pre-specified theory-based constructs and organised codes into themes within each construct using thematic analysis. Results Most GPs reported strong intention to prescribe to reduce BP but expressed reasons why they would not. Intention to provide PA advice was variable. Most GPs reported that time constraints and patient preference detrimentally affected their control over providing PA advice and prescribing to reduce BP, respectively. Most GPs perceived many of their other goal-directed behaviours as interfering with providing PA advice, while fewer GPs reported goal-directed behaviours that interfere with prescribing to reduce BP. Providing PA advice and prescribing to reduce BP were perceived to be facilitated by similar diabetes-related behaviours (e

  20. Examining the Impact of Prior Models in Transmural Electrophysiological Imaging: A Hierarchical Multiple-Model Bayesian Approach.

    PubMed

    Rahimi, Azar; Sapp, John; Xu, Jingjia; Bajorski, Peter; Horacek, Milan; Wang, Linwei

    2016-01-01

    Noninvasive cardiac electrophysiological (EP) imaging aims to mathematically reconstruct the spatiotemporal dynamics of cardiac sources from body-surface electrocardiographic (ECG) data. This ill-posed problem is often regularized by a fixed constraining model. However, a fixed-model approach enforces the source distribution to follow a pre-assumed structure that does not always match the varying spatiotemporal distribution of actual sources. To understand the model-data relation and examine the impact of prior models, we present a multiple-model approach for volumetric cardiac EP imaging where multiple prior models are included and automatically picked by the available ECG data. Multiple models are incorporated as an Lp-norm prior for sources, where p is an unknown hyperparameter with a prior uniform distribution. To examine how different combinations of models may be favored by different measurement data, the posterior distribution of cardiac sources and hyperparameter p is calculated using a Markov Chain Monte Carlo (MCMC) technique. The importance of multiple-model prior was assessed in two sets of synthetic and real-data experiments, compared to fixed-model priors (using Laplace and Gaussian priors). The results showed that the posterior combination of models (the posterior distribution of p) as determined by the ECG data differed substantially when reconstructing sources with different sizes and structures. While the use of fixed models is best suited in situations where the prior assumption fits the actual source structures, the use of an automatically adaptive set of models may have the ability to better address model-data mismatch and to provide consistent performance in reconstructing sources with different properties. PMID:26259018

  1. Impact of the in-medium conservation of energy on the π-/π+ multiplicity ratio

    NASA Astrophysics Data System (ADS)

    Cozma, M. D.

    2016-05-01

    An upgraded version of the isospin dependent T¨ubingen QMD transport model, which allows the conservation of the total energy, is presented. This is achieved by including in the energy-balance equations of the density, isospin asymmetry and momentum dependent inmedium baryon potential energies. It leads to an effective modification of particle production thresholds with respect to the vacuum ones. Compatible constraints for the symmetry energy stiffness from π-/π+ multiplicity ratio and elliptic flow experimental data of Au+Au collisions at 400 MeV/nucleon can be extracted in this case. However, an important dependence of the π-/π+ observable on the strength of the isovector part of the Δ(1232) isobar potential is also demonstrated. The present lack of information on this quantity prevents a precise extraction of the value for the symmetry energy stiffness employing the mentioned observable alone.

  2. Transferring Transformations: Learning Gains, Student Attitudes, and the Impacts of Multiple Instructors in Large Lecture Courses

    NASA Astrophysics Data System (ADS)

    Pollock, Steven J.

    2006-02-01

    We have implemented several research-based transformations in our introductory calculus-based physics course at CU Boulder. These include Peer Instruction with student response system in lecture, Tutorials with trained undergraduate learning assistants in recitations, and personalized computer assignments. In an effort to distinguish the effects of instructor, TA preparation, and particular research-based activities, we present extensive new measurements from six courses representing a spectrum of reforms. This study includes data from Physics I with and without Tutorials, and Physics II with Tutorials. We present multiple quantitative and qualitative measures of success, including validated pre/post content- and attitude-surveys and common exam questions. We investigate the hand-off of reforms between faculty implementing different suites of activities, and begin to assess elements and requirements for success with these transformations. We present evidence that combining research-based interactive engagement methods in lecture, Tutorials, and homework plays a significant positive role in conceptual and attitudinal development.

  3. Developmental issues impacting military families with young children during single and multiple deployments.

    PubMed

    Barker, Lisa Hains; Berry, Kathy D

    2009-10-01

    Recent years have seen a dramatic increase in war time deployments for military service members. How have young children been affected by single and multiple Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) deployments? We found young children with a deployed parent showed increased behavior problems during deployment and increased attachment behaviors at reunion compared with children whose parents had not experienced a recent deployment. Child behavior problems were related to many individual child and family characteristics, such as child age and temperament, length of the deployment, total time deployed parent was absent, number of moves, and number of stressors reported by parent. Child attachment behaviors were related to the length of the deployment, number of deployments, and the number of stressors faced by the parent. Soldiers and spouses of soldiers who chose not to re-enlist more often described themselves as depressed, and had children with many more behavior problems at reunion. PMID:19891214

  4. Multiple-electron removal and molecular fragmentation of CO by fast F4+ impact

    NASA Astrophysics Data System (ADS)

    Ben-Itzhak, I.; Ginther, S. G.; Carnes, K. D.

    1993-04-01

    Multiple-electron removal from and molecular fragmentation of carbon monoxide molecules caused by collisions with 1-MeV/amu F4+ ions were studied using the coincidence time-of-flight technique. In these collisions, multiple-electron removal of the target molecule is a dominant process. Cross sections for the different levels of ionization of the CO molecule during the collision were determined. The relative cross sections of ionization decrease with increasing number of electrons removed in a similar way as seen in atomic targets. This behavior is in agreement with a two-step mechanism, where first the molecule is ionized by a Franck-Condon ionization and then the molecular ion dissociates. Most of the highly charged intermediate states of the molecule dissociate rapidly. Only CO+ and CO2+ molecular ions have been seen to survive long enough to be detected as molecular ions. The relative cross sections for the different breakup channels were evaluated for collisions in which the molecule broke into two charged fragments as well as for collisions where only a single charged molecular ion or fragment were produced. The average charge state of each fragment resulting from COQ+-->Ci++Oj+ breakup increases with the number of electrons removed from the molecule approximately following the relationship i¯=j¯=Q/2 as long as K-shell electrons are not removed. This does not mean that the charge-state distribution is exactly symmetric, as, in general, removing electrons from the carbon fragment is slightly more likely than removing electrons from the oxygen due to the difference in binding energy. The cross sections for molecular breakup into a charged fragment and a neutral fragment drop rapidly with an increasing number of electrons removed.

  5. Therapeutic Impact of Sphingosine 1-phosphate Receptor Signaling in Multiple Sclerosis.

    PubMed

    Candido, Kristina; Soufi, Henry; Bandyopadhyay, Mausumi; Dasgupta, Subhajit

    2016-01-01

    Multiple sclerosis (MS) is a female predominant autoimmune demyelinating disease of central nervous system. The proper etiology is not clear. The existing therapies with interferon beta (Betaseron, Rebif), glatiramer acetate (copolymer 1, copaxone) are found to be promising for MS patients. The alpha-4 integrin antagonist monoclonal antibody Natalizumab has been found to decrease brain inflammation in relapsing-remitting MS via inhibition of alpha-4 beta- 1 integrinmediated mode of action of antigen -primed T cells to enter into central nervous system through blood brain barrier. The advancement of drug development introduced prospects of CD52 monoclonal antibody Alemtuzumab and CD20 monoclonal antibody Rituximab in MS therapy. The benefit versus risk ratios of these therapeutic monoclonal antibodies are currently under clinical trial. The ongoing researches demonstrated the importance of HMG-CoA reductase inhibitor statins, NF-κBp65 inhibitor NBD peptide, and antagonist of poly-ADP-ribose polymerase (PARP) in experimental autoimmune encephalomyelitis (EAE), animal model for MS. Recently, the clinical trials indicated the therapeutic prospect of G-protein coupled sphingosine 1-phosphate receptor (S1PR) in MS patients. Recent studies showed remyelination through selective activation of oligodendrocyte progenitor cells. In the context, role of S1PR-mediated signals following interaction with natural ligand S1P and agonist Fingolimod (FTY720) gain profound therapeutic importance in prevention of demyelination in MS brain. The S1PR agonist Fingolimod (FTY 720) has recently been approved by Food and Drug Administration for MS therapy. In the review, we provided an insight on S1PR mode of action in the aspect of treatment of autoimmune disorder, re-myelination and regeneration of axons in damaged central nervous system in multiple sclerosis. PMID:26156414

  6. Analytical and experimental investigation on a multiple-mass-element pendulum impact damper for vibration mitigation

    NASA Astrophysics Data System (ADS)

    Egger, Philipp; Caracoglia, Luca

    2015-09-01

    Impact dampers are often used in the field of civil, mechanical and aerospace engineering for reducing structural vibrations. The behavior of this type of passive control device has been investigated for several decades. In this research a distributed-mass impact damper, similar to the "chain damper" used in wind engineering, has been examined and applied to the vibration reduction on a slender line-like structural element (stay-cable). This study is motivated by a practical problem and describes the derivation of a reduced-order model for explaining the behavior, observed during a field experiment on a prototype system. In its simplest form, the dynamics of the apparatus is modeled as a "resilient damper", composed of mass-spring-dashpot secondary elements, attached to the primary structure. Various sources of excitation are analyzed: free vibration, external harmonic force and random excitation. The proposed model is general and potentially applicable to the analysis of several structural systems. The study also shows that the model can adequately describe and explain the experimentally observed behavior.

  7. Dependence of the multiplicities of secondary particles on the impact parameter in collisions of high-energy neon and iron nuclei with photoemulsion nuclei

    NASA Technical Reports Server (NTRS)

    Dudkin, V. E.; Kovalev, E. E.; Nefedov, N. A.; Antonchik, V. A.; Bogdanov, S. D.; Kosmach, V. F.; Likhachev, A. YU.; Benton, E. V.; Crawford, H. J.

    1995-01-01

    A method is proposed for finding the dependence of mean multiplicities of secondaries on the nucleus-collision impact parameter from the data on the total interaction ensemble. The impact parameter has been shown to completely define the mean characteristics of an individual interaction event. A difference has been found between experimental results and the data calculated in terms of the cascade-evaporation model at impact-parameter values below 3 fm.

  8. Dependence of the multiplicities of secondary particles on the impact parameter in collisions of high-energy neon and iron nuclei with photoemulsion nuclei

    NASA Technical Reports Server (NTRS)

    Dudkin, V. E.; Kovalev, E. E.; Nefedov, N. A.; Antonchik, V. A.; Bogdanov, S. D.; Kosmach, V. F.; Benton, E. V.; Crawford, H. J.

    1993-01-01

    A method is proposed for finding the dependence of mean multiplicities of secondaries on the nucleus-collision impact parameter from the data on the total interaction ensemble. The impact parameter has been shown to completely define the mean characteristics of an individual interaction event. A difference has been found between experimental results and the data calculated in terms of the cascade-evaporation model at impact-parameter values below 3 fm.

  9. Opposing oncogenic activities of small DNA tumor virus transforming proteins

    PubMed Central

    Chinnadurai, G.

    2011-01-01

    The E1A gene of species C human adenovirus is an intensely investigated model viral oncogene that immortalizes primary cells and mediates oncogenic cell transformation in cooperation with other viral or cellular oncogenes. Investigations using E1A proteins have illuminated important paradigms in cell proliferation and the functions of cellular proteins such as the retinoblastoma protein. Studies with E1A have led to the surprising discovery that E1A also suppresses cell transformation and oncogenesis. Here, I review our current understanding of the transforming and tumor suppressive functions of E1A, and how E1A studies led to the discovery of a related tumor suppressive function in benign human papillomaviruses. The potential role of these opposing functions in viral replication in epithelial cells is also discussed. PMID:21330137

  10. Abnormal structure of the canine oncogene, related to the human c-yes-1 oncogene, in canine mammary tumor tissue.

    PubMed

    Miyoshi, N; Tateyama, S; Ogawa, K; Yamaguchi, R; Kuroda, H; Yasuda, N; Shimizu, T

    1991-12-01

    Cellular oncogenes of genomic DNA in 6 canine primary mammary tumors were screened by Southern blot analysis, using 7 oncogene probes. A canine genomic oncogene related to the human c-yes-1 oncogene was detected as abnormal bands in solid carcinoma genomic DNA digested with EcoRI, HindIII, HindIII-EcoRI, or HindIII-BamHI. Comparison was made between other tumor specimens and control specimens obtained from 4 clinically normal dogs--1 mixed breed and 3 Shiba Inu dogs (the same breed as the dog from which the solid carcinoma was obtained). These abnormal bands were 0.1 to 1 kilobase shorter than the normal gene. However, digestion of genomic DNA obtained from normal WBC of this dog also produced all of the abnormal bands as observed in digested DNA from the solid carcinoma tissue. Therefore, in this dog, the genomic DNA of all somatic cells from the ontogenic stage still had the abnormal sequences related to the human c-yes-1 oncogene, and it is possible that this abnormal structure may have some role (eg, as an initiator) in tumorigenesis or the progression of this tumor. PMID:1789521