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Sample records for naturally occurring her2

  1. Identifying HER2 inhibitors from natural products database.

    Directory of Open Access Journals (Sweden)

    Shun-Chieh Yang

    Full Text Available The relationship between abnormal HER2 expression and cancer is important in cancer therapeutics. Formation and spread of cancer cells may be restricted by inhibiting HER2. We conducted ligand-based and structure-based studies to assess the potency of natural compounds as potential HER2 inhibitors. Multiple linear regression (MLR and support vector machine (SVM models were constructed to predict biological activities of natural compounds, and molecular dynamics (MD was used to assess their stability with HER2 under a dynamic environment. Predicted bioactivities of the natural compounds ranged from 6.014-9.077 using MLR (r(2 = 0.7954 and 5.122-6.950 using SVM (r(2 = 0.8620. Both models were in agreement and suggest bioactivity based on candidate structure. Conformation changes caused by MD favored the formation of stabilizing H-bonds. All candidates had higher stability than Lapinatib, which may be due to the number and spatial distribution of additional H-bonds and hydrophobic interactions. Amino acids Lys724 and Lys736 are critical for binding in HER2, and Thr798, Cys805, and Asp808 are also important for increased stability. Candidates may block the entrance to the ATP binding site located within the inner regions and prevent downstream activation of HER2. Our multidirectional approach indicates that the natural compounds have good ligand efficacy in addition to stable binding affinities to HER2, and should be potent candidates of HER2 inhibitors. With regard to drug design, designing HER2 inhibitors with carboxyl or carbonyl groups available for H-bond formation with Lys724 and Lys736, and benzene groups for hydrophobic contact with Cys805 may improve protein-ligand stability.

  2. Targeting breast cancer stem cells with HER2-specific antibodies and natural killer cells.

    Science.gov (United States)

    Diessner, Joachim; Bruttel, Valentin; Becker, Kathrin; Pawlik, Miriam; Stein, Roland; Häusler, Sebastian; Dietl, Johannes; Wischhusen, Jörg; Hönig, Arnd

    2013-01-01

    Breast cancer is the most common cancer among women worldwide. Every year, nearly 1.4 million new cases of breast cancer are diagnosed, and about 450.000 women die of the disease. Approximately 15-25% of breast cancer cases exhibit increased quantities of the trans-membrane receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2) on the tumor cell surface. Previous studies showed that blockade of this HER2 proto-oncogene with the antibody trastuzumab substantially improved the overall survival of patients with this aggressive type of breast cancer. Recruitment of natural killer (NK) cells and subsequent induction of antibody-dependent cell-mediated cytotoxicity (ADCC) contributed to this beneficial effect. We hypothesized that antibody binding to HER2-positive breast cancer cells and thus ADCC might be further improved by synergistically applying two different HER2-specific antibodies, trastuzumab and pertuzumab. We found that tumor cell killing via ADCC was increased when the combination of trastuzumab, pertuzumab, and NK cells was applied to HER2-positive breast cancer cells, as compared to the extent of ADCC induced by a single antibody. Furthermore, a subset of CD44(high)CD24(low)HER2(low) cells, which possessed characteristics of cancer stem cells, could be targeted more efficiently by the combination of two HER2-specific antibodies compared to the efficiency of one antibody. These in vitro results demonstrated the immunotherapeutic benefit achieved by the combined application of trastuzumab and pertuzumab. These findings are consistent with the positive results of the clinical studies, CLEOPATRA and NEOSPHERE, conducted with patients that had HER2-positive breast cancer. Compared to a single antibody treatment, the combined application of trastuzumab and pertuzumab showed a stronger ADCC effect and improved the targeting of breast cancer stem cells.

  3. Pharmacological blockade of fatty acid synthase (FASN) reverses acquired autoresistance to trastuzumab (Herceptin by transcriptionally inhibiting 'HER2 super-expression' occurring in high-dose trastuzumab-conditioned SKBR3/Tzb100 breast cancer cells.

    Science.gov (United States)

    Vazquez-Martin, Alejandro; Colomer, Ramon; Brunet, Joan; Menendez, Javier A

    2007-10-01

    the cytotoxic effects occurring upon C75-induced inhibition of FASN enzymatic activity. Both HER2 mRNA and HER2 protein 'super-expression', which have not been reported in earlier Tzb-resistant breast cancer models, were entirely suppressed following pharmacological blockade of FASN activity. Moreover, while Tzb was still able to reduce HER2 protein expression by approximately 20% in SKBR/Tzb100 cells, C75 and Tzb co-exposure synergistically down-regulated HER2 protein levels by >85%. The nature of the interaction between Tzb and C75 in Tzb-resistant SKBR3/Tzb100 cells was also found to be strongly synergistic when analyzing the extent of apoptotic cell death using ELISA-based detection of histone-associated DNA fragments. In summary, a) the molecular mechanism(s) contributing to Tzb resistance in our SKBR3/Tzb100 model appear to be clearly different to those previously reported as we found important transcriptional up-regulatory transcriptional changes in HER2 gene expression levels relative to parental cells; b) since FASN inhibition acts on HER2 gene expression via reduction of its transcription rate, Tzb-conditioned HER2-overexpressing breast cancer cells not only retain but further gain sensitivity to FASN inhibition; and c) transcriptional suppression of HER2 expression using FASN blockers may represent a new molecular strategy in the management of Tzb-resistant breast cancer disease.

  4. Naturally Occurring Radioactive Materials (NORM)

    Energy Technology Data Exchange (ETDEWEB)

    Gray, P. [ed.

    1997-02-01

    This paper discusses the broad problems presented by Naturally Occuring Radioactive Materials (NORM). Technologically Enhanced naturally occuring radioactive material includes any radionuclides whose physical, chemical, radiological properties or radionuclide concentration have been altered from their natural state. With regard to NORM in particular, radioactive contamination is radioactive material in an undesired location. This is a concern in a range of industries: petroleum; uranium mining; phosphorus and phosphates; fertilizers; fossil fuels; forestry products; water treatment; metal mining and processing; geothermal energy. The author discusses in more detail the problem in the petroleum industry, including the isotopes of concern, the hazards they present, the contamination which they cause, ways to dispose of contaminated materials, and regulatory issues. He points out there are three key programs to reduce legal exposure and problems due to these contaminants: waste minimization; NORM assesment (surveys); NORM compliance (training).

  5. Designing HER2 vaccines.

    Science.gov (United States)

    Foy, Teresa M; Fanger, Gary R; Hand, Susan; Gerard, Catherine; Bruck, Claudine; Cheever, Martin A

    2002-06-01

    HER2/neu is a compelling cancer vaccine candidate because it is overexpressed on some cancer cells relative to normal tissues, it is known to be immunogenic in both animal models and in humans, and it is already known to be targetable by the antibody component of the immune system in the form of monoclonal antibody therapy with trastuzumab. Vaccines offer the theoretical advantage of being able to elicit T-cell responses in addition to antibody responses. HER2 vaccines have been shown to provide benefit in animal models and to be immunogenic in humans. However, the optimal vaccine formulation is not yet known and the therapeutic efficacy of the vaccines in humans has not yet been evaluated. HER2 vaccine approaches currently being tested include peptide-based, DNA plasmid-based, and protein-based vaccines. Our group has developed and started testing a protein-based vaccine composed of both the extracellular domain of HER2 and the carboxyl terminal autophosphorylation portion of the intracellular domain. The extracellular domain was retained to provide for antibody targeting. The kinase domain of the intracellular domain was excluded because of its high degree of homology to other human kinases. The carboxyl terminal autophosphorylation domain was retained because it is the most unique and possibly most immunogenic portion of the HER2 molecule with the least homology to other members of the HER family. The vaccine, termed dHER2, is immunogenic in mice and primates. In animal models it can elicit CD8 and CD4 T-cell responses as well as antibody responses that suppress the growth of HER2-positive cancer cells in vitro and in vivo. Vaccine trials are contemplated in patients with breast cancer that will determine whether the vaccine construct is similarly immunogenic in humans.

  6. anticorpo monoclonal her2

    OpenAIRE

    Silva, Ana; Soares, Mariana; Guedes, Cátia

    2005-01-01

    Actualmente as terapêuticas tradicionais para neoplasias com grande invasão tecidular, não são suficientes, optando-se cada vez mais por estratégias de imunoterapia, dependente, claro, das características do tumor e do próprio sistema imunitário. A imunoterapia com anticorpos monoclonais, mais especificamente o Trastuzumab, dirigido para a neoplasia metastizada da mama, cujos tumores primários apresentam amplificação do HER2/neu tem apresentado grande eficácia, proporcionando uma melhoria ...

  7. Percieved functions of naturally occurring autobiographical memories

    DEFF Research Database (Denmark)

    Treebak, L. S.; Henriksen, J. R.; Lundhus, S.

    2005-01-01

    The main empirical reference on functions of autobiographical memories is still Hyman & Faries (1992) who used the cue-word-method and retrospective judgements. We used diaries to sample naturally occurring autobiographical memories and participants? perceived use of these. Results partly replicate...

  8. Naturally occurring radionuclides and Earth sciences

    Directory of Open Access Journals (Sweden)

    G. Ferrara

    1997-06-01

    Full Text Available Naturally occurring radionuclides are used in Earth sciences for two fundamental purposes: age determination of rocks and minerals and studies of variation of the isotopic composition of radiogenic nuclides. The methodologies that are in use today allow us to determine ages spanning from the Earth's age to the late Quaternary. The variations of isotopic composition of radiogenic nuclides can be applied to problems of mantle evolution, magma genesis and characterization with respect to different geodynamic situations and can provide valuable information not obtainable by elemental geochemistry.

  9. Introduction to naturally occurring radioactive material

    Energy Technology Data Exchange (ETDEWEB)

    Egidi, P.

    1997-08-01

    Naturally occurring radioactive material (NORM) is everywhere; we are exposed to it every day. It is found in our bodies, the food we eat, the places where we live and work, and in products we use. We are also bathed in a sea of natural radiation coming from the sun and deep space. Living systems have adapted to these levels of radiation and radioactivity. But some industrial practices involving natural resources concentrate these radionuclides to a degree that they may pose risk to humans and the environment if they are not controlled. Other activities, such as flying at high altitudes, expose us to elevated levels of NORM. This session will concentrate on diffuse sources of technologically-enhanced (TE) NORM, which are generally large-volume, low-activity waste streams produced by industries such as mineral mining, ore benefication, production of phosphate Fertilizers, water treatment and purification, and oil and gas production. The majority of radionuclides in TENORM are found in the uranium and thorium decay chains. Radium and its subsequent decay products (radon) are the principal radionuclides used in characterizing the redistribution of TENORM in the environment by human activity. We will briefly review other radionuclides occurring in nature (potassium and rubidium) that contribute primarily to background doses. TENORM is found in many waste streams; for example, scrap metal, sludges, slags, fluids, and is being discovered in industries traditionally not thought of as affected by radionuclide contamination. Not only the forms and volumes, but the levels of radioactivity in TENORM vary. Current discussions about the validity of the linear no dose threshold theory are central to the TENORM issue. TENORM is not regulated by the Atomic Energy Act or other Federal regulations. Control and regulation of TENORM is not consistent from industry to industry nor from state to state. Proposed regulations are moving from concentration-based standards to dose

  10. Introduction to naturally occurring radioactive material

    Energy Technology Data Exchange (ETDEWEB)

    Egidi, P.

    1997-08-01

    Naturally occurring radioactive material (NORM) is everywhere; we are exposed to it every day. It is found in our bodies, the food we eat, the places where we live and work, and in products we use. We are also bathed in a sea of natural radiation coming from the sun and deep space. Living systems have adapted to these levels of radiation and radioactivity. But some industrial practices involving natural resources concentrate these radionuclides to a degree that they may pose risk to humans and the environment if they are not controlled. Other activities, such as flying at high altitudes, expose us to elevated levels of NORM. This session will concentrate on diffuse sources of technologically-enhanced (TE) NORM, which are generally large-volume, low-activity waste streams produced by industries such as mineral mining, ore benefication, production of phosphate Fertilizers, water treatment and purification, and oil and gas production. The majority of radionuclides in TENORM are found in the uranium and thorium decay chains. Radium and its subsequent decay products (radon) are the principal radionuclides used in characterizing the redistribution of TENORM in the environment by human activity. We will briefly review other radionuclides occurring in nature (potassium and rubidium) that contribute primarily to background doses. TENORM is found in many waste streams; for example, scrap metal, sludges, slags, fluids, and is being discovered in industries traditionally not thought of as affected by radionuclide contamination. Not only the forms and volumes, but the levels of radioactivity in TENORM vary. Current discussions about the validity of the linear no dose threshold theory are central to the TENORM issue. TENORM is not regulated by the Atomic Energy Act or other Federal regulations. Control and regulation of TENORM is not consistent from industry to industry nor from state to state. Proposed regulations are moving from concentration-based standards to dose

  11. Tetrahydroberberine, a pharmacologically active naturally occurring alkaloid.

    Science.gov (United States)

    Pingali, Subramanya; Donahue, James P; Payton-Stewart, Florastina

    2015-04-01

    Tetrahydroberberine (systematic name: 9,10-dimethoxy-5,8,13,13a-tetrahydro-6H-benzo[g][1,3]benzodioxolo[5,6-a]quinolizine), C20H21NO4, a widely distributed naturally occurring alkaloid, has been crystallized as a racemic mixture about an inversion center. A bent conformation of the molecule is observed, with an angle of 24.72 (5)° between the arene rings at the two ends of the reduced quinolizinium core. The intermolecular hydrogen bonds that play an apparent role in crystal packing are 1,3-benzodioxole -CH2···OCH3 and -OCH3···OCH3 interactions between neighboring molecules.

  12. Targeting HER2 amplifications in gastric cancer

    Directory of Open Access Journals (Sweden)

    Ung L

    2014-01-01

    Full Text Available Lawson Ung, Terence C Chua, Neil D Merrett Department of Surgery, South Western Sydney Upper GI Surgical Unit, Bankstown Hospital, University of Western Sydney, Sydney, NSW, Australia Abstract: While multimodality treatments, including neoadjuvant and adjuvant chemotherapy or chemoradiation, have become the global standard of care in patients with locally advanced and metastatic gastric cancers (GCs, long-term outcomes for patients remain poor. This reflects the aggressive tumor biology of GCs and occult nature of the disease, often presenting in its advanced stages, as well as the challenges of developing effective targeted therapy to treat this disease. The Trastuzumab for Gastric Cancer trial demonstrates that the addition of human epidermal growth factor 2 (HER2 monoclonal antibody trastuzumab to standard chemotherapy regimen consisting of 5-fluorouracil (5-FU or capecitabine with cisplatin results in significant improvement in overall and progression-free survival. Although questions remain regarding the best methods by which to determine HER2 mutation positivity and amplification, through immunohistochemistry or in situ hybridization, and whether trastuzumab is effective for locally advanced, nonmetastatic GC in an adjuvant setting, the trial has led to a surge of clinical trials investigating the potential role of other HER2- and non-HER2-targeted therapies to improve patient outcomes. This review will discuss our current understanding of GC pathogenesis, current available treatments, and the potential impact that targeting HER2 amplifications may have in our efforts to individualize and optimize cancer care in GC individuals. Keywords: Personalized cancer therapy, surgical oncology, gastrectomy, adjuvant treatment, targeted therapies

  13. Naturally occurring esterification reactions with bryostatin.

    Science.gov (United States)

    Abadi, Giso; Manning, Thomas J; McLeod, Kristen; Phillips, Dennis; Groundwater, Paul; Noble, Lyn; Potter, Thomas

    2008-01-01

    Bryostatin structures share a commonality of a central bryophan ring, but each differs due to two groups (R(1) and R(2)) that are attached to the bryophan ring via ester bonds. This research examines the impact that conditions such as UV light, acidic and basic conditions can have on the bryostatin structure in the presence of octanoic acid and water. Mass spectrometry (MS) measurements suggest that bryostatin can easily rearrange into various structures under natural conditions by reacting with carboxylates that are ubiquitous in nature. A second set of measurements suggest bryostatin can be hydrolyzed by water, a reaction that has significant implications in both medicinal applications and extraction procedures.

  14. Naturally Occurring Cinnamic Acid Sugar Ester Derivatives

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    Yuxin Tian

    2016-10-01

    Full Text Available Cinnamic acid sugar ester derivatives (CASEDs are a class of natural product with one or several phenylacrylic moieties linked with the non-anomeric carbon of a glycosyl skeleton part through ester bonds. Their notable anti-depressant and brains protective activities have made them a topic of great interest over the past several decades. In particular the compound 3′,6-disinapoylsucrose, the index component of Yuanzhi (a well-known Traditional Chinese Medicine or TCM, presents antidepressant effects at a molecular level, and has become a hotspot of research on new lead drug compounds. Several other similar cinnamic acid sugar ester derivatives are reported in traditional medicine as compounds to calm the nerves and display anti-depression and neuroprotective activity. Interestingly, more than one third of CASEDs are distributed in the family Polygalaceae. This overview discusses the isolation of cinnamic acid sugar ester derivatives from plants, together with a systematic discussion of their distribution, chemical structures and properties and pharmacological activities, with the hope of providing references for natural product researchers and draw attention to these interesting compounds.

  15. Dog models of naturally occurring cancer.

    Science.gov (United States)

    Rowell, Jennie L; McCarthy, Donna O; Alvarez, Carlos E

    2011-07-01

    Studies using dogs provide an ideal solution to the gap in animal models for natural disease and translational medicine. This is evidenced by approximately 400 inherited disorders being characterized in domesticated dogs, most of which are relevant to humans. There are several hundred isolated populations of dogs (breeds) and each has a vastly reduced genetic variation compared with humans; this simplifies disease mapping and pharmacogenomics. Dogs age five- to eight-fold faster than do humans, share environments with their owners, are usually kept until old age and receive a high level of health care. Farseeing investigators recognized this potential and, over the past decade, have developed the necessary tools and infrastructure to utilize this powerful model of human disease, including the sequencing of the dog genome in 2005. Here, we review the nascent convergence of genetic and translational canine models of spontaneous disease, focusing on cancer.

  16. Structural studies of naturally occurring toxicogenic compounds

    Energy Technology Data Exchange (ETDEWEB)

    Springer, J. P.

    1977-10-01

    The paralytic shellfish poison (PSP), saxitoxin, is a neurotoxin isolated from Alaska butter clams (Saxidomus giganteus), mussels (Mytilus californianus) and axenic cultures of the dinoflagellate Gonyaulax catenella. The structure of saxitoxin has been determined through the use of single crystal X-ray diffraction. It possesses a unique tricyclic arrangement of atoms containing two guanidinium moieties and also a hydrated ketone. The relative stereochemistry is presented as well as the absolute configuration. The chemical constitution of a tremorgenic metabolite, paxilline, isolated from extracts of the fungus Penicillium paxilli Bainier has been determined. Paxilline represents a previously unreported class of natural compounds formed by the combination of tryptophan and mevalonate subunits. The complete stereostructure of two other fungal metabolites, paspaline and paspalicine, closely related to paxilline but isolated from Claviceps paspali Stammes have also been determined and are presented. The stereochemistries of paxilline, paspaline and paspalicine are identical at corresponding chiral centers.

  17. Naturally occurring toxic substances in foods.

    Science.gov (United States)

    Gross, R L; Newberne, P M

    1977-11-01

    Numerous chemical toxins, including normal components of natural foods, e.g., mycotoxins, and toxic chemicals as contaminants such as pesticides, fertilizers, food additives, and preservatives, which are potentially toxic to humans, are discussed. Potential toxicity, the hazard to man represented by most of these chemicals, may be low because the concentration in food may be low. The gap in our knowledge of long-term effects makes rational decisions as to allowable levels of these substances a major problem. On the other hand, nitrosamines and aflatoxins are toxins for which there exists a voluminous literature documentaing extreme biologic activity in experimental animals and indirect evidence for activity in man. Epidemiologic evidence has linked them to human cancers, and because of increasing evidence of long-term human exposure to these toxins either as inadvertent contaminants during food preparation or as the metabolites of mycotic infestation this possible hazard demands intensive investigation. An exhaustive review of data from epidemiologic surveys in various parts of the world, as well as from long-term laboratory studies, represents an impressive start in this direction.

  18. Estrogenic activity of naturally occurring anthocyanidins.

    Science.gov (United States)

    Schmitt, E; Stopper, H

    2001-01-01

    Anthocyanins, which are natural plant pigments from the flavonoid family, represent substantial constituents of the human diet. Because some other bioflavonoids are known to have estrogenic activity, the aim of this study was to determine the estrogenic activity of the anthocyanine aglycones. Binding affinity to the estrogen receptor-alpha was 10,000- to 20,000-fold lower than that of the endogenous estrogen estradiol. In the estrogen receptor-positive cell line MCF-7, the anthocyanidins induced expression of a reporter gene. The tested anthocyanidins showed estrogen-inducible cell proliferation in two cell lines (MCF-7 and BG-1), but not in the receptor-negative human breast cancer cell line MDA-MB-231. The phytoestrogen-induced cell proliferation could be blocked by addition of the receptor antagonist 4-hydroxytamoxifen. Combination treatments with the endogenous estrogen estradiol resulted in a reduction of estradiol-induced cell proliferation. Overall, the tested anthocyanidins exert estrogenic activity, which might play a role in altering the development of hormone-dependent adverse effects.

  19. Comparison of HER2 and phospho-HER2 expression between biopsy and resected breast cancer specimens using a quantitative assessment method.

    Directory of Open Access Journals (Sweden)

    Yalai Bai

    Full Text Available BACKGROUND: HER2/Neu (ErbB-2 overexpression, which occurs in 15-20% of breast cancer cases, is associated with better response to treatment with the drug trastuzumab. PhosphoHER2 (pHER2 has been evaluated for prediction of response to trastuzumab. Both markers are heterogeneously detected and are potentially subject to loss as a consequence of delayed time to fixation. Here, we quantitatively assess both markers in core needle biopsies (CNBs and matched tumor resections to assess concordance between the core and the resection and between HER2 and pHER2. METHODS: A selected retrospective collection of archival breast cancer cases yielded 67 cases with both core and resection specimens. Both HER2 and pTyr(1248HER2 were analyzed by the AQUA® method of quantitative immunofluorescence on each specimen pair. RESULTS: Both HER2 immunoreactivity (P<0.0001 and pTyr(1248HER2 immunoreactivity (P<0.0001 were lower in resections relative to CNB specimens. However, clinical implications of this change may not be evident since no case changed from 3+ (CNB to negative (resection. Assessment of pTyr(1248HER2 showed no direct correlation with HER2 in either CNB or resection specimens. CONCLUSIONS: The data suggest that measurement of both HER2 and phospho- Tyr(1248HER2, in formalin-fixed tissue by immunological methods is significantly affected by pre-analytic variables. The current study warrants the adequate handling of resected specimens for the reproducible evaluation of HER2 and pHER2. The level of pTyr(1248HER2, was not correlated to total HER2 protein. Further studies are required to determine the significance of these observations with respect to response to HER2 directed therapies.

  20. Naturally Occuring Brands: a New Perspective on Place Marketing

    National Research Council Canada - National Science Library

    Christine Wright-Isak

    2010-01-01

      Naturally Occurring Brands: A New Perspective on Place Marketing We suggest community types are "natural brands," because their differentiated imagery has meaning that influences consumer housing choices...

  1. Olive oil's bitter principle reverses acquired autoresistance to trastuzumab (Herceptin™ in HER2-overexpressing breast cancer cells

    Directory of Open Access Journals (Sweden)

    Brunet Joan

    2007-05-01

    Full Text Available Abstract Background A low incidence of breast cancer in the Mediterranean basin suggests that a high consumption of Extra Virgin Olive Oil (EVOO might confer this benefit. While the anti-HER2 oncogene effects of the main ω-9 fatty acid present in EVOO triacylglycerols (i.e., oleic acid have been recently described, the anti-breast cancer activities of EVOO non-glyceridic constituents -which consist of at least 30 phenolic compounds-, remained to be evaluated. Methods Semi-preparative HPLC was used to isolate EVOO polyphenols (i.e., tyrosol, hydroxytyrosol, oleuropein. Both the anti-proliferative and the pro-apoptotic effects of EVOO phenolics were evaluated by using MTT-based quantification of metabolically viable cells and ELISA-based detection of histone-associated DNA fragments, respectively. The nature of the interaction between oleuropein aglycone and the anti-HER2 monoclonal antibody trastuzumab (Herceptin™ was mathematically evaluated by the dose-oriented isobologram technique. HER2-specific ELISAs were employed to quantitatively assess both the basal cleavage of the HER2 extracellular domain (ECD and the expression level of total HER2. The activation status of HER2 was evaluated by immunoblotting procedures using a monoclonal antibody specifically recognizing the tyrosine phosphorylated (Phosphor-Tyr1248 form of HER2. Results Among EVOO polyphenols tested, oleuropein aglycone was the most potent EVOO phenolic in decreasing breast cancer cell viability. HER2 gene-amplified SKBR3 cells were ~5-times more sensitive to oleuropein aglycone than HER2-negative MCF-7 cells. Retroviral infection of the HER2 oncogene in MCF-7 cells resulted in a "SKBR3-assimilated" phenotype of hypersensitivity to oleuropein aglycone. An up to 50-fold increase in the efficacy of trastuzumab occurred in the presence of oleuropein aglycone. A preclinical model of acquired autoresistance to trastuzumab (SKBR3/Tzb100 cells completely recovered trastuzumab

  2. In vitro HER2 protein-induced affinity dissociation of carbon nanotube-wrapped anti-HER2 aptamers for HER2 protein detection.

    Science.gov (United States)

    Niazi, Javed H; Verma, Sandeep K; Niazi, Sarfaraj; Qureshi, Anjum

    2015-01-07

    A new in vitro assay was developed to detect human epidermal growth factor receptor 2 (HER2) protein, based on affinity dissociation of carbon nanotube (CNT)-wrapped anti-HER2 ssDNA aptamers. First, we selected an anti-HER2 ssDNA aptamer (H2) using an in vitro serial evolution of ligands by an exponential enrichment (SELEX) process. Then the fluorescently labelled H2 ssDNAs were tightly packed on CNTs that had previously been coupled with magnetic microbeads (MBs), forming MB-CNT-H2 hybrids. The loading capacity of these MB-CNTs heterostructures (2.8 × 10(8)) was determined to be 0.025 to 3.125 μM of H2. HER2 protein-induced H2 dissociation occurred from MB-CNT-H2 hybrids, which was specifically induced by the target HER2 protein, with a dissociation constant (Kd) of 270 nM. The stoichiometric affinity dissociation ratio with respect to H2-to-HER2 protein was shown to be approximately 1 : 1. Our results demonstrated that the developed assay can be an effective approach in detecting native forms of disease biomarkers in free solutions or in biological samples, for accurate diagnosis.

  3. tabAnti-HER2 (erbB-2 oncogene effects of phenolic compounds directly isolated from commercial Extra-Virgin Olive Oil (EVOO

    Directory of Open Access Journals (Sweden)

    Carrasco-Pancorbo Alegria

    2008-12-01

    occurred regardless the molecular mechanism contributing to HER2 overexpression (i.e. naturally by gene amplification and ectopically driven by a viral promoter. Pre-treatment with the proteasome inhibitor MG132 prevented EVOO polyphenols-induced HER2 depletion. Conclusion The ability of EVOO-derived polyphenols to inhibit HER2 activity by promoting the proteasomal degradation of the HER2 protein itself, together with the fact that humans have safely been ingesting secoiridoids and lignans as long as they have been consuming olives and OO, support the notion that the stereochemistry of these phytochemicals might provide an excellent and safe platform for the design of new HER2-targeting agents.

  4. HER-2 status in gastrointestinal stromal tumor.

    Science.gov (United States)

    Lopes, Lisandro Ferreira; Bacchi, Carlos E

    2008-08-01

    Human epidermal growth factor receptor-2 (HER-2) encodes for the transmembrane glycoprotein HER-2 that is involved in activation of intracellular signal transduction pathways that control cell growth and differentiation. HER-2 is overexpressed in approximately 20% of patients with breast cancer and has been associated with poorer prognosis. Since 1998, the anti-HER-2 antibody trastuzumab has been used for the treatment of patients with HER-2-positive breast cancers. However, little information is available about the relationship between HER-2 and gastrointestinal stromal tumors. This study's purpose was to determine the HER-2 status in gastrointestinal stromal tumors. We found that all 477 cases included in this study were negative (score 0) by immunohistochemistry using HercepTest, and no HER-2 gene amplification was detected in 71 cases submitted to fluorescence in situ hybridization. These results show that HER-2 may not have any role in gastrointestinal stromal tumor pathogenesis and that the neoplasm may not be suitable for treatment with trastuzumab.

  5. Heterogenous high-level HER-2 amplification in a small subset of colorectal cancers.

    Science.gov (United States)

    Marx, Andreas H; Burandt, Eike C; Choschzick, Matthias; Simon, Ronald; Yekebas, Emre; Kaifi, Jussuf T; Mirlacher, Martina; Atanackovic, Djordje; Bokemeyer, Carsten; Fiedler, Walter; Terracciano, Luigi; Sauter, Guido; Izbicki, Jakob R

    2010-11-01

    HER-2 is the molecular target for antibody-based treatment of breast cancer (trastuzumab). The potential benefit of anti-HER-2 therapy is currently investigated in several other HER-2 amplified cancers. For example, trastuzumab was recently shown to be effective in HER-2 positive gastric cancer. To address the potential applicability of anti-HER-2 therapy in colorectal cancer, tissue microarray sections and colorectal resection specimens of 1851 colorectal cancers were analyzed for HER-2 overexpression and amplification using FDA approved reagents for immunohistochemistry and fluorescence in situ hybridization. HER-2 amplification was seen in 2.5% and HER-2 overexpression in 2.7% of 1439 interpretable colorectal cancers. Amplification was often high level with HER-2 copies ranging from 4 to 60 per tumor cell and was strongly related to protein overexpression. HER-2 amplification and overexpression were unrelated to histological tumor type, tumor localization, grading, pT, pN, pM or survival. As heterogeneity of drug target expression could represent a major drawback for targeted cancer therapy we next studied HER-2 heterogeneity in selected cases. Extensive evaluation of all available large sections from patients with HER-2 positive colorectal cancer revealed heterogenous findings in 3 of 4 cases. In summary, high-level HER-2 amplification occurs in a small fraction of colorectal cancers. Heterogeneity of amplification may limit the utility of anti- HER-2 therapy in some of these tumors and therefore, adequate clinical trials are needed to further evaluate this approach.

  6. Optimizing HER2 assessment in breast cancer

    DEFF Research Database (Denmark)

    Holten-Rossing, Henrik; Møller Talman, Maj-Lis; Kristensson, Martin

    2015-01-01

    In breast cancer, analysis of HER2 expression is pivotal for treatment decision. This study aimed at comparing digital, automated image analysis with manual reading using the HER2-CONNECT algorithm (Visiopharm) in order to minimize the number of equivocal 2+ scores and the need for reflex...

  7. HER2 testing in gastric cancer.

    Science.gov (United States)

    Albarello, Luca; Pecciarini, Lorenza; Doglioni, Claudio

    2011-01-01

    Molecular therapies targeting HER2 are part of the established drug armamentarium in breast carcinoma. Now the ToGA trial, an international multicenter phase III clinical study, involving 24 countries globally, has shown that the anti-HER2 humanized monoclonal antibody Trastuzumab is effective in prolonging survival in HER2-positive carcinoma of the stomach and the gastroesophageal junction (GEJ). Similarly to breast carcinoma, >20% of gastric cancers show HER2 overexpression and/or amplification, and this percentage increases to 33% in GEJ tumors. Thus, as in breast carcinoma, pathologists are now asked to evaluate HER2 status in gastric carcinoma samples. As validated in the ToGA trial, the HER2 testing criteria that must be used in evaluating both gastric carcinoma biopsies and surgical specimens significantly differ from those routinely applied in breast carcinoma. The main variations with regard to the pattern of reactivity in HER2-expressing cells are as follows: the completeness of membrane staining is not a "conditio sine qua non" and the number of stained cells necessary to consider a case as positive is different. We must also take note of the much more frequent heterogeneity of HER2 positivity in gastric cancer compared with breast carcinoma and the less stringent correlation between HER2 amplification and protein overexpression that is observed in gastric carcinoma, where more than 20% of cases may carry HER2 amplification, although of low level, without HER2 expression. In these patients, in the ToGA trial, there was no apparent benefit from adding Trastuzumab to chemotherapy: for this reason the European Medicines Agency, while approving usage of Trastuzumab for metastatic adenocarcinoma treatment, indicated HER2 testing by immunohistochemistry as first evaluation assay, followed by fluorescence in situ hybridization in 2+ equivocal cases. HER2 testing in gastric carcinoma is a new field, opening several opportunities: for patients with gastric cancer

  8. HER2 missense mutations have distinct effects on oncogenic signaling and migration

    Science.gov (United States)

    Zabransky, Daniel J.; Yankaskas, Christopher L.; Cochran, Rory L.; Wong, Hong Yuen; Croessmann, Sarah; Chu, David; Kavuri, Shyam M.; Red Brewer, Monica; Rosen, D. Marc; Dalton, W. Brian; Cimino-Mathews, Ashley; Cravero, Karen; Button, Berry; Kyker-Snowman, Kelly; Cidado, Justin; Erlanger, Bracha; Parsons, Heather A.; Manto, Kristen M.; Bose, Ron; Lauring, Josh; Arteaga, Carlos L.; Konstantopoulos, Konstantinos; Park, Ben Ho

    2015-01-01

    Recurrent human epidermal growth factor receptor 2 (HER2) missense mutations have been reported in human cancers. These mutations occur primarily in the absence of HER2 gene amplification such that most HER2-mutant tumors are classified as “negative” by FISH or immunohistochemistry assays. It remains unclear whether nonamplified HER2 missense mutations are oncogenic and whether they are targets for HER2-directed therapies that are currently approved for the treatment of HER2 gene-amplified breast cancers. Here we functionally characterize HER2 kinase and extracellular domain mutations through gene editing of the endogenous loci in HER2 nonamplified human breast epithelial cells. In in vitro and in vivo assays, the majority of HER2 missense mutations do not impart detectable oncogenic changes. However, the HER2 V777L mutation increased biochemical pathway activation and, in the context of a PIK3CA mutation, enhanced migratory features in vitro. However, the V777L mutation did not alter in vivo tumorigenicity or sensitivity to HER2-directed therapies in proliferation assays. Our results suggest the oncogenicity and potential targeting of HER2 missense mutations should be considered in the context of cooperating genetic alterations and provide previously unidentified insights into functional analysis of HER2 mutations and strategies to target them. PMID:26508629

  9. HER2 missense mutations have distinct effects on oncogenic signaling and migration.

    Science.gov (United States)

    Zabransky, Daniel J; Yankaskas, Christopher L; Cochran, Rory L; Wong, Hong Yuen; Croessmann, Sarah; Chu, David; Kavuri, Shyam M; Red Brewer, Monica; Rosen, D Marc; Dalton, W Brian; Cimino-Mathews, Ashley; Cravero, Karen; Button, Berry; Kyker-Snowman, Kelly; Cidado, Justin; Erlanger, Bracha; Parsons, Heather A; Manto, Kristen M; Bose, Ron; Lauring, Josh; Arteaga, Carlos L; Konstantopoulos, Konstantinos; Park, Ben Ho

    2015-11-10

    Recurrent human epidermal growth factor receptor 2 (HER2) missense mutations have been reported in human cancers. These mutations occur primarily in the absence of HER2 gene amplification such that most HER2-mutant tumors are classified as "negative" by FISH or immunohistochemistry assays. It remains unclear whether nonamplified HER2 missense mutations are oncogenic and whether they are targets for HER2-directed therapies that are currently approved for the treatment of HER2 gene-amplified breast cancers. Here we functionally characterize HER2 kinase and extracellular domain mutations through gene editing of the endogenous loci in HER2 nonamplified human breast epithelial cells. In in vitro and in vivo assays, the majority of HER2 missense mutations do not impart detectable oncogenic changes. However, the HER2 V777L mutation increased biochemical pathway activation and, in the context of a PIK3CA mutation, enhanced migratory features in vitro. However, the V777L mutation did not alter in vivo tumorigenicity or sensitivity to HER2-directed therapies in proliferation assays. Our results suggest the oncogenicity and potential targeting of HER2 missense mutations should be considered in the context of cooperating genetic alterations and provide previously unidentified insights into functional analysis of HER2 mutations and strategies to target them.

  10. HER 2 Expression in Gastric Cancer

    Directory of Open Access Journals (Sweden)

    Arsenal Alikanoðlu

    2013-07-01

    Full Text Available     Aim: Even though gastric cancer incidence decline in many countries, it is still among the mostly witnessed cancers in the world. Gastric cancer is a biologically  heterogeneous disease with many genetic and epigenetic variations. Despite this heterogeneity of the illness, patients in same stages received similar treatments. This changes as transtuzumab shows survival advantages in patients with metastatic gastric cancer. Therefore it is important to know the rate of HER 2 expression in patients with gastric cancer. In this study, we examined the rate of HER 2 expression in patients with gastric cancer by immunohistochemical method. Material and Method: A total of 50 patients with gastric adenocarcinoma who underwent diagnosed at Antalya  Education and Research Hospital from 2008 to 2011 were enrolled in this study. Results: HER 2 expression of the 50 gastric carcinoma in tissue samples, 25 (50% were scored as 0, 11 (22% as 1, 7 (14% as 2, and 7 (14% as 3. The positive rate was   approximately 14% (7/50. The HER-2 status was not correlated with the TNM stage, lymph node status, distant metastasis and age ( p:0.344, p:0.315, p:0.181, p:0.96. The HER-2 status was correlated with sex (p:0.041. All of the HER-2 positive patients were male. Discussion: In our study only IHC method was performed and patients who had a score of 2+ were considered to have negative HER 2 expression. It is known that  some of the patients with breast cancer with a score of 2+ established HER 2  expression by FISH method. Therefore, we think that HER 2 expression ratio may differ from the values we have obtained.  

  11. Phase I clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibtion

    Directory of Open Access Journals (Sweden)

    Hamilton Erika

    2012-02-01

    Full Text Available Abstract Background Patients with HER2-overexpressing metastatic breast cancer, despite initially benefiting from the monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib, will eventually have progressive disease. HER2-based vaccines induce polyclonal antibody responses against HER2 that demonstrate enhanced anti-tumor activity when combined with lapatinib in murine models. We wished to test the clinical safety, immunogenicity, and activity of a HER2-based cancer vaccine, when combined with lapatinib. Methods We immunized women (n = 12 with metastatic, trastuzumab-refractory, HER2-overexpressing breast cancer with dHER2, a recombinant protein consisting of extracellular domain (ECD and a portion of the intracellular domain (ICD of HER2 combined with the adjuvant AS15, containing MPL, QS21, CpG and liposome. Lapatinib (1250 mg/day was administered concurrently. Peripheral blood antibody and T cell responses were measured. Results This regimen was well tolerated, with no cardiotoxicity. Anti-HER2-specific antibody was induced in all patients whereas HER2-specific T cells were detected in one patient. Preliminary analyses of patient serum demonstrated downstream signaling inhibition in HER2 expressing tumor cells. The median time to progression was 55 days, with the majority of patients progressing prior to induction of peak anti-HER2 immune responses; however, 300-day overall survival was 92% (95% CI: 77-100%. Conclusions dHER2 combined with lapatinib was safe and immunogenic with promising long term survival in those with HER2-overexpressing breast cancers refractory to trastuzumab. Further studies to define the anticancer activity of the antibodies induced by HER2 vaccines along with lapatinib are underway. Trial registry ClinicalTrials.gov NCT00952692

  12. Quantification of HER2 autoantibodies in the amplification phenomenon of HER2 in breast cancer

    DEFF Research Database (Denmark)

    Lauterlein, Jens-Jacob L; Petersen, Eva R B; Olsen, Dorte Aa

    2011-01-01

    Gene amplification of HER2 (human epidermal growth factor receptor 2) is a well-known phenomenon in various cancers. However, little is known about the mechanism of the gene amplification phenomenon itself. Autoantibodies to cellular receptors have been described in several cancer types. We hypot...... hypothesised that autoantibodies against HER2 might have a stimulatory capacity and could be the cause of the HER2 gene amplification phenomenon. To investigate this, we developed a test for the detection of autoantibodies against HER2 in serum (S-HER2Ab)....

  13. Efficacy and Safety of HER2-Targeted Agents for Breast Cancer with HER2-Overexpression: A Network Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Qiuyan Yu

    Full Text Available Clinical trials of human epidermal growth factor receptor 2 (HER2-targeted agents added to standard treatment have been efficacious for HER2-positive (HER2+ advanced breast cancer. To our knowledge, no meta-analysis has evaluated HER2-targeted therapy including trastuzumab emtansine (T-DM1 and pertuzumab for HER2-positive breast caner and ranked the targeted treatments. We performed a network meta-analysis of both direct and indirect comparisons to evaluate the effect of adding HER2-targeted agents to standard treatment and examined side effects.We performed a Bayesian-framework network meta-analysis of randomized controlled trials to compare 6 HER2-targeted treatment regimens and 1 naïve standard treatment (NST, without any-targeted drugs in targeted treatment of HER2+ breast cancer in adults. These treatment regimens were T-DM1, LC (lapatinib, HC (trastuzumab, PEC (pertuzumab, LHC (lapatinib and trastuzumab, and PEHC (pertuzumab and trastuzumab. The main outcomes were overall survival and response rates. We also examined side effects of rash, LVEF (left ventricular ejection fraction, fatigue, and gastrointestinal disorders, and performed subgroup analysis for the different treatment regimens in metastatic or advanced breast cancer.We identified 25 articles of 21 trials, with data for 11,276 participants. T-DM1 and PEHC were more efficient drug regimens with regard to overall survival as compared with LHC, LC, HC and PEC. The incidence of treatment-related rash occurs more frequently in the patients who received LC treatment regimen than PEHC and T-DM1 and HC. In subgroup analysis, T-DM1 was associated with increased overall survival as compared with LC and HC. PEHC was associated with increased overall response as compared with LC, HC, and NST.Overall, the regimen of T-DM1 as well as pertuzumab in combination with trastuzumab and docetaxel is efficacious with fewer side effects as compared with other regimens, especially for advanced HER2

  14. Comparative Toxicology of Libby Amphibole and Naturally Occurring Asbestos

    Science.gov (United States)

    Summary sentence: Comparative toxicology of Libby amphibole (LA) and site-specific naturally occurring asbestos (NOA) provides new insights on physical properties influencing health effects and mechanisms of asbestos-induced inflammation, fibrosis, and tumorigenesis.Introduction/...

  15. Comparative Toxicology of Libby Amphibole and Naturally Occurring Asbestos

    Science.gov (United States)

    Summary sentence: Comparative toxicology of Libby amphibole (LA) and site-specific naturally occurring asbestos (NOA) provides new insights on physical properties influencing health effects and mechanisms of asbestos-induced inflammation, fibrosis, and tumorigenesis.Introduction/...

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

    Science.gov (United States)

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

    2013-08-27

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

  17. Patterns of HER2 Gene Amplification and Response to Anti-HER2 Therapies.

    Directory of Open Access Journals (Sweden)

    Rocio Vicario

    Full Text Available A chromosomal region that includes the gene encoding HER2, a receptor tyrosine kinase (RTK, is amplified in 20% of breast cancers. Although these tumors tend to respond to drugs directed against HER2, they frequently become resistant and resume their malignant progression. Gene amplification in double minutes (DMs, which are extrachromosomal entities whose number can be dynamically regulated, has been suggested to facilitate the acquisition of resistance to therapies targeting RTKs. Here we show that ~30% of HER2-positive tumors show amplification in DMs. However, these tumors respond to trastuzumab in a similar fashion than those with amplification of the HER2 gene within chromosomes. Furthermore, in different models of resistance to anti-HER2 therapies, the number of DMs containing HER2 is maintained, even when the acquisition of resistance is concomitant with loss of HER2 protein expression. Thus, both clinical and preclinical data show that, despite expectations, loss of HER2 protein expression due to loss of DMs containing HER2 is not a likely mechanism of resistance to anti-HER2 therapies.

  18. HER2 phosphorylation is maintained by a PKB negative feedback loop in response to anti-HER2 herceptin in breast cancer.

    Science.gov (United States)

    Gijsen, Merel; King, Peter; Perera, Tim; Parker, Peter J; Harris, Adrian L; Larijani, Banafshé; Kong, Anthony

    2010-12-21

    Herceptin (trastuzumab) is used in patients with breast cancer who have HER2 (ErbB2)-positive tumours. However, its mechanisms of action and how acquired resistance to Herceptin occurs are still poorly understood. It was previously thought that the anti-HER2 monoclonal antibody Herceptin inhibits HER2 signalling, but recent studies have shown that Herceptin does not decrease HER2 phosphorylation. Its failure to abolish HER2 phosphorylation may be a key to why acquired resistance inevitably occurs for all responders if Herceptin is given as monotherapy. To date, no studies have explained why Herceptin does not abolish HER2 phosphorylation. The objective of this study was to investigate why Herceptin did not decrease HER2 phosphorylation despite being an anti-HER2 monoclonal antibody. We also investigated the effects of acute and chronic Herceptin treatment on HER3 and PKB phosphorylation in HER2-positive breast cancer cells. Using both Förster resonance energy transfer (FRET) methodology and conventional Western blot, we have found the molecular mechanisms whereby Herceptin fails to abolish HER2 phosphorylation. HER2 phosphorylation is maintained by ligand-mediated activation of EGFR, HER3, and HER4 receptors, resulting in their dimerisation with HER2. The release of HER ligands was mediated by ADAM17 through a PKB negative feedback loop. The feedback loop was activated because of the inhibition of PKB by Herceptin treatment since up-regulation of HER ligands and ADAM17 also occurred when PKB phosphorylation was inhibited by a PKB inhibitor (Akt inhibitor VIII, Akti-1/2). The combination of Herceptin with ADAM17 inhibitors or the panHER inhibitor JNJ-26483327 was able to abrogate the feedback loop and decrease HER2 phosphorylation. Furthermore, the combination of Herceptin with JNJ-26483327 was synergistic in tumour inhibition in a BT474 xenograft model. We have determined that a PKB negative feedback loop links ADAM17 and HER ligands in maintaining HER2

  19. HER2 phosphorylation is maintained by a PKB negative feedback loop in response to anti-HER2 herceptin in breast cancer.

    Directory of Open Access Journals (Sweden)

    Merel Gijsen

    Full Text Available Herceptin (trastuzumab is used in patients with breast cancer who have HER2 (ErbB2-positive tumours. However, its mechanisms of action and how acquired resistance to Herceptin occurs are still poorly understood. It was previously thought that the anti-HER2 monoclonal antibody Herceptin inhibits HER2 signalling, but recent studies have shown that Herceptin does not decrease HER2 phosphorylation. Its failure to abolish HER2 phosphorylation may be a key to why acquired resistance inevitably occurs for all responders if Herceptin is given as monotherapy. To date, no studies have explained why Herceptin does not abolish HER2 phosphorylation. The objective of this study was to investigate why Herceptin did not decrease HER2 phosphorylation despite being an anti-HER2 monoclonal antibody. We also investigated the effects of acute and chronic Herceptin treatment on HER3 and PKB phosphorylation in HER2-positive breast cancer cells. Using both Förster resonance energy transfer (FRET methodology and conventional Western blot, we have found the molecular mechanisms whereby Herceptin fails to abolish HER2 phosphorylation. HER2 phosphorylation is maintained by ligand-mediated activation of EGFR, HER3, and HER4 receptors, resulting in their dimerisation with HER2. The release of HER ligands was mediated by ADAM17 through a PKB negative feedback loop. The feedback loop was activated because of the inhibition of PKB by Herceptin treatment since up-regulation of HER ligands and ADAM17 also occurred when PKB phosphorylation was inhibited by a PKB inhibitor (Akt inhibitor VIII, Akti-1/2. The combination of Herceptin with ADAM17 inhibitors or the panHER inhibitor JNJ-26483327 was able to abrogate the feedback loop and decrease HER2 phosphorylation. Furthermore, the combination of Herceptin with JNJ-26483327 was synergistic in tumour inhibition in a BT474 xenograft model. We have determined that a PKB negative feedback loop links ADAM17 and HER ligands in maintaining

  20. Long term disease-free survival and T cell and antibody responses in women with high-risk Her2+ breast cancer following vaccination against Her2

    Directory of Open Access Journals (Sweden)

    Anders Carey

    2007-09-01

    Full Text Available Abstract Background The HER2-inhibiting antibody trastuzumab, in combination with chemotherapy, significantly improves survival of women with resected, HER2-overexpressing breast cancers, but is associated with toxicities including a risk of cardiomyopathy. Additionally, the beneficial effect of trastuzumab is expected to decrease once the drug is discontinued. We proposed to address these concerns by using cancer vaccines to stimulate HER2 intracellular domain (ICD-specific T cell and antibody responses. Methods Subjects with stage II (≥ 6 +LN, III, or stage IV breast cancerwith > 50% HER2 overexpressing tumor cells who were disease-free after surgery and adjuvant therapy were eligible. Vaccines consisted of immature, cultured DC (n = 3, mature cultured DC (n = 3, or mature Flt3-ligand mobilized peripheral blood DC (n = 1 loaded with ICD, or tetanus toxoid, keyhole limpet hemocyanin or CMV peptide as controls, and were administered intradermally/subcutaneously four times at 3 week intervals. ICD-specific T cell and antibody responses were measured. Cardiac function was determined by MUGA or ECHO; long term disease status was obtained from patient contact. Results All seven patients successfully underwent DC generation and five received all 4 immunizations. There were no toxicities greater than grade 1 or ejection fraction decrements below normal. Delayed-type hypersensitivity (DTH reactions at the injection site occurred in 6/7 patients and HER2 specificity was detected by cytokine flow cytometry or ELISPOT in 5 patients. At more than 5 years of follow-up, 6/7 had detectable anti-ICD antibodies. One patient experienced a pulmonary recurrence at 4 years from their study immunizations. This recurrence was resected and they are without evidence of disease. All patients are alive and disease-free at 4.6–6.7 years of follow-up. Conclusion Although this was a small pilot study, the well-tolerated nature of the vaccines, the lack of cardiac

  1. Naturally occurring fatty acids: source, chemistry and uses

    Science.gov (United States)

    Natural occurring fatty acids are a large and complex class of compounds found in plants and animals. Fatty acids are abundant and of interest because of their renewability, biodegradability, biocompatibility, low cost, and fascinating chemistry. Of the many fatty acids, only 20-25 of them are widel...

  2. Selective extraction of naturally occurring radioactive Ra2+

    NARCIS (Netherlands)

    van Leeuwen, F.W.B.; Verboom, Willem; Reinhoudt, David

    2005-01-01

    Organic extractants play a significant role in the selective removal of radioactive cations from waste streams. Although, literature on the selective removal of man-made radioactive material such as Americium (Am) is widespread, the selective removal of naturally occurring radioactive material such

  3. The characteristics of gas hydrates occurring in natural environment

    Science.gov (United States)

    Lu, H.; Moudrakovski, I.; Udachin, K.; Enright, G.; Ratcliffe, C.; Ripmeester, J.

    2009-12-01

    In the past few years, extensive analyses have been carried out for characterizing the natural gas hydrate samples from Cascadia, offshore Vancouver Island; Mallik, Mackenzie Delta; Mount Elbert, Alaska North Slope; Nankai Trough, offshore Japan; Japan Sea and offshore India. With the results obtained, it is possible to give a general picture of the characteristics of gas hydrates occurring in natural environment. Gas hydrate can occur in sediments of various types, from sands to clay, although it is preferentially enriched in sediments of certain types, for example coarse sands and fine volcanic ash. Most of the gas hydrates in sediments are invisible, occurring in the pores of the sediments, while some hydrates are visible, appearing as massive, nodular, planar, vein-like forms and occurring around the seafloor, in the fractures related to fault systems, or any other large spaces available in sediments. Although methane is the main component of most of the natural gas hydrates, C2 to C7 hydrocarbons have been recognized in hydrates, sometimes even in significant amounts. Shallow marine gas hydrates have been found generally to contain minor amounts of hydrogen sulfide. Gas hydrate samples with complex gas compositions have been found to have heterogeneous distributions in composition, which might reflect changes in the composition of the available gas in the surrounding environment. Depending on the gas compositions, the structure type of a natural gas hydrate can be structure I, II or H. For structure I methane hydrate, the large cages are almost fully occupied by methane molecules, while the small cages are only partly occupied. Methane hydrates occurring in different environments have been identified with almost the same crystallographic parameters.

  4. Naturally occurring crystalline phases: analogues for radioactive waste forms

    Energy Technology Data Exchange (ETDEWEB)

    Haaker, R.F.; Ewing, R.C.

    1981-01-01

    Naturally occurring mineral analogues to crystalline phases that are constituents of crystalline radioactive waste forms provide a basis for comparison by which the long-term stability of these phases may be estimated. The crystal structures and the crystal chemistry of the following natural analogues are presented: baddeleyite, hematite, nepheline; pollucite, scheelite;sodalite, spinel, apatite, monazite, uraninite, hollandite-priderite, perovskite, and zirconolite. For each phase in geochemistry, occurrence, alteration and radiation effects are described. A selected bibliography for each phase is included.

  5. Immunoregulation by naturally occurring and disease-associated autoantibodies

    DEFF Research Database (Denmark)

    Nielsen, Claus H; Bendtzen, Klaus

    2012-01-01

    -receptors on antigen-presenting cells and thereby regulate T-cell activity. Knowledge of the influence of NAbs against cytokines on immune homeostasis is likely to have wide-ranging implications both in understanding pathogenesis and in treatment of many immunoinflammatory disorders, including a number of autoimmune......The role of naturally occurring autoantibodies (NAbs) in homeostasis and in disease manifestations is poorly understood. In the present chapter, we review how NAbs may interfere with the cytokine network and how NAbs, through formation of complement-activating immune complexes with soluble self......-antigens, may promote the uptake and presentation of self-molecules by antigen-presenting cells. Both naturally occurring and disease-associated autoantibodies against a variety of cytokines have been reported, including NAbs against interleukin (IL)-1α, IL-6, IL-8, IL-10, granulocyte-macrophage colony...

  6. Naturally occurring pentaoxygenated, hexaoxygenated and dimeric xanthones: a literature survey

    Directory of Open Access Journals (Sweden)

    V. Peres

    1997-08-01

    Full Text Available This review gives information on the chemical study of 71 pentaoxygenated, 11 hexaoxygenated and 9 dimeric and more complex xanthones naturally occurring in 7 families, 29 genus and 62 species of higher plants, and 11 described as fern and fungal metabolites. The value of these groups of substances in the connection with the pharmacological activity and the therapeutic use of some species is shown. The structural formulas of 23 isolated compounds and their distribution in the species studied are given.

  7. The effects of naturally occurring impurities in rock salt

    Indian Academy of Sciences (India)

    Alina-Mihaela Badescu; Alexandra Saftoiu

    2014-09-01

    In this paper we investigate the effect that naturally occurring impurities in salt mines have both on effective permittivity of the medium and on radio wave propagation at ∼200 MHz. The effective permittivity is determined based on the dielectric properties of salt and the characteristics of the main impurities. We conclude that at such frequencies the scattering is negligible compared to absorptions. The effect of trapped water in different forms is also evaluated.

  8. Interaction of Siglec-4 with naturally occurring and synthetic glycoconjugates

    OpenAIRE

    Koliwer-Brandl, Hendrik

    2011-01-01

    The aim of this work has been to provide insights into the structure-function relationship of Siglec-4 binding naturally occurring sialic acids as well as synthetic sialic acid derivatives. Structural information of the Siglec binding site and its interactions with glycoconjugates were obtained from homology modeling of the sialic acid binding domain and molecular docking calculations with several sialosides. Furthermore, the interaction of chemically synthesized sialic acid derivatives with ...

  9. Natural transformation of Campylobacter jejuni occurs beyond limits of growth.

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    Christina S Vegge

    Full Text Available Campylobacter jejuni is a human bacterial pathogen. While poultry is considered to be a major source of food borne campylobacteriosis, C. jejuni is frequently found in the external environment, and water is another well-known source of human infections. Natural transformation is considered to be one of the main mechanisms for mediating transfer of genetic material and evolution of the organism. Given the diverse habitats of C. jejuni we set out to examine how environmental conditions and physiological processes affect natural transformation of C. jejuni. We show that the efficiency of transformation is correlated to the growth conditions, but more importantly that transformation occurs at growth-restrictive conditions as well as in the late stationary phase; hence revealing that growth per se is not required for C. jejuni to be competent. Yet, natural transformation of C. jejuni is an energy dependent process, that occurs in the absence of transcription but requires an active translational machinery. Moreover, we show the ATP dependent ClpP protease to be important for transformation, which possibly could be associated with reduced protein glycosylation in the ClpP mutant. In contrast, competence of C. jejuni was neither found to be involved in DNA repair following DNA damage nor to provide a growth benefit. Kinetic studies revealed that several transformation events occur per cell cycle indicating that natural transformation of C. jejuni is a highly efficient process. Thus, our findings suggest that horizontal gene transfer by natural transformation takes place in various habitats occupied by C. jejuni.

  10. Naturally Occurring Anthraquinones: Chemistry and Therapeutic Potential in Autoimmune Diabetes

    Directory of Open Access Journals (Sweden)

    Shih-Chang Chien

    2015-01-01

    Full Text Available Anthraquinones are a class of aromatic compounds with a 9,10-dioxoanthracene core. So far, 79 naturally occurring anthraquinones have been identified which include emodin, physcion, cascarin, catenarin, and rhein. A large body of literature has demonstrated that the naturally occurring anthraquinones possess a broad spectrum of bioactivities, such as cathartic, anticancer, anti-inflammatory, antimicrobial, diuretic, vasorelaxing, and phytoestrogen activities, suggesting their possible clinical application in many diseases. Despite the advances that have been made in understanding the chemistry and biology of the anthraquinones in recent years, research into their mechanisms of action and therapeutic potential in autoimmune disorders is still at an early stage. In this paper, we briefly introduce the etiology of autoimmune diabetes, an autoimmune disorder that affects as many as 10 million worldwide, and the role of chemotaxis in autoimmune diabetes. We then outline the chemical structure and biological properties of the naturally occurring anthraquinones and their derivatives with an emphasis on recent findings about their immune regulation. We discuss the structure and activity relationship, mode of action, and therapeutic potential of the anthraquinones in autoimmune diabetes, including a new strategy for the use of the anthraquinones in autoimmune diabetes.

  11. Clinical Significance of HER-2 Splice Variants in Breast Cancer Progression and Drug Resistance

    Directory of Open Access Journals (Sweden)

    Claire Jackson

    2013-01-01

    Full Text Available Overexpression of human epidermal growth factor receptor (HER-2 occurs in 20–30% of breast cancers and confers survival and proliferative advantages on the tumour cells making HER-2 an ideal therapeutic target for drugs like Herceptin. Continued delineation of tumour biology has identified splice variants of HER-2, with contrasting roles in tumour cell biology. For example, the splice variant 16HER-2 (results from exon 16 skipping increases transformation of cancer cells and is associated with treatment resistance; conversely, Herstatin (results from intron 8 retention and p100 (results from intron 15 retention inhibit tumour cell proliferation. This review focuses on the potential clinical implications of the expression and coexistence of HER-2 splice variants in cancer cells in relation to breast cancer progression and drug resistance. “Individualised” strategies currently guide breast cancer management; in accordance, HER-2 splice variants may prove valuable as future prognostic and predictive factors, as well as potential therapeutic targets.

  12. Naturally occurring Trichogramma species in olive farms in Egypt

    Institute of Scientific and Technical Information of China (English)

    ESMATMOHAMEDHEGAZI; ANNETTEHERZ; SHERIFHASSAN; ESSAMAGAMY; WEDADKHAFAGI; SANIASHWEIL; AHMEDZAITUN; SAFAAMOSTAFA; MOHAMEDHAFEZ; AHMEDEL-SHAZLY; SOMAIAEL-SAID; LAMIAABO-ABDALA; NOHAKHAMIS; SAMIAEL-KEMNY

    2005-01-01

    A survey of two-year studies (2001-2003) was carried out in two olive groves sited at two representative olive growing areas, namely Paradise Park (arid area) and Burg E1-Arab farm (semi-arid area) to monitor the frequency of endemic Trichogramma species on olive moth (Prays oleae) and jasmine moth (Palpita unionalis). The suspended host bait traps were found to be a more practical and effective tool for collecting Trichogramma wasps than the attached ones. Four naturally occurring Trichogramma species were collected for the first time in Egypt from the olive groves, where releases have never been conducted. T.bourarachae was collected exclusively from Burg El-Arab farm. It seems that this wasp species adapts well to the semi-arid area. Three species, namely T. cordubensis, T. nr.pretiosum and T. cacociae were isolated from Paradise Park farm. All of these wasps were also bred from naturally parasitized host eggs during favorable and even at unfavorable temperature conditions of June-August. However, these endemic species did not occur naturally in sufficient numbers to keep the pest populations from reaching damaging levels.The excessive usage of insecticides and the oophagous predators (e.g., ants and lacewing larvae) are some factors that affect the performance of Trichogramma wasps in olive farms.The presence of warm weather wasp strains suggests the existence of well-adapted wasp species or swains which may be appropriate candidates for the control of target pests in olive groves. Additional study is required to determine the best “habitat-specific” species/strains of Trichogramma for augmentative release of naturally occurring wasps and to incorporate them into integrated pest management programs. Efforts should be made to conserve these endemic species from oophagous predators, hot weather and insecticides.The olive and jasmine moth-larvae and pupae found under tree canopies were bred and emerged parasitoids were listed.

  13. Dual HER2 blockade in the neoadjuvant and adjuvant treatment of HER2-positive breast cancer

    Directory of Open Access Journals (Sweden)

    Advani P

    2015-09-01

    Full Text Available Pooja Advani,1 Lauren Cornell,2 Saranya Chumsri,1 Alvaro Moreno-Aspitia1 1Division of Hematology and Oncology, 2Department of Internal Medicine, Mayo Clinic, Jacksonville, FL, USA Abstract: Human epidermal growth factor receptor 2 (HER2 is a tyrosine kinase transmembrane receptor that is overexpressed on the surface of 15%–20% of breast tumors and has been associated with poor prognosis. Consistently improved pathologic response and survival rates have been demonstrated with use of trastuzumab in combination with standard chemotherapy in both early and advanced breast cancer. However, resistance to trastuzumab may pose a major problem in the effective treatment of HER2-positive breast cancer. Dual HER2 blockade, using agents that work in a complimentary fashion to trastuzumab, has more recently been explored to evade resistance in both the preoperative (neoadjuvant and adjuvant settings. Increased effectiveness of dual anti-HER2 agents over single blockade has been recently reported in clinical studies. Pertuzumab in combination with trastuzumab and taxane is currently approved in the metastatic and neoadjuvant treatment of HER2-positive breast cancer. Various biomarkers have also been investigated to identify subsets of patients with HER2-positive tumors who would likely respond best to these targeted therapy combinations. In this article, available trial data regarding efficacy and toxicity of treatment with combination HER2 agents in the neoadjuvant and adjuvant setting have been reviewed, and relevant correlative biomarker data from these trials have been discussed. Keywords: HER2, dual blockade, neoadjuvant, adjuvant, breast cancer, trastuzumab

  14. Could HER2 Heterogeneity Open New Therapeutic Options in Patients with HER2-Primary Breast Cancer

    Science.gov (United States)

    2016-10-01

    AWARD NUMBER: W81XWH-14-1-0444 TITLE: Could HER2 Heterogeneity Open New Therapeutic Options in Patients with HER2- Primary Breast Cancer ...PRINCIPAL INVESTIGATOR: Gary Ulaner, MD, PhD CONTRACTING ORGANIZATION: Memorial Sloan Kettering Cancer Center New York, NY, 10065 REPORT DATE: Oct... Cancer Center 1275 AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER York Avenue New York, NY, 10065 9. SPONSORING / MONITORING AGENCY

  15. Hemostatic abnormalities in dogs with naturally occurring heatstroke.

    Science.gov (United States)

    Bruchim, Yaron; Kelmer, Efrat; Cohen, Adar; Codner, Carolina; Segev, Gilad; Aroch, Itamar

    2017-05-01

    To investigate hemostatic analyte abnormalities and their association with mortality in dogs with naturally occurring heatstroke. Prospective observational study. University teaching hospital. Thirty client-owned dogs with naturally occurring heatstroke. None. Citrated and EDTA blood samples were collected at presentation and at 4, 12, 24, 36, and 48 hours postpresentation (PP). Hemostatic tests performed included platelet count, prothrombin and activated partial thromboplastin times (PT and aPTT, respectively), antithrombin activity (ATA), total protein C activity (tPCA), fibrinogen, and D-dimer concentrations. The overall survival rate was 60% (18/30 dogs). Older age, higher heart rate and rectal temperature at presentation, and time from onset of clinical signs to presentation were significantly associated with mortality. Hemostatic analytes at presentation were not associated with mortality. Prolonged PT and aPTT at 12-24 hours PP, lower tPCA at 12 hours PP, and hypofibrinogenemia at 24 hours PP were significantly (P ATA were common at all time points, but were not associated with mortality. The frequency of disseminated intravascular coagulation (DIC) increased in nonsurvivors throughout hospitalization, but the development of DIC was not associated with mortality. The number of abnormal coagulation disturbances during the first 24 hours was significantly higher in nonsurvivors (P = 0.04). Hemostatic derangements are common in dogs with naturally occurring heatstroke. Alterations in PT, aPTT, tPCA, and fibrinogen concentrations appear to be associated with the outcome at 12-24 hours PP, exemplifying the need for serial measurement of multiple laboratory hemostatic tests during hospitalization, even when within reference interval on presentation. The development of DIC, as defined in this cohort, was not associated with mortality; however, nonsurvivors had significantly more coagulation abnormalities during the first 24 hours PP. © Veterinary Emergency and

  16. Genistein inhibits the proliferation of human HER2-positive cancer cells by downregulating HER2 receptor

    Directory of Open Access Journals (Sweden)

    Guodong Shen

    2013-07-01

    Full Text Available Functional Foods in Health and Disease 2013; 3(7:291-299Research Article Open AccessGenistein inhibits the proliferation of human HER2-positive cancer cells by downregulating HER2 receptorGuodong Shen, Haiying Yu, Geng Bian, Min Gao, Lingqing Liu, Min Cheng, Gan Shen, Shilian HuGeriatrics Department, Gerontology Institute, Anhui Provincial Hospital; Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei 230001, ChinaCorresponding Author: Shilian Hu, Department of Geriatrics, Anhui Provincial Hospital, No. 17 Lujiang Road, Hefei 230001, China Submission date: June 9, 2013; Acceptance date: July 19, 2013; Publication date: July 20, 2013ABSTRACTBackground: It was well studied that HER2/ErbB2/p185 overexpression in human malignant cancers correlates with poor prognosis and chemo-resistance. Meanwhile, Genistein (4,5,7-trihydroxyisoflavone, a major isoflavone component of soybeans and other leguminous plants, has been shown to exhibit a potent anti-proliferative effect on some sex hormone dependent cancers. Objective: The effects of genistein on the proliferation of human HER2-overexpressing breast and ovarian cancer cell lines were investigated, and the action mechanism was explored.Methods: Western blotting, fluorescence-activated cell sorting (FACS and immunofluorescence methods, cell proliferation assay kit from Promega and cell apoptosis assay kit from Biolegend were used. The dose- or time-response relationship of genistein were observed on the HER2-negative breast cancer cell line MCF-7 or HER2-positive breast cancer cell lines BT-474 and MCF-7/Her2 derived from MCF-7, and ovarian cancer cell line SKOV-3.Results: The addition of genistein ranged from 1-10g/ml in the medium for 48 hours had a marked inhibition on the proliferation of HER2-positive cancer cell lines MCF-7/Her2, BT-474 and SKOV-3, compared with tamoxifen and DMSO control (P<0.01, and a dose-dependent response was presented. However, genistein

  17. Genetic and molecular dissection of naturally occurring variations in rice

    Energy Technology Data Exchange (ETDEWEB)

    Yano, Masahiro [National Institute of Agrobiological Sciences, Tsukuba, Ibaraki (Japan)

    2002-02-01

    The progress for structural analysis of the rice genome has allowed us to embark on the sequencing of the whole rice genome. Resources - genetic markers, sequence data, and genomic clones - derived from many efforts will be used for the functional analysis of rice genes in the next decade. Although artificially induced variations, such as mutants, have been used mainly for genetic and physiological studies in rice and other plant species, the development of DNA markers has made possible access to naturally occurring allelic variations underlying complex traits. Such analysis is often referred to as quantitative traits locus (QTL) analysis. Many QTLs have been mapped for many complex traits in rice. During the analyses of several quantitative traits by the DNA marker-assisted strategy, two questions about QTL analysis have been raised: 1) Does a QTL represent a single Mendelian locus or a cluster of multiple loci? 2) Is it possible to precisely map a QTL and identify QTLs at the molecular level using map-based or other strategies? To answer these questions, a series of analyses on heading date, including the identification of putative QTLs, characterization and fine mapping of QTLs using nearly isogenic lines (NILs), and identification of genes at QTLs for heading date by the map-based strategy has been performed. In addition, several primary permanent mapping populations and secondary genetic resources, such as chromosomal segmental substitution lines, have been developed to facilitate the genetic analysis of naturally occurring allelic variation. (M. Suetake)

  18. Regulation of naturally occurring radioactive materials in Australia.

    Science.gov (United States)

    Jeffries, Cameron; Akber, Riaz; Johnston, Andrew; Cassels, Brad

    2011-07-01

    In order to promote uniformity between jurisdictions, the Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) has developed the National Directory for Radiation Protection, which is a regulatory framework that all Australian governments have agreed to adopt. There is a large and diverse range of industries involved in mining or mineral processing, and the production of fossil fuels in Australia. Enhanced levels of naturally occurring radionuclides can be associated with mineral extraction and processing, other industries (e.g. metal recycling) and some products (e.g. plasterboard). ARPANSA, in conjunction with industry and State regulators, has undertaken a review and assessment of naturally occurring radioactive material (NORM) management in Australian industries. This review has resulted in guidance on the management of NORM that will be included in the National Directory for Radiation Protection. The first NORM safety guide provides the framework for NORM management and addresses specific NORM issues in oil and gas production, bauxite, aluminium and phosphate industries. Over time further guidance material for other NORM-related industries will be developed. This presentation will provide an overview of the regulatory approach to managing NORM industries in Australia.

  19. Prevalence and Clinicopathological Characteristics of HER2 and BRAF Mutation in Chinese Patients with Lung Adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Ling Shan

    Full Text Available To determine the prevalence and clinicopathological characteristics of BRAF V600E mutation and HER2 exon 20 insertions in Chinese lung adenocarcinoma (ADC patients.Given the fact that the driver mutations are mutually exclusive in lung ADCs, 204 EGFR/KRAS wild-type cases were enrolled in this study. Direct Sanger sequencing was performed to examine BRAF V600E and HER2 exon 20 mutations. The association of BRAF and HER2 mutations with clinicopathological characteristics was statistically analyzed.Among the 204 lung ADCs tested, 11 cases (5.4% carried HER2 exon 20 insertions and 4 cases (2.0% had BRAF V600E mutation. HER2 mutation status was identified to be associated with a non-smoking history (p<0.05. HER2 mutation occurs in 9.4% of never smokers (10/106, 8.7% of female (8/92 and 2.7% of male (3/112 in this selected cohort. All four BRAF mutated patients were women and three of them were never-smokers. No HER2 mutant patients harbor BRAF mutation.HER2 and BRAF mutations identify a distinct subset of lung ADCs. Given the high prevalence of lung cancer and the availability of targeted therapy, Chinese lung ADC patients without EGFR and KRAS mutations are recommended for HER2 and BRAF mutations detection, especially for those never smokers.

  20. A conformationally constrained peptidomimetic binds to the extracellular region of HER2 protein.

    Science.gov (United States)

    Banappagari, Sashikanth; Ronald, Sharon; Satyanarayanajois, Seetharama D

    2010-12-01

    Human epidermal growth factor receptor 2 (HER2) is a member of the human epidermal growth factor receptor kinases (other members include EGFR or HER1, HER3, and HER4) that are involved in signaling cascades for cell growth and differentiation. It is well established that HER2-mediated heterodimerization has important implications in cancer. Deregulation of signaling pathways and overexpression of HER2 is known to occur in cancer cells, indicating a role of HER2 in tumorigenesis. Therefore, blocking HER2-mediated signaling has potential therapeutic value. We have designed several peptidomimetics to inhibit HER2-mediated signaling for cell growth. One of the compounds (HERP5, Arg-beta Naph-Phe) exhibited antiproliferative activity with IC(50) values in the micromolar-to-nanomolar range in breast cancer cell lines. Binding of fluorescently labeled HERP5 to HER2 protein was evaluated by fluorescence assay, microscopy, and circular dichroism spectroscopy. Results indicated that HERP5 binds to the extracellular region of the HER2 protein. Structure of the peptidomimetic HERP5 was studied by NMR and molecular dynamics simulations. Based on these results a model was proposed for HER2-EGFR dimerization and possible blocking by HERP5 peptidomimetic using a protein-protein docking method.

  1. Altered dopamine signaling in naturally occurring maternal neglect.

    Directory of Open Access Journals (Sweden)

    Stephen C Gammie

    , especially within regions involved in reward, is involved in naturally occurring neglect and that MaD1 mice are a useful model for understanding the basis of naturally occurring neglect.

  2. Multifaceted ability of naturally occurring polyphenols against metastatic cancer.

    Science.gov (United States)

    Zhou, Qingyu; Bennett, Lunawati L; Zhou, Shufeng

    2016-04-01

    Although cancer metastases are known to be the main cause of cancer-related deaths, truly effective antimetastatic therapeutics remain scarce in clinical practice. Naturally occurring polyphenols are the most abundant antioxidants in human diets. Many of them possess chemopreventive and chemotherapeutic properties against various types of cancer. Recent advances in understanding the molecular pathways that mediate cancer development and progression have led to an increase of interest in preclinical investigations on the mechanisms underlying anticancer activity of polyphenols. In particular, an increasing number of preclinical studies using cultured cells and animal models have demonstrated the inhibitory effects of polyphenols on tumour cell invasion and metastasis, thereby highlighting the potential of polyphenols against metastatic cancer. This review specifically addresses growing evidence of the capability of polyphenols to impair the invasion and migration of tumour cells through a diverse set of mechanisms, including downregulation of expression of matrix metalloproteinases, modulation of regulators of epithelial-mesenchymal transition, interference with Met signalling, inhibition of nuclear factor-kappa B mediated transcription, and so on. Given that metastasis occurs through a multistep process in which each step is regulated by a complex network of signalling pathways, the multi-function and multi-target characteristics of polyphenols render those promising candidates for effective adjuvant therapy against metastatic cancer.

  3. Discovering Psychological Principles by Mining Naturally Occurring Data Sets.

    Science.gov (United States)

    Goldstone, Robert L; Lupyan, Gary

    2016-07-01

    The very expertise with which psychologists wield their tools for achieving laboratory control may have had the unwelcome effect of blinding psychologists to the possibilities of discovering principles of behavior without conducting experiments. When creatively interrogated, a diverse range of large, real-world data sets provides powerful diagnostic tools for revealing principles of human judgment, perception, categorization, decision-making, language use, inference, problem solving, and representation. Examples of these data sets include patterns of website links, dictionaries, logs of group interactions, collections of images and image tags, text corpora, history of financial transactions, trends in twitter tag usage and propagation, patents, consumer product sales, performance in high-stakes sporting events, dialect maps, and scientific citations. The goal of this issue is to present some exemplary case studies of mining naturally existing data sets to reveal important principles and phenomena in cognitive science, and to discuss some of the underlying issues involved with conducting traditional experiments, analyses of naturally occurring data, computational modeling, and the synthesis of all three methods.

  4. Assessment of HER2 testing patterns, HER2+ disease, and the utilization of HER2-directed therapy in early breast cancer

    Directory of Open Access Journals (Sweden)

    Stenehjem DD

    2014-10-01

    Full Text Available David D Stenehjem,1,2 Minkyoung Yoo,1 Sudhir K Unni,1 Mukul Singhal,1 Hillevi Bauer,1 Kim Saverno,1 Cheng Quah,3 Anthony Masaquel,3 Diana I Brixner1,41Pharmacotherapy Outcomes Research Center (PORC, College of Pharmacy, University of Utah, Salt Lake City, UT, USA; 2Huntsman Cancer Institute, Salt Lake City, UT, USA; 3Genentech, Inc., South San Francisco, CA, USA; 4Program in Personalized Health Care, University of Utah, Salt Lake City, UT, USAContext: Determining human epidermal growth factor receptor 2 (HER2 status is critical for the management of early-stage breast cancer (ESBC. An understanding of HER2 testing practices can provide insight into how test results influence the use of HER2-directed therapy.Objective: To assess HER2 testing, HER2+ disease, and HER2-directed therapy in ESBC at the Huntsman Cancer Institute before and after the 2007 American Society of Clinical Oncology and College of American Pathologist (ASCO/CAP guidelines on HER2 testing were published.Methods: Patients were identified from an institutional tumor registry. HER2 testing patterns and results were examined using a chart review of pathology and clinical notes. Patient characteristics, HER2+ rate, and trastuzumab use were evaluated descriptively. Discordance rate with reflex testing (immunohistochemistry [IHC]2+ retested by fluorescence in situ hybridization [FISH] was also evaluated.Results: A total of 1,459 women were included (mean age: 57 years. The rate of HER2+ disease was 17% (number [N] =245. The discordance rate between IHC2+ and FISH was 10%. After the 2007 ASCO/CAP guidelines, fewer tumors were classified as IHC3+ (16% post- versus 21.9% pre-2007, more tumors were characterized as IHC2+ (26.4% post- versus 20.7% pre-2007, and the overall HER2+ rate was decreased (18.7% versus 21.9%, but this was not statistically significant (P=0.519. Most patients with HER2+ ESBC received HER2-targeted therapy (N=185.Conclusion: The HER2+ rate was 17% and within the

  5. Intravenous Topiramate: Pharmacokinetics in Dogs with Naturally-Occurring Epilepsy

    Directory of Open Access Journals (Sweden)

    Irene Vuu

    2016-12-01

    Full Text Available Barriers to developing treatments for human status epilepticus (SE include the inadequacy of experimental animal models. In contrast, naturally-occurring canine epilepsy is similar to the human condition and can serve as a platform to translate research from rodents to humans. The objectives of this study were to characterize the pharmacokinetics (PK of an intravenous (IV dose of topiramate (TPM in dogs with epilepsy, and evaluate its effect on intracranial electroencephalographic (iEEG features. Five dogs with naturally occurring epilepsy were used for this study. Three were getting at least one antiseizure drug as maintenance therapy including phenobarbital (PB. Four (ID 1-4 were used for the 10 mg/kg IV TPM + PO TPM study, and three (ID 3-5 were used for the 20 mg/kg IV TPM study. IV TPM was infused over 5 minutes at both doses. The animals were observed for vomiting, diarrhea, ataxia, and lethargy. Blood samples were collected at scheduled pre- and post-dose times. Plasma concentrations were measured using a validated HPLC-MS method. Non-compartmental and population compartmental modeling were performed (Phoenix WinNonLin and NLME using plasma concentrations from all dogs in the study. Intracranial EEG (iEEG was acquired in one dog. The difference between averaged iEEG energy levels at 15 minutes pre- and post-dose was assessed using a Kruskal-Wallis test. No adverse events were noted. Topiramate concentration-time profiles were best fit by a two-compartment model. PB co-administration was associated with a 5.6 fold greater clearance and a ~4 fold shorter elimination half-life. iEEG data showed that TPM produced a significant energy increase at frequencies >4 Hz across all 16 electrodes within 15 minutes of dosing. Simulations suggested that dogs on an enzyme inducer would require 25 mg/kg, while dogs on non-inducing drugs would need 20 mg/kg to attain the target concentration (20-30 µg/mL at 30-minutes post-dose.This study shows that IV

  6. Forecasting seizures in dogs with naturally occurring epilepsy.

    Science.gov (United States)

    Howbert, J Jeffry; Patterson, Edward E; Stead, S Matt; Brinkmann, Ben; Vasoli, Vincent; Crepeau, Daniel; Vite, Charles H; Sturges, Beverly; Ruedebusch, Vanessa; Mavoori, Jaideep; Leyde, Kent; Sheffield, W Douglas; Litt, Brian; Worrell, Gregory A

    2014-01-01

    Seizure forecasting has the potential to create new therapeutic strategies for epilepsy, such as providing patient warnings and delivering preemptive therapy. Progress on seizure forecasting, however, has been hindered by lack of sufficient data to rigorously evaluate the hypothesis that seizures are preceded by physiological changes, and are not simply random events. We investigated seizure forecasting in three dogs with naturally occurring focal epilepsy implanted with a device recording continuous intracranial EEG (iEEG). The iEEG spectral power in six frequency bands: delta (0.1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12-30 Hz), low-gamma (30-70 Hz), and high-gamma (70-180 Hz), were used as features. Logistic regression classifiers were trained to discriminate labeled pre-ictal and inter-ictal data segments using combinations of the band spectral power features. Performance was assessed on separate test data sets via 10-fold cross-validation. A total of 125 spontaneous seizures were detected in continuous iEEG recordings spanning 6.5 to 15 months from 3 dogs. When considering all seizures, the seizure forecasting algorithm performed significantly better than a Poisson-model chance predictor constrained to have the same time in warning for all 3 dogs over a range of total warning times. Seizure clusters were observed in all 3 dogs, and when the effect of seizure clusters was decreased by considering the subset of seizures separated by at least 4 hours, the forecasting performance remained better than chance for a subset of algorithm parameters. These results demonstrate that seizures in canine epilepsy are not randomly occurring events, and highlight the feasibility of long-term seizure forecasting using iEEG monitoring.

  7. Preparation of metagenomic libraries from naturally occurring marine viruses.

    Science.gov (United States)

    Solonenko, Sergei A; Sullivan, Matthew B

    2013-01-01

    Microbes are now well recognized as major drivers of the biogeochemical cycling that fuels the Earth, and their viruses (phages) are known to be abundant and important in microbial mortality, horizontal gene transfer, and modulating microbial metabolic output. Investigation of environmental phages has been frustrated by an inability to culture the vast majority of naturally occurring diversity coupled with the lack of robust, quantitative, culture-independent methods for studying this uncultured majority. However, for double-stranded DNA phages, a quantitative viral metagenomic sample-to-sequence workflow now exists. Here, we review these advances with special emphasis on the technical details of preparing DNA sequencing libraries for metagenomic sequencing from environmentally relevant low-input DNA samples. Library preparation steps broadly involve manipulating the sample DNA by fragmentation, end repair and adaptor ligation, size fractionation, and amplification. One critical area of future research and development is parallel advances for alternate nucleic acid types such as single-stranded DNA and RNA viruses that are also abundant in nature. Combinations of recent advances in fragmentation (e.g., acoustic shearing and tagmentation), ligation reactions (adaptor-to-template ratio reference table availability), size fractionation (non-gel-sizing), and amplification (linear amplification for deep sequencing and linker amplification protocols) enhance our ability to generate quantitatively representative metagenomic datasets from low-input DNA samples. Such datasets are already providing new insights into the role of viruses in marine systems and will continue to do so as new environments are explored and synergies and paradigms emerge from large-scale comparative analyses.

  8. Role of HER2 in NSCLC%HER2在NSCLC中的作用

    Institute of Scientific and Technical Information of China (English)

    张坤(综述); 王红(审校)

    2015-01-01

    过去几年中,随着分子靶向药物的引入,非小细胞肺癌(non-small cell lung cancer, NSCLC)的药物治疗策略发生了巨大变化,向基于组织学和分子水平的治疗手段转变。表皮生长因子受体(epidermal growth factor receptor, EGFR)突变、Kirsten鼠肉瘤(Kirsten rat sarcoma, KARS)癌基因突变、间变淋巴瘤激酶(anaplastic lymphoma kinase, ALK)重排等的发现,影响着NSCLC治疗的发展。最近,对人表皮生长因子受体2(human epidermal growth factor receptor 2, HER2)研究重燃兴趣,这一基因改变与NSCLC对不同酪氨酸激酶抑制剂(tyrosine kinase inhibitors, TKIs)的敏感性相关,其具有可能的预测作用,HER2扩增可能是EGFR突变肿瘤对EGFR-TKIs获得性耐药的机制之一。其次,HER2突变可能阐明一条新的靶向治疗NSCLC的策略。本文将对NSCLC中HER2异常调节发挥的作用做一简要介绍。%hTe therapeutic strategy of non-small cell lung cancer (NSCLC) is dramatically changed with the intro-duction of molecular targeted drugs in the last years, resulting in a series of results in histologic and molecular level. hTe discov-ery of epidermal growth factor receptor (EGFR) mutation, Kirsten rat sarcoma (KARS) viral oncogene mutation and anaplastic lymphoma kinase (ALK) rearrangement, has profoundly inlfuenced the development of treatment of NSCLC. Recently, there is a renewed interest in the human epidermal growth receptor 2 (HER2), where genetic alteration in NSCLC is associated with the different sensetivity of EGFR tyrosine kinase inhibitors (TKIs), to have a prognostic effect. HER2 ampliifcation in EGFR mutation tumors may become a mechanism of acquired resistance to the TKIs. Besides, HER2 mutation may become a novel therapeutic strategy of NSCLC.

  9. GROWTH OF NATURALLY OCCURING Listeria innocua IN COPPA DI TESTA

    Directory of Open Access Journals (Sweden)

    G. Merialdi

    2010-06-01

    Full Text Available Coppa di testa is a traditional cooked pork salami produced in different Italian regions. The main raw material is deboned meat of pork head with the addition of tongue and rind. After a long (3-5 h high temperature (97°C cooking, additives and flavourings are added and the salami is prepared. After cooling the salami is often portioned and vacuum- packaged. In this study the growth of naturally occurring contamination of Listeria innocua in three batches of vacuum packaged Coppa di testa, stored at 4°C for 80 days, is described. The average max was 0.24 (days-1 and the average doubling time was 2.87 days. The maximum growth level ranged from 4.90 to 8.17 (log10 cfu/g. These results indicate that Coppa di testa definitely supports the growth of Listeria innocua in the considered storage conditions. Taking into account that at 4°C Listeria monocytogenes strains are associated with higher grow rates than L. innocua, these results emphasize the importance of preventing Listeria monocytogenes contamination in the production stages following cooking.

  10. Conformational Flexibility Differentiates Naturally Occurring Bet v 1 Isoforms.

    Science.gov (United States)

    Grutsch, Sarina; Fuchs, Julian E; Ahammer, Linda; Kamenik, Anna S; Liedl, Klaus R; Tollinger, Martin

    2017-06-03

    The protein Bet v 1 represents the main cause for allergic reactions to birch pollen in Europe and North America. Structurally homologous isoforms of Bet v 1 can have different properties regarding allergic sensitization and Th2 polarization, most likely due to differential susceptibility to proteolytic cleavage. Using NMR relaxation experiments and molecular dynamics simulations, we demonstrate that the initial proteolytic cleavage sites in two naturally occurring Bet v 1 isoforms, Bet v 1.0101 (Bet v 1a) and Bet v 1.0102 (Bet v 1d), are conformationally flexible. Inaccessible cleavage sites in helices and strands are highly flexible on the microsecond-millisecond time scale, whereas those located in loops display faster nanosecond-microsecond flexibility. The data consistently show that Bet v 1.0102 is more flexible and conformationally heterogeneous than Bet v 1.0101. Moreover, NMR hydrogen-deuterium exchange measurements reveal that the backbone amides in Bet v 1.0102 are significantly more solvent exposed, in agreement with this isoform's higher susceptibility to proteolytic cleavage. The differential conformational flexibility of Bet v 1 isoforms, along with the transient exposure of inaccessible sites to the protein surface, may be linked to proteolytic susceptibility, representing a potential structure-based rationale for the observed differences in Th2 polarization and allergic sensitization.

  11. Characteristics of Cherenkov Radiation in Naturally Occuring Ice

    CERN Document Server

    Mikkelsen, R E; Uggerhøj, U I; Klein, S R

    2016-01-01

    We revisit the theory of Cherenkov radiation in uniaxial crystals. Historically, a number of flawed attempts have been made at explaining this radiation phenomenon and a consistent error-free description is nowhere available. We apply our calculation to a large modern day telescope - IceCube. Being located at the Antarctica, this detector makes use of the naturally occuring ice as a medium to generate Cherenkov radiation. However, due to the high pressure at the depth of the detector site, large volumes of hexagonal ice crystals are formed. We calculate how this affects the Cherenkov radiation yield and angular dependence. We conclude that the effect is small, at most about a percent, and would only be relevant in future high precision instruments like e.g. Precision IceCube Next Generation Upgrade (PINGU). For radio-Cherenkov experiments which use the presence of a clear Cherenkov cone to determine the arrival direction, any variation in emission angle will directly and linearly translate into a change in ap...

  12. Naturally occurring regulatory T cells: markers, mechanisms, and manipulation.

    Science.gov (United States)

    Schmetterer, Klaus G; Neunkirchner, Alina; Pickl, Winfried F

    2012-06-01

    Naturally occurring CD4(+)CD25(high) forkhead box protein 3 (FOXP3)(+) regulatory T cells (nTregs) are key mediators of immunity, which orchestrate and maintain tolerance to self and foreign antigens. In the recent 1.5 decades, a multitude of studies have aimed to define the phenotype and function of nTregs and to assess their therapeutic potential for modulating immune mediated disorders such as autoimmunity, allergy, and episodes of transplant rejection. In this review, we summarize the current knowledge on the biology of nTregs. We address the exact definition of nTregs by specific markers and combinations thereof, which is a prerequisite for the state-of-the-art isolation of defined nTreg populations. Furthermore, we discuss the mechanism by which nTregs mediate immunosuppression and how this knowledge might translate into novel therapeutic modalities. With first clinical studies of nTreg-based therapies being finished, questions concerning the reliable sources of nTregs are becoming more and more eminent. Consequently, approaches allowing conversion of CD4(+) T cells into nTregs by coculture with antigen-presenting cells, cytokines, and/or pharmacological agents are discussed. In addition, genetic engineering approaches for the generation of antigen-specific nTregs are described.

  13. Franckeite as a naturally occurring van der Waals heterostructure

    Science.gov (United States)

    Molina-Mendoza, Aday J.; Giovanelli, Emerson; Paz, Wendel S.; Niño, Miguel Angel; Island, Joshua O.; Evangeli, Charalambos; Aballe, Lucía; Foerster, Michael; van der Zant, Herre S. J.; Rubio-Bollinger, Gabino; Agraït, Nicolás; Palacios, J. J.; Pérez, Emilio M.; Castellanos-Gomez, Andres

    2017-01-01

    The fabrication of van der Waals heterostructures, artificial materials assembled by individual stacking of 2D layers, is among the most promising directions in 2D materials research. Until now, the most widespread approach to stack 2D layers relies on deterministic placement methods, which are cumbersome and tend to suffer from poor control over the lattice orientations and the presence of unwanted interlayer adsorbates. Here, we present a different approach to fabricate ultrathin heterostructures by exfoliation of bulk franckeite which is a naturally occurring and air stable van der Waals heterostructure (composed of alternating SnS2-like and PbS-like layers stacked on top of each other). Presenting both an attractive narrow bandgap (<0.7 eV) and p-type doping, we find that the material can be exfoliated both mechanically and chemically down to few-layer thicknesses. We present extensive theoretical and experimental characterizations of the material's electronic properties and crystal structure, and explore applications for near-infrared photodetectors. PMID:28194037

  14. Pulsed light inactivation of naturally occurring moulds on wheat grain.

    Science.gov (United States)

    Aron Maftei, Nicoleta; Ramos-Villarroel, Ana Y; Nicolau, Anca I; Martín-Belloso, Olga; Soliva-Fortuny, Robert

    2014-03-15

    Pulsed light (PL) is emerging as a non-thermal technology with excellent prospects for the decontamination of foods and food contact surfaces. Its application for mould inactivation on cereal grains would allow a reduction of storage losses as well as the prevention of mycotoxin contamination at a post-harvest level. The potential of PL for the decontamination of naturally occurring moulds on wheat grain was investigated in this study. Treatments of up to 40 flashes of a fluence of 0.4 J cm⁻² per pulse were applied to both sides of the grain, with an overall energy release ranging from 6.4 to 51.2 J g⁻¹. The most powerful treatment applied to wheat in this study (51.2 J g⁻¹) resulted in a mould reduction of approximately 4 log cycles on samples displaying an initial mould contamination level of 2.2 × 10⁵ CFU g⁻¹. At the same time, the seed germination percentage was only slightly affected. For PL treatments causing an inactivation of 3-4 log cycles, only 14-15% of the germination power of the wheat seeds was lost. The PL treatments attained greater microbial reductions for higher treatment times and lower initial mould loads. The absence of the UV portion of the radiation spectrum was found to significantly reduce the treatment effectiveness. © 2013 Society of Chemical Industry.

  15. Naturally-occurring anti-Jka in infant twins.

    Science.gov (United States)

    Rumsey, D H; Nance, S J; Rubino, M; Sandler, S G

    1999-01-01

    Anti-Jka was detected by solid-phase red cell adherence (SPRCA) antibody detection and identification tests in the plasma of a 9-month-old female infant during a routine presurgical evaluation. The patient and her nonidentical twin sister, who also had anti-Jka in her plasma, were products of an uncomplicated in vitro fertilization, full-term pregnancy, and vaginal delivery. Neither twin had been transfused, recently infected, or treated with medication. Their mother had no prior pregnancies or transfusions. Red blood cells (RBCs) from the patient and her sister typed as Jk(a-b+) by direct hemagglutination, and this phenotype was confirmed by negative adsorption and elution studies. Both infants' plasma samples were strongly reactive with 20 examples of Jk(a+) RBCs and nonreactive with 20 examples of Jk(a-) RBCs by SPRCA assays. Anti-Jka was not detected in either twins' plasma by indirect antiglobulin tests by tube method in low-ionic- strength saline solution or polyethylene glycol, or with ficin- or papain-treated RBCs. Monocyte monolayer assays using Jk(a+) RBCs sensitized by either twins' serum were nonreactive (0%). RBCs from both parents typed as Jk(a+b+). Both parents' antibody detection test results by SPRCA assay were negative. The absence of a history of exposure to allogeneic RBCs or possible passive transfer of maternal or other alloantibody classifies these antibodies as naturally-occurring anti-Jka.

  16. Characteristics of Cherenkov radiation in naturally occurring ice

    Science.gov (United States)

    Mikkelsen, R. E.; Poulsen, T.; Uggerhøj, U. I.; Klein, S. R.

    2016-03-01

    We revisit the theory of Cherenkov radiation in uniaxial crystals. Historically, a number of flawed attempts have been made at explaining this radiation phenomenon, and a consistent error-free description is nowhere available. We apply our calculation to a large modern day telescope—IceCube. Located in Antarctica, this detector makes use of the naturally occurring ice as a medium to generate Cherenkov radiation. However, due to the high pressure at the depth of the detector site, large volumes of hexagonal ice crystals are formed. We calculate how this affects the Cherenkov radiation yield and angular dependence. We conclude that the effect is small, at most about a percent, and would only be relevant in future high-precision instruments like e.g. Precision IceCube Next Generation Upgrade (PINGU). For radio-Cherenkov experiments which use the presence of a clear Cherenkov cone to determine the arrival direction, any variation in emission angle will directly and linearly translate into a change in apparent neutrino direction. In closing, we also describe a simple experiment to test this formalism and calculate the impact of anisotropy on light yields from lead tungstate crystals as used, for example, in the CMS calorimeter at the CERN LHC.

  17. HER2 Amplification Has no Prognostic Value in Sporadic and Hereditary Ovarian Tumours

    Directory of Open Access Journals (Sweden)

    Brożek Izabela

    2006-11-01

    Full Text Available Abstract Whereas HER2 amplification is a well-known phenomenon in breast tumours, its frequency and clinical importance in ovarian cancer have not been established. The aim of the study was to compare the frequency of HER2 amplification in hereditary (BRCA-positive and sporadic (BRCA-negative ovarian tumours and to estimate the association of this gene alteration on clinical outcome in ovarian cancer patients. We analysed HER2 amplification in 53 ovarian tumours: 20 from mutation carriers (18 in BRCA1 and 2 in BRCA2 gene and 33 from non-carriers. Fluorescence in situ hybridization for HER2 was performed on 'touch' slides from frozen tumour samples or formalin-fixed, paraffin-embedded tissue. Our results indicate that high amplification (HER2: centromere ratio>5 is an infrequent phenomenon in ovarian tumours (6/53 cases. It occurs in both hereditary (4/20 and sporadic (2/33 tumours and no difference in the frequency of HER2 amplification exists between these groups. There is no significant difference in the clinical outcome of patients with HER2 amplified and non-amplified tumours (p = 0.3. Our results suggest a different biological role of HER2 amplification in ovarian and breast cancer.

  18. Naturally occurring radiation sources: existing or planned exposure situation?

    Energy Technology Data Exchange (ETDEWEB)

    Hedemann-Jensen, Per [Danish Decommissioning, DK-4000 Roskilde (Denmark)

    2010-12-01

    After more than fifteen years of application, ICRP Publication 60 has been revised. The revision was based upon the concept of 'controllable dose' as the dose or sum of doses to an individual from a particular source that can reasonably be controlled by whatever means. The new recommendations have been published as ICRP Publication 103. The European Basic Safety Standards as well as the International Basic Safety Standards are currently under revision as a result of the new recommendations from ICRP. According to the ICRP, there have been indications that some changes to the structure and terminology of the system of protection were desirable in order to improve clarity and utility. In particular the distinction between practices and interventions may not have been clearly understood and the ICRP now recognises three types of exposure situations, which replace the previous categorisation into practices and interventions. These exposure situations are intended to cover the entire range of exposure situations: (1) planned exposure, (2) existing exposure and (3) emergency exposure. There are situations of exposure to naturally occurring radiation sources in different occupations, e.g. exposure to radon and radon progeny in workplaces other than where the exposure is required by or is directly related to the work and aircrew exposed to cosmic radiation. In the European (Euratom) and the International Basic Safety Standards, these exposure situations are treated conceptually different-either as a planned exposure situation or as an existing exposure situation. This note reviews the change of exposure situations from Publication 60 to Publication 103 and the implications for the revision of both the International and the European Basic Safety Standards. The paper draws some conclusions on the classification of the exposure situations in the two basic safety standards based on a logical interpretation of the ICRP recommendations. It is recommended that the

  19. Antituberculosis Activity of a Naturally Occurring Flavonoid, Isorhamnetin.

    Science.gov (United States)

    Jnawali, Hum Nath; Jeon, Dasom; Jeong, Min-Cheol; Lee, Eunjung; Jin, Bongwhan; Ryoo, Sungweon; Yoo, Jungheon; Jung, In Duk; Lee, Seung Jun; Park, Yeong-Min; Kim, Yangmee

    2016-04-22

    Isorhamnetin (1) is a naturally occurring flavonoid having anticancer and anti-inflammatory properties. The present study demonstrated that 1 had antimycobacterial effects on Mycobacterium tuberculosis H37Rv, multi-drug- and extensively drug-resistant clinical isolates with minimum inhibitory concentrations of 158 and 316 μM, respectively. Mycobacteria mainly affect the lungs, causing an intense local inflammatory response that is critical to the pathogenesis of tuberculosis. We investigated the effects of 1 on interferon (IFN)-γ-stimulated human lung fibroblast MRC-5 cells. Isorhamnetin suppressed the release of tumor necrosis factor (TNF)-α and interleukin (IL)-12. A nontoxic dose of 1 reduced mRNA expression of TNF-α, IL-1β, IL-6, IL-12, and matrix metalloproteinase-1 in IFN-γ-stimulated cells. Isorhamnetin inhibited IFN-γ-mediated stimulation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase and showed high-affinity binding to these kinases (binding constants: 4.46 × 10(6) M(-1) and 7.6 × 10(6) M(-1), respectively). The 4'-hydroxy group and the 3'-methoxy group of the B-ring and the 5-hydroxy group of the A-ring of 1 play key roles in these binding interactions. A mouse in vivo study of lipopolysaccharide-induced lung inflammation revealed that a nontoxic dose of 1 reduced the levels of IL-1β, IL-6, IL-12, and INF-γ in lung tissue. These data provide the first evidence that 1 could be developed as a potent antituberculosis drug.

  20. Probabilities of Natural Events Occurring at Savannah River Plant

    Energy Technology Data Exchange (ETDEWEB)

    Huang, J.C.

    2001-07-17

    This report documents the comprehensive evaluation of probability models of natural events which are applicable to Savannah River Plant. The probability curves selected for these natural events are recommended to be used by all SRP/SRL safety analysts. This will ensure a consistency in analysis methodology for postulated SAR incidents involving natural phenomena.

  1. Molecular imaging of HER2-positive breast cancer

    DEFF Research Database (Denmark)

    Capala, Jacek; Bouchelouche, Kirsten

    2010-01-01

    HER2 overexpression is correlated with aggressive tumor behavior and poor clinical outcome. Therefore, HER2 has become an important prognostic and predictive factor, as well as a target for molecular therapies. The article reviews recent advances in molecular imaging of HER2 that could facilitate...

  2. HER2 specific delivery of methotrexate by dendrimer conjugated anti-HER2 mAb

    Energy Technology Data Exchange (ETDEWEB)

    Shukla, Rameshwer; Thomas, Thommey P; Desai, Ankur M; Kotlyar, Alina; Park, Steve J; Baker, James R Jr [Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, 9220 MSRB III, Box 0648, Ann Arbor, MI 48109 (United States)], E-mail: rameshwe@umich.edu, E-mail: jbakerjr@med.umich.edu

    2008-07-23

    Herceptin, a humanized monoclonal antibody that binds to human growth factor receptor-2 (HER2), was covalently attached to a fifth-generation (G5) polyamidoamine dendrimer containing the cytotoxic drug methotrexate. The specific binding and internalization of this conjugate labeled with FITC was clearly demonstrated in cell lines overexpressing HER2 by flow cytometry as well as confocal microscopic analysis. In addition, binding and uptake of antibody conjugated dendrimers was completely blocked by excess non-conjugated herceptin. The dendrimer conjugate was also shown to inhibit the dihydrofolate reductase with similar activity to methotrexate. Co-localization experiments with lysotracker red indicate that antibody conjugate, although internalized efficiently into cells, has an unusually long residence time in the lysosome. Somewhat lower cytotoxicity of the conjugate in comparison to free methotrexate was attributed to the slow release of methotrexate from the conjugate and its long retention in the lysosomal pocket.

  3. Committed effective dose from naturally occuring radionuclides in shellfish

    Science.gov (United States)

    Khandaker, Mayeen Uddin; Wahib, Norfadira Binti; Amin, Yusoff Mohd.; Bradley, D. A.

    2013-07-01

    Recognizing their importance in the average Malaysian daily diet, the radioactivity concentrations in mollusc- and crustacean-based food have been determined for key naturally occuring radionuclides. Fresh samples collected from various maritime locations around peninsular Malaysia have been processed using standard procedures; the radionuclide concentrations being determined using an HPGe γ-ray spectrometer. For molluscs, assuming secular equilibrium, the range of activities of 238U (226Ra), 232Th (228Ra) and 40K were found to be 3.28±0.35 to 5.34±0.52, 1.20±0.21 to 2.44±0.21 and 118±6 to 281±14 Bq kg-1 dry weight, respectively. The respective values for crustaceans were 3.02±0.57 to 4.70±0.52, 1.38±0.21 to 2.40±0.35 and 216±11 to 316±15 Bq kg-1. The estimated average daily intake of radioactivity from consumption of molluscs are 0.37 Bq kg-1 for 238U (226Ra), 0.16 Bq kg-1 for 232Th (228Ra) and 18 Bq kg-1 for 40K; the respective daily intake values from crustaceans are 0.36 Bq kg-1, 0.16 Bq kg-1 and 23 Bq kg-1. Associated annual committed effective doses from molluscs are estimated to be in the range 21.3 to 34.7 μSv for 226Ra, 19.3 to 39.1 μSv for 228Ra and 17.0 to 40.4 μSv for 40K. For crustaceans, the respective dose ranges are 19.6 to 30.5 μSv, 22.0 to 38.4 μSv and 31.1 to 45.5 μSv, being some several times world average values.

  4. Manufactured Home Testing in Simulated and Naturally Occurring High Winds

    Energy Technology Data Exchange (ETDEWEB)

    W. D. Richins; T. K. Larson

    2006-08-01

    A typical double-wide manufactured home was tested in simulated and naturally occurring high winds to understand structural behavior and improve performance during severe windstorms. Seven (7) lateral load tests were conducted on a double-wide manufactured home at a remote field test site in Wyoming. An extensive instrumentation package monitored the overall behavior of the home and collected data vital to validating computational software for the manufactured housing industry. The tests were designed to approach the design load of the home without causing structural damage, thus allowing the behavior of the home to be accessed when the home was later exposed to high winds (to 80-mph). The data generally show near-linear initial system response with significant non-linear behavior as the applied loads increase. Load transfer across the marriage line is primarily compression. Racking, while present, is very small. Interface slip and shear displacement along the marriage line are nearly insignificant. Horizontal global displacements reached 0.6 inch. These tests were designed primarily to collect data necessary to calibrate a desktop analysis and design software tool, MHTool, under development at the Idaho National Laboratory specifically for manufactured housing. Currently available analysis tools are, for the most part, based on methods developed for “stick built” structures and are inappropriate for manufactured homes. The special materials utilized in manufactured homes, such as rigid adhesives used in the connection of the sheathing materials to the studs, significantly alter the behavior of manufactured homes under lateral loads. Previous full scale tests of laterally loaded manufactured homes confirm the contention that conventional analysis methods are not applicable. System behavior dominates the structural action of manufactured homes and its prediction requires a three dimensional analysis of the complete unit, including tiedowns. This project was

  5. Hyperthermia-triggered intracellular delivery of anticancer agent to HER2(+) cells by HER2-specific affibody (ZHER2-GS-Cys)-conjugated thermosensitive liposomes (HER2(+) affisomes).

    Science.gov (United States)

    Smith, Brandon; Lyakhov, Ilya; Loomis, Kristin; Needle, Danielle; Baxa, Ulrich; Yavlovich, Amichai; Capala, Jacek; Blumenthal, Robert; Puri, Anu

    2011-07-30

    We previously reported the formulation and physical properties of HER2 (human epidermal growth factor receptor 2)-specific affibody (ZHER2:342-Cys) conjugated thermosensitive liposomes (HER2(+)affisomes). Here we examined localized delivery potential of these affisomes by monitoring cellular interactions, intracellular uptake, and hyperthermia-induced effects on drug delivery. We modified ZHER2:342-Cys by introducing a glycine-serine spacer before the C-terminus cysteine (called ZHER2-GS-Cys) to achieve accessibility to cell surface expressed HER2. This modification did not affect HER2-specific binding and ZHER2-GS-Cys retained its ability to conjugate to the liposomes containing dipalmitoyl phosphatidyl choline: DSPE-PEG2000-Malemide, 96:04 mole ratios (HER2(+)affisomes). HER2(+)affisomes were either (i) fluorescently labeled with rhodamine-PE and calcein or (ii) loaded with an anticancer drug doxorubicin (DOX). Fluorescently labeled HER2(+) affisomes showed at least 10-fold increase in binding to HER2(+) cells (SK-BR-3) when compared to HER2(-) cells (MDA-MB-468) at 37°C. A competition experiment using free ZHER2-GS-Cys blocked HER2(+) affisome-SK-BR-3 cell associations. Imaging with confocal microscopy showed that HER2(+) affisomes accumulated in the cytosol of SK-BR-3 cells at 37°C. Hyperthermia-induced intracellular release experiments showed that the treatment of HER2(+) affisome/SK-BR-3 cell complexes with a 45°C (±1°C) pre-equilibrated buffer resulted in cytosolic delivery of calcein. Substantial calcein release was observed within 20min at 45°C, with no effect on cell viability under these conditions. Similarly, DOX-loaded HER2(+)affisomes showed at least 2- to 3-fold higher accumulation of DOX in SK-BR-3 cells as compared to control liposomes. DOX-mediated cytotoxicity was more pronounced in SK-BR-3 cells especially at lower doses of HER2(+)affisomes. Brief exposure of liposome-cell complexes at 45°C prior to the onset of incubations for cell

  6. Could HER2 Heterogeneity Open New Therapeutic Options in Patients with HER2-Primary Breast Cancer

    Science.gov (United States)

    2015-10-01

    October 2015 TYPE OF REPORT: Annual PREPARED FOR: U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 DISTRIBUTION...currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE October 2015 2. REPORT TYPE Annual 3. DATES...PET/CT. Two of five patients with suspicious foci had biopsy proven HER2-positive metastases. In this early stage clinical trial, 89 Zr-trastuzumab

  7. Human epidermal growth factor receptor 2 (HER2) immunoreactivity

    DEFF Research Database (Denmark)

    Rasmussen, Anne-Sofie Schrohl; Pedersen, Hans Christian; Jensen, Sussie Steen

    2011-01-01

    The availability of specific antibody-based test systems is essential to testing of HER2 protein expression. Here, we mapped epitopes recognized by three pharmacodiagnostic HER2 antibodies and investigated their specificity towards peptides and fusion proteins homologous to the intracellular doma...... domains of HER1, HER2, HER3 and HER4. The investigated antibodies were PATHWAY(®) HER2 (clone 4B5; Ventana Medical Systems Inc., Tucson, AZ, USA), HercepTest™ (Dako Denmark A/S, Glostrup, Denmark), and Oracle(®) HER2 (clone CB11; Leica Microsystems GmbH, Wetzlar, Germany)....

  8. ATM kinase sustains HER2 tumorigenicity in breast cancer.

    Science.gov (United States)

    Stagni, Venturina; Manni, Isabella; Oropallo, Veronica; Mottolese, Marcella; Di Benedetto, Anna; Piaggio, Giulia; Falcioni, Rita; Giaccari, Danilo; Di Carlo, Selene; Sperati, Francesca; Cencioni, Maria Teresa; Barilà, Daniela

    2015-04-16

    ATM kinase preserves genomic stability by acting as a tumour suppressor. However, its identification as a component of several signalling networks suggests a dualism for ATM in cancer. Here we report that ATM expression and activity promotes HER2-dependent tumorigenicity in vitro and in vivo. We reveal a correlation between ATM activation and the reduced time to recurrence in patients diagnosed with invasive HER2-positive breast cancer. Furthermore, we identify ATM as a novel modulator of HER2 protein stability that acts by promoting a complex of HER2 with the chaperone HSP90, therefore preventing HER2 ubiquitination and degradation. As a consequence, ATM sustains AKT activation downstream of HER2 and may modulate the response to therapeutic approaches, suggesting that the status of ATM activity may be informative for the treatment and prognosis of HER2-positive tumours. Our findings provide evidence for ATM's tumorigenic potential revising the canonical role of ATM as a pure tumour suppressor.

  9. Naturally occurring and process-induced trans fatty acids and ...

    African Journals Online (AJOL)

    CHOKRI

    2013-05-22

    May 22, 2013 ... found in position 9, such as elaidic acid, with a Gaussian distribution of FAs with the ... traditional method of manually churning the naturally fermented milk and heating the ..... trans PUFA and CLA. PC1 was heavily weighted.

  10. Role of HER2/HER3 co-receptor in breast carcinogenesis.

    Science.gov (United States)

    Way, Tzong-Der; Lin, Jen-Kun

    2005-12-01

    ErbB receptors are essential mediators of cell proliferation and differentiation. Their aberrant activation is associated with the development and severity of many cancers. Homo- and heterodimerization of ErbB receptors result in a wide variety of cellular signal transduction. Dimerization of human epidermal growth-factor receptor (HER)2 and HER3 occurs frequently and is a preferred heterodimer. The HER2/HER3 dimer constitutes a high affinity co-receptor for heregulin, which is capable of potent mitogenic signaling. HER3 is a kinase-defective protein that is phosphorylated by HER2. Tyrosine phosphorylated HER3 is able to directly couple to phosphatidylinositide 3-kinase, a lipid kinase involved in the proliferation, survival, adhesion and motility of tumor cells. The authors' research provides mechanistic evidence that apigenin induces apoptosis by depleting the HER2 protein and, in turn, suppressing the signaling of the HER2/HER3-phosphatidylinositide 3-kinase/Akt pathway. This indicates that inhibition of HER2/HER3 heterodimer function may be an especially effective and unique strategy for blocking the HER2-mediated carcinogenesis of breast cancer cells.

  11. Lin28 promotes Her2 expression and Lin28/Her2 predicts poorer survival in gastric cancer.

    Science.gov (United States)

    Wang, Qinchuan; Zhou, Jichun; Guo, Jufeng; Teng, Rongyue; Shen, Jianguo; Huang, Yasheng; Xie, Shuduo; Wei, Qun; Zhao, Wenhe; Chen, Wenjun; Yuan, Xiaoming; Chen, Yongxia; Wang, Linbo

    2014-11-01

    The main purpose of this study is to investigate the interactions between Lin28 and Her2 in gastric cancer. Lin28 and Her2 expression were evaluated in surgically resected samples of 298 gastric cancer patients using immunohistochemical staining. The correlations between Lin28/Her2 expression and clinical variables were retrospectively analyzed. The mRNA level of LIN28 and HER2 was detected by reverse-transcriptase polymerase chain reaction. Among all gastric cancer patients, 33.9% (101/298) were determined as Her2-positive, and 43.0% (128/298) were defined as Lin28-positive. Lin28 was significantly associated with Her2, advanced tumor stage, lesion size, and Ki67 level (pLin28 and Her2 are poor prognostic factors in gastric cancer; Lin28(+)/Her2(+) patients have the poorest survival (median survival = 17 months, pLin28 is a significant prognostic factor (hazard ratio (HR) = 1.79, 95% confidence interval (CI) 1.23-2.62). Further stratification analysis indicated that Lin28 may be a prognostic factor in chemotherapy. In vitro data on MKN-28 and MKN-45 cells showed that Lin28 can upregulate Her2 expression at translational level. Both Lin28 and Her2 are poor prognostic factors in gastric cancer. Lin28 may regulate Her2 post-transcriptionally in gastric cancer cells, which indicates it might be a potential target in the treatment of gastric cancer.

  12. Overview of naturally occurring Earth materials and human health concerns

    Science.gov (United States)

    Ernst, W. G.

    2012-10-01

    The biosphere and the Earth's critical zone have maintained a dynamic equilibrium for more than 3.5 billion years. Except for solar energy, almost all terrestrial substances necessary for life have been derived from near-surface portions of the land, hydrosphere, and atmosphere. If aggregate biological activities are less than the rate of nutrient supply and/or resource renewal, sustained population growth is possible. Where the replenishment rate of a life-sustaining Earth material is finite, usage may reach a condition of dynamic equilibrium in which biological consumption equals but on average cannot exceed the overall supply. Although large, most natural resources are present in finite abundances; for such commodities, excessive present-day human utilization reduces future availability, and thus the ultimate planetary carrying capacity for civilization. Intensive use of Earth materials has enhanced the quality of life, especially in the developed nations. Still, natural background levels, and Earth processes such as volcanic eruptions, as well as human activities involving agriculture, construction, and the extraction, refining, and transformation of mineral resources have led to harmful side effects involving environmental degradation and public health hazards. Among naturally and anthropogenically induced risks are bioaccessible airborne dusts and gases, soluble pollutants in agricultural, industrial, and residential waters, and toxic chemical species in foods and manufactured products. At appropriate levels of ingestion, many Earth materials are necessary for existence, but underdoses and overdoses have mild to serious consequences for human health and longevity. This overview briefly sketches several natural resource health hazards. Included are volcanic ash + aerosols + gases, mineral dusts, non-volcanic aerosols + nanoparticles, asbestos + fibrous zeolites, arsenic, fluorine, iodine, uranium + thorium + radium + radon + polonium, selenium, mercury, copper

  13. HER2 and COX2 expression in human prostate cancer.

    Science.gov (United States)

    Edwards, J; Mukherjee, R; Munro, A F; Wells, A C; Almushatat, A; Bartlett, J M S

    2004-01-01

    COX2 and HER2 expression are associated with a poor prognosis in prostate cancer and HER2 has been linked to COX2 expression in colorectal cancer. The association between COX2 and HER2 expression was investigated in 117 patients with prostate cancer (89) or Benign prostatic hyperplasia (BPH) (28). Tissue was analysed for HER2 amplification by fluorescent in situ hybridisation, and HER2 and COX2 protein expression by immunohistochemistry (IHC). All tumours analysed expressed COX2 at a significantly higher level than BPH tissue (P=0.041). Only low levels of HER2 gene amplification (8%, 7/89) and HER2 protein expression (12%, 11/89) were observed. HER2 protein expression was rarely observed and did not correlate with HER2 amplification or COX2 expression. Although HER2 does not drive COX2 expression in prostate cancer, this study identified high levels of COX2 expressed in locally advanced prostate cancer, suggesting COX2 could be a potential therapeutic target. COX2 inhibitors are currently being used in clinical trials for the treatment of other tumour types.

  14. Genetic heterogeneity in HER2 testing may influence therapy eligibility.

    Science.gov (United States)

    Bernasconi, Barbara; Chiaravalli, Anna Maria; Finzi, Giovanna; Milani, Katia; Tibiletti, Maria Grazia

    2012-05-01

    Prospective studies have demonstrated that approximately 20% of HER2 testing may be inaccurate. When carefully validated testing is conducted, available data do not clearly demonstrate the superiority of either IHC or fluorescence in situ hybridization (FISH) as a predictor of benefit from anti-HER2 therapy. In addition, the interpretation of the findings of HER2 tests according to international guidelines is not uniform. The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) recently published practice guidelines for a definition of HER2 amplification heterogeneity that can give rise to discrepant results between IHC and FISH assays for HER2. In this article, we compare the HER2 status of 291 non consecutive breast cancers. The status is determined by both IHC and FISH approaches, using a specific FISH strategy to investigate genetic heterogeneity. Our data demonstrate that HER2 amplified cells may be found as diffuse, clustered in a specific area or section, intermingled with non-amplified cells or confined to metastatic nodules. The correct evaluation of ratio value in the presence of genetic heterogeneity and of polysomy contributes to the accurate assessment of HER2 status and potentially affects the selection of appropriate anti-HER2 therapy. By taking into account the presence of different genetic cell populations, the immunotherapy eligibility criteria for HER2 FISH scoring proposed in the CAP (2009) and SIGU guidelines identify an additional subset of cases for trastuzumab or lapatinib therapy compared to the ASCO/CAP (2007) guidelines.

  15. The Frequency, Nature, and Effects of Naturally Occurring Appearance-Focused Social Comparisons

    Science.gov (United States)

    Leahey, Tricia M.; Crowther, Janis H.; Mickelson, Kristin D.

    2007-01-01

    This research examined the effects of naturally occurring appearance-focused social comparisons on women's affect, body satisfaction, and weight-related cognitions. During their daily activities, women reporting body dissatisfaction (n = 53) and women reporting body satisfaction (n = 34) recorded their reactions to comparison information.…

  16. ION EXCHANGE MECHANISM OF Cr+3 ON NATURALLY OCCURRING CLINOPTILOLITE

    Directory of Open Access Journals (Sweden)

    M.A.S.D. de Barros

    1997-09-01

    Full Text Available Ion exchange isotherms are very important tools to achieve a better comprehension of cation removal by means of zeolite treatment. In this work, three isotherms were obtained (at 298K, at 313K and at 333K from natural pretreated Na+ clinoptilolite. The ion exchange was carried out with Cr+3 ions. The isotherms’ shape is similar to the classical type "b" isotherm, according to the arrangement proposed by Breck (1984. Mathematical fitting was applied to the experimental points (Table Curve software to obtain a representative curve thereof. From such fittings, points were simulated and then used to construct the Kielland plots, whose shape was associated with an ion exchange mechanism. Straight lines were obtained as an indication that, although the zeolite used is of natural occurrence and presents impurities such as mordenite and clays, only one site is involved in the ion exchange process

  17. Shear wave filtering in naturally-occurring Bouligand structures.

    Science.gov (United States)

    Guarín-Zapata, Nicolás; Gomez, Juan; Yaraghi, Nick; Kisailus, David; Zavattieri, Pablo D

    2015-09-01

    Wave propagation was investigated in the Bouligand-like structure from within the dactyl club of the stomatopod, a crustacean that is known to smash their heavily shelled preys with high accelerations. We incorporate the layered nature in a unitary material cell through the propagator matrix formalism while the periodic nature of the material is considered via Bloch boundary conditions as applied in the theory of solid state physics. Our results show that these materials exhibit bandgaps at frequencies related to the stress pulse generated by the impact of the dactyl club to its prey, and therefore exhibiting wave filtering in addition to the already known mechanisms of macroscopic isotropic behavior and toughness. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  18. Interactions between plasma proteins and naturally occurring polyphenols.

    Science.gov (United States)

    Li, Min; Hagerman, Ann E

    2013-05-01

    The plant natural products known as polyphenols are found at micronutrient levels in fruits, vegetables, and plant-based beverages such as wine, tea, coffee and cocoa. Consumption of a fruit- and vegetable-rich diet, the "Mediterranean diet", has been epidemiologically related to health benefits especially for chronic diseases including diabetes, cardiovascular disease, and Alzheimer's disease. The abundance of polyphenols in plant-rich diets, and the potent bioactivities of polyphenols, provide indirect evidence for a role for polyphenols in maintaining good health. However, molecular mechanisms for therapeutic or preventative activity have not been demonstrated in vivo. We summarize the chemical classes of natural polyphenols, their bioactivities and bioavailability and metabolism. Because many polyphenols bind protein, we focus on the potential of protein binding to mediate the health-related effects of polyphenols. We discuss interactions with plasma proteins as the first target organ past the digestive tract for these orally-ingested compounds.

  19. Going Wild: Lessons from Naturally Occurring T-Lymphotropic Lentiviruses

    OpenAIRE

    VandeWoude, Sue; Apetrei, Cristian

    2006-01-01

    Over 40 nonhuman primate (NHP) species harbor species-specific simian immunodeficiency viruses (SIVs). Similarly, more than 20 species of nondomestic felids and African hyenids demonstrate seroreactivity against feline immunodeficiency virus (FIV) antigens. While it has been challenging to study the biological implications of nonfatal infections in natural populations, epidemiologic and clinical studies performed thus far have only rarely detected increased morbidity or impaired fecundity/sur...

  20. Virological and serological findings in dogs with naturally occurring distemper.

    Science.gov (United States)

    Elia, Gabriella; Camero, Michele; Losurdo, Michele; Lucente, Maria Stella; Larocca, Vittorio; Martella, Vito; Decaro, Nicola; Buonavoglia, Canio

    2015-03-01

    Canine distemper virus (CDV) is the cause of a severe and highly contagious disease in dogs. The unpredictable and variable course of CDV-related disease may hamper correct diagnosis of infection and makes it crucial the collection of samples suitable for laboratory confirmation. In the present study we were able to follow the disease in two dogs infected naturally, collecting different biological matrices during the entire period of infection. By real time RT-PCR, viral RNA was detected and quantified, suggesting that urine and rectal swabs would be useful for ante-mortem diagnosis of distemper in dogs, regardless of the clinical stage and form of the illness.

  1. Testing for HER2 in Breast Cancer: A Continuing Evolution

    Directory of Open Access Journals (Sweden)

    Sejal Shah

    2011-01-01

    Full Text Available Human epidermal growth factor receptor 2 (HER2 is an important prognostic and predictive factor in breast cancer. HER2 is overexpressed in approximately 15%–20% of invasive breast carcinomas and is associated with earlier recurrence, shortened disease free survival, and poor prognosis. Trastuzumab (Herceptin a “humanized” monoclonal antibody targets the extracellular domain of HER2 and is widely used in the management of HER2 positive breast cancers. Accurate assessment of HER2 is thus critical in the management of breast cancer. The aim of this paper is to present a comprehensive review of HER2 with reference to its discovery and biology, clinical significance, prognostic value, targeted therapy, current and new testing modalities, and the interpretation guidelines and pitfalls.

  2. Antitumor effects of naturally occurring cardiac glycosides convallatoxin and peruvoside on human ER+ and triple-negative breast cancers

    Science.gov (United States)

    Kaushik, Vivek; Azad, Neelam; Yakisich, Juan Sebastian; Iyer, Anand Krishnan V

    2017-01-01

    Breast cancer is second most prevalent cancer in women, and the second only to lung cancer in cancer-related deaths. It is a heterogeneous disease and has several subtypes based on the presence or absence of hormone receptors and/or human epidermal growth factor receptor 2 (HER2). Hormone receptor-positive and HER2-enriched cancers can be targeted using hormone and HER2-targeting therapies such as trastuzumab or lapatinib. However, triple-negative breast cancers (TNBCs) do not express any of the receptors and therefore are resistant to most targeted therapies, and cytotoxic chemotherapies are the only viable option available for the treatment of TNBCs. Recently, cardiac glycosides (CGs) have emerged as potential anticancer agents that impart their antiproliferative effect by targeting multiple pathways. In this study our aim was to evaluate anticancer effects of two naturally occurring CGs, Convallatoxin (CT) and Peruvoside (PS), on ER+ and TNBCs cells. CT and PS demonstrated dose- and time-dependent cytotoxic effect on MCF-7 cells, which was further supported by loss of colony formation on drug treatment. CT and PS arrested MCF-7 cells in the G0/G1 phase and reduced the viability of MCF-7-derived mammospheres (MMs). Interestingly, while CT and PS imparted cell death in TNBCs cells from both Caucasians (MDA-MB-231 cells) and African Americans (MDA-MB-468 cells) in a dose- and time-dependent manner, the drugs were much more potent in MDA-MB-468 as compared with TNBC MDA-MB-231 cells. Both drugs significantly inhibited migration and invasion of both MCF-7 and MDA-MB-468 cells. An assessment of intracellular pathways indicated that both drugs were able to modulate several key cellular pathways such as EMT, cell cycle, proliferation and cell death in both cell types. Our data suggest a promising role for CGs in breast cancer treatment specifically in targeting TNBCs derived from African Americans, and provides impetus for further investigation of the anticancer

  3. A naturally-occurring 'cold earth' spot in Northern China.

    Science.gov (United States)

    Niu, Fujun; Cheng, Guodong; Niu, Yonghong; Zhang, Mingyi; Luo, Jing; Lin, Zhanju

    2016-09-29

    Permafrost is determined to a large extent by the Earth's surface temperature, therefore it distributes mainly in high altitude and latitude regions. However, stable, warm (about -1 °C) permafrost occurs within a scree slope in northern China that is more than 600 km south of the southernmost limit of latitudinal permafrost on the Eurasian Continent. It is at an elevation of only 900 m above sea level (ASL). The area has a mean annual air temperature (MAAT) of 6 to 8 °C. Thermal processes of the scree slope, investigated through field monitoring and numerical simulation, showed that the permafrost is caused by winter air convection within the porous rock deposits and is stable as air convection does not occur in summer time. The deposit is covered by a 30-cm-thick peaty soil layer dated (carbon C-14) to between 1,000 to 1,600 years ago. The layer also contributes to the permafrost's existence due to the peat's thermal conductivity offset when frozen and thawed. The existence of permafrost under such warm climatic conditions confirms the effectiveness of using crushed rock layer as basement or slope cover to protect the warm permafrost subgrade of the recently-constructed Qinghai-Tibet Railway (QTR), even under the predicted climate warming conditions.

  4. HER2/CEP17 Ratios and Clinical Outcome in HER2-Positive Early Breast Cancer Undergoing Trastuzumab-Containing Therapy.

    Directory of Open Access Journals (Sweden)

    Albina Stocker

    Full Text Available Adjuvant therapy comprising the HER2 receptor antagonist trastuzumab is associated with a significant improvement in disease-free and overall survival as compared to chemotherapy alone in localized HER2-positive breast cancer (BC. However, a subset of HER2-positive tumors seems to respond less favorably to trastuzumab. Various mechanisms have been proposed for trastuzumab resistance, such as high HER2 to Chromosome 17 FISH (HER2/CEP17 ratios and the possibility that single agent trastuzumab may not suffice to efficiently block HER2 downstream signaling thresholds. In a retrospective analysis we evaluated whether HER2/CEP17 ratios might have an impact on disease-free survival (DFS.Clinical records of Stage I-III BC patients with HER2-positive tumors were reviewed at our institution from 2007-2013. We analyzed demographics, tumor characteristics including tumor size and grade, lymph node involvement and estrogen receptor expression as well as treatment with respect to chemotherapeutic regimens from the clinical charts. HER2/CEP17 ratios were determined by routine pathology analysis using in situ fluorescent hybridization (FISH. Upon statistical preview we defined three groups of HER2 amplification based on FISH ratio (2.2 to 4, >4 to 8, >8, in order to evaluate an association between HER2 gene amplification and DFS with trastuzumab containing therapies. DFS was analyzed using Cox-regression.A total of 332 patients with HER2-positive BC were reviewed. Median age was 54 (range 23-89 years. The majority of tumors were classified T1 (50% or T2 (39%, node negative (52% and of high grade G3 histology (70%. We identified 312 (94% tumors as immunohistochemistry (IHC score 3+ and HER2/CEP17 ratios were available from 278 patients (84%. 30% (N = 84 had tumors with high HER2/CEP17 ratios (>8. Univariate analysis found no correlation between outcome, age, histological grade, sequence as well as anthracycline content of chemotherapy. However, a prognostic

  5. Polyomavirus and Naturally Occuring Neuroglial Tumors in Raccoons (Procyon Lotor).

    Science.gov (United States)

    Pesavento, Patricia A; Brostoff, Terza; Church, Molly E; Dela Cruz, Florante N; Woolard, Kevin D

    2016-01-01

    Polyomavirus (PyV) infections are widespread in human populations and, although generally associated with silent persistence, rarely cause severe disease. Among diseases convincingly associated with natural PyV infections of humans, there are remarkably different tissue tropisms and outcomes, including progressive multifocal leukoencephalopathy, transient or progressive nephropathy, and cancer. The variable character and unpredictable outcomes of infection attest to large gaps in our basic understanding of PyV biology. In particular, the rich history of research demonstrating the oncogenic potential of PyVs in laboratory animals begs the question of why cancer is not more often associated with infection. Raccoon polyomavirus (RacPyV), discovered in 2010, is consistently identified in neuroglial tumors in free-ranging raccoons in the western United States. Exposure to RacPyV is widespread, and RacPyV is detected in tissues of raccoons without tumors. Studying the relationship of RacPyV with its natural host is a unique opportunity to uncover cogent cellular targets and protein interactions between the virus and its host. Our hypothesis is that RacPyV, as an intact episome, alters cellular pathways within neural progenitor cells and drives oncogenesis. © The Author 2016. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  6. The HER2-binding affibody molecule (Z(HER2∶342₂ increases radiosensitivity in SKBR-3 cells.

    Directory of Open Access Journals (Sweden)

    Lina Ekerljung

    Full Text Available We have previously shown that the HER2-specific affibody molecule (Z(HER2∶342₂ inhibits proliferation of SKBR-3 cells. Here, we continue to investigate its biological effects in vitro by studying receptor dimerization and clonogenic survival following irradiation. We found that (Z(HER2∶342₂ sensitizes the HER2-overexpressing cell line SKBR-3 to ionizing radiation. The survival after exposure to (Z(HER2∶342₂ and 8 Gy (S(8Gy 0.006 was decreased by a factor four compared to the untreated (S(8Gy 0.023. The low HER2-expressing cell line MCF-7 was more radiosensitive than SKBR-3 but did not respond to (Z(HER2∶342₂. Treatment by (Z(HER2∶342₂ strongly increased the levels of dimerized and phosphorylated HER2 even after 5 minutes of stimulation. The monomeric Z(HER2∶342 does not seem to be able to induce receptor phosphorylation and dimerization or sensitize cells to irradiation.

  7. Dual blockade of HER2 in HER2-overexpressing tumor cells does not completely eliminate HER3 function

    Science.gov (United States)

    Garrett, Joan T.; Sutton, Cammie R.; Kuba, María Gabriela; Cook, Rebecca S .; Arteaga, Carlos L.

    2012-01-01

    Purpose Dual blockade of HER2 with trastuzumab with lapatinib or with pertuzumab is a superior treatment approach compared to single agent HER2 inhibitors. However, many HER2-overexpressing breast cancers still escape from this combinatorial approach. Inhibition of HER2 and downstream phosphatidylinositol-3 kinase (PI3K)/AKT causes a transcriptional and post-translational upregulation of HER3 which, in turn, counteracts the antitumor action of the HER2-directed therapies. We hypothesized that suppression of HER3 would synergize with dual blockade of HER2 in breast cancer cells sensitive and refractory to HER2 antagonists. Experimental Design Inhibition of HER2/HER3 in HER2+ breast cancer cell lines was evaluated by western blot. We analyzed drug-induced apoptosis and 2- and 3-dimensional growth in vitro. Growth inhibition of PI3K was examined in vivo in xenografts treated with combinations of trastuzumab, lapatinib, and the HER3 neutralizing monoclonal antibody U3-1287. Results Treatment with U3-1287 blocked the upregulation of total and phosphorylated HER3 that followed treatment with lapatinib and trastuzumab and, in turn, enhanced the anti-tumor action of the combination against trastuzumab-sensitive and -resistant cells. Mice bearing HER2+ xenografts treated with lapatinib, trastuzumab, and U3-1287 exhibited fewer recurrences and better survival compared to mice treated with lapatinib and trastuzumab. Conclusions Dual blockade of HER2 with trastuzumab and lapatinib does not eliminate the compensatory upregulation of HER3. Therapeutic inhibitors of HER3 should be considered as part of multi-drug combinations aimed at completely and rapidly disabling the HER2 network in HER2-overexpressing breast cancers. PMID:23224399

  8. Structures and Properties of Naturally Occurring Polyether Antibiotics

    Directory of Open Access Journals (Sweden)

    Jacek Rutkowski

    2013-01-01

    Full Text Available Polyether ionophores represent a large group of natural, biologically active substances produced by Streptomyces spp. They are lipid soluble and able to transport metal cations across cell membranes. Several of polyether ionophores are widely used as growth promoters in veterinary. Polyether antibiotics show a broad spectrum of bioactivity ranging from antibacterial, antifungal, antiparasitic, antiviral, and tumour cell cytotoxicity. Recently, it has been shown that some of these compounds are able to selectively kill cancer stem cells and multidrug-resistant cancer cells. Thus, they are recognized as new potential anticancer drugs. The biological activity of polyether ionophores is strictly connected with their molecular structure; therefore, the purpose of this paper is to present an overview of their formula, molecular structure, and properties.

  9. Super resolution imaging of HER2 gene amplification

    Science.gov (United States)

    Okada, Masaya; Kubo, Takuya; Masumoto, Kanako; Iwanaga, Shigeki

    2016-02-01

    HER2 positive breast cancer is currently examined by counting HER2 genes using fluorescence in situ hybridization (FISH)-stained breast carcinoma samples. In this research, two-dimensional super resolution fluorescence microscopy based on stochastic optical reconstruction microscopy (STORM), with a spatial resolution of approximately 20 nm in the lateral direction, was used to more precisely distinguish and count HER2 genes in a FISH-stained tissue section. Furthermore, by introducing double-helix point spread function (DH-PSF), an optical phase modulation technique, to super resolution microscopy, three-dimensional images were obtained of HER2 in a breast carcinoma sample approximately 4 μm thick.

  10. Naturally occurring glasses: analogues for radioactive waste forms

    Energy Technology Data Exchange (ETDEWEB)

    Ewing, R.C.; Haaker, R.F.

    1979-04-01

    Volcanic glasses are very often altered by weathering and leaching and recrystallize to their fine-grained equivalents (rhyolites, felsites). The oldest volcanic glasses are dated at 40 million years before the present, but the majority are much younger. Devitrification textures was produced experimentally; and hydration rates for volcanic glasses were determined as a function of composition, temperature, and climate. Presence of water and temperature are the most important rate controlling variables. Even material that may still be described as glassy often exhibits evidence of alteration and recrystallization. Of the volcanic glasses that are preserved in the geologic record, it would be rare to describe such a glass as pristine. Despite the common alteration and recrystallization effects observed in volcanic glasses, glasses formed as a result of impact, tektites and lunar glasses, may occur in substantially unaltered form. In the case of tektites, their resistance to alteration is a result of their high SiO/sub 2/ content and low alkali content. Lunar glasses have been preserved for hundreds of millions of years because they exist in an environment with a low oxygen fugacity and an extremely low water vapor partial presssure. Thus one might expect glasses of particular compositions or in specific types of environment to be stable for long periods of time. These conclusions are applied to radioactive waste disposal over several time periods (0-30h, 30h-20y, 20-200y).

  11. Naturally occurring glasses: analogues for radioactive waste forms

    Energy Technology Data Exchange (ETDEWEB)

    Ewing, R.C.; Haaker, R.F.

    1979-04-01

    Volcanic glasses are very often altered by weathering and leaching and recrystallize to their fine-grained equivalents (rhyolites, felsites). The oldest volcanic glasses are dated at 40 million years before the present, but the majority are much younger. Devitrification textures was produced experimentally; and hydration rates for volcanic glasses were determined as a function of composition, temperature, and climate. Presence of water and temperature are the most important rate controlling variables. Even material that may still be described as glassy often exhibits evidence of alteration and recrystallization. Of the volcanic glasses that are preserved in the geologic record, it would be rare to describe such a glass as pristine. Despite the common alteration and recrystallization effects observed in volcanic glasses, glasses formed as a result of impact, tektites and lunar glasses, may occur in substantially unaltered form. In the case of tektites, their resistance to alteration is a result of their high SiO/sub 2/ content and low alkali content. Lunar glasses have been preserved for hundreds of millions of years because they exist in an environment with a low oxygen fugacity and an extremely low water vapor partial presssure. Thus one might expect glasses of particular compositions or in specific types of environment to be stable for long periods of time. These conclusions are applied to radioactive waste disposal over several time periods (0-30h, 30h-20y, 20-200y).

  12. Naturally Occurring Off-Switches for CRISPR-Cas9.

    Science.gov (United States)

    Pawluk, April; Amrani, Nadia; Zhang, Yan; Garcia, Bianca; Hidalgo-Reyes, Yurima; Lee, Jooyoung; Edraki, Alireza; Shah, Megha; Sontheimer, Erik J; Maxwell, Karen L; Davidson, Alan R

    2016-12-15

    CRISPR-Cas9 technology would be enhanced by the ability to inhibit Cas9 function spatially, temporally, or conditionally. Previously, we discovered small proteins encoded by bacteriophages that inhibit the CRISPR-Cas systems of their host bacteria. These "anti-CRISPRs" were specific to type I CRISPR-Cas systems that do not employ the Cas9 protein. We posited that nature would also yield Cas9 inhibitors in response to the evolutionary arms race between bacteriophages and their hosts. Here, we report the discovery of three distinct families of anti-CRISPRs that specifically inhibit the CRISPR-Cas9 system of Neisseria meningitidis. We show that these proteins bind directly to N. meningitidis Cas9 (NmeCas9) and can be used as potent inhibitors of genome editing by this system in human cells. These anti-CRISPR proteins now enable "off-switches" for CRISPR-Cas9 activity and provide a genetically encodable means to inhibit CRISPR-Cas9 genome editing in eukaryotes. VIDEO ABSTRACT. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Naturally occurring antifouling substances. Kaiyo fuchaku seibutsu no kiraina mono

    Energy Technology Data Exchange (ETDEWEB)

    Ina, K. (Shizuoka University, Sizuoka (Japan). Faculty of Agriculture)

    1991-07-20

    Prohibition would be imposed on a method of mixing organic tin or copper suboxide into paints coated on vessel hulls or seawater ducts as a means to prevent deposition of marine contaminant organisms, such as barnacles and Mytilidae, Mytilidae, because the method can cause detrimental contamination. Therefore, this paper describes an attempt to find antifouling substances from plant extracts with Mytilus as the object. The antifouling activity was determined by a uniquely devised test plate method (count and evaluate the positions and number of moving tracks of shells utilizing their nature that shells extend their byssuses rear to their body when they face aversive substances, and the number of byssus reduces when their living energy gets weakened), and the toxicity was determined by the number of dead shells opening their shells after they have been immersed for a predetermined time. Thus, tests were carried out on methanol extracts of about 100 kinds of ground plants and seaweeds, whereas some of them were found having antifouling activity of several times that of copper sulfate, but the plant genera and families were unspecified. 14 refs., 3 figs., 4 tabs.

  14. Evidence of sublaminar drag naturally occurring in a curved pipe

    Science.gov (United States)

    Noorani, A.; Schlatter, P.

    2015-03-01

    Steady and unsteady flows in a mildly curved pipe for a wide range of Reynolds numbers are examined with direct numerical simulation. It is shown that in a range of Reynolds numbers in the vicinity of Reb ≈ 3400, based on bulk velocity and pipe diameter, a marginally turbulent flow is established in which the friction drag naturally reduces below the laminar solution at the same Reynolds number. The obtained values for friction drag for the laminar and turbulent (sublaminar) flows turn out to be in excellent agreement with experimental measurements in the literature. Our results are also in agreement with Fukagata et al. ["On the lower bound of net driving power in controlled duct flows," Phys. D 238, 1082 (2009)], as the lower bound of net power required to drive the flow, i.e., the pressure drop of the Stokes solution, is still lower than our marginally turbulent flow. A large-scale traveling structure that is thought to be responsible for that behaviour is identified in the instantaneous field. This mode could also be extracted using proper orthogonal decomposition. The effect of this mode is to redistribute the mean flow in the circular cross section which leads to lower gradients at the wall compared to the laminar flow.

  15. Naturally-occurring dimers of flavonoids as anticarcinogens.

    Science.gov (United States)

    Mercader, Andrew G; Pomilio, Alicia B

    2013-10-01

    Biflavonoids are dimers of flavonoid moieties linked by a C-C or C-O-C bond. Simple, complex, rearranged, natural and ketalized Diels-Alder adducts, benzofuran derivatives, and spirobiflavonoids are some of the structural groups of biflavonoids. These compounds are mainly distributed in the Gymnosperms, Angiosperms (monocots and dicots), ferns (Pteridophyta), and mosses (Bryophyta). Biflavonoids have shown a variety of biological activities, including anticancer, antibacterial, antifungal, antiviral, antiinflammatory, analgesic, antioxidant, vasorelaxant, anticlotting, among others. This work is focused on probably the most potentially relevant biological activity of biflavonoids, the anticancer activity and the involved mechanisms of action, such as induction of apoptosis [inhibition of cyclic nucleotide phosphodiesterases; effects on NF-κB family of transcription factors; activation of caspase(s); inhibition effects on bcl-2 expression, and upregulation of p53 and caspase-3 gene expression]; inhibition of angiogenesis [anti-proliferative effects; activation of Rho-GTPases and ERK signaling pathways; inhibition of FASN activity]; inhibition of pre-mRNA splicing; inhibition of human DNA topoisomerases I and II-α; anti-inflammatory/ immunoregulatory effects [inhibition of XO; inhibition of proinflammatory enzymes, such as PLA2 and COX; effects on cytokines mediated COX-2 and iNOS expression]; modulation of immune response; inhibition of protein tyrosine phosphorylation; antioxidant and analgesic activities in relation to the anticarcinogen behavior. For that reason the structures and anticarcinogenic activities of 83 biflavonoids are thoroughly discussed. The results of this work indicate that biflavonoids strongly affect the cancer cells with little effect on normal cell proliferation, suggesting a therapeutic potential against cancer.

  16. Hsf1 in Her2-Positive Breast Cancer

    Science.gov (United States)

    2012-10-01

    these effects were not limited to Her2-positive breast cancer cells, since they were seen in Her2-negative, estrogen receptor (ER)-positive MCF7...diseases, diabetes, osteoporosis , and many types of cancer. Various age-associated disorders are characterized by accumulation of damaged proteins (Jana et

  17. HER2 testing in gastric and gastroesophageal adenocarcinomas.

    Science.gov (United States)

    Vakiani, Efsevia

    2015-05-01

    The human epidermal growth factor receptor 2 (HER2) is overexpressed in 10% to 35% of gastric and gastroesophageal junction (GEJ) adenocarcinomas. In 2010, the phase III Trastuzumab for Gastric Cancer (ToGA) trial showed that addition of the anti-HER2 monoclonal antibody trastuzumab to chemotherapy significantly improved survival of patients with advanced or metastatic tumors that were positive for HER2 overexpression. As a result, HER2 testing is now recommended for all patients with advanced or metastatic disease, although there is still some debate as to the optimal methods of assessment. HER2 expression in gastric and GEJ tumors shows several differences compared with breast tumors and, for this reason, the proposed criteria for scoring HER2 expression in biopsies and resections of gastric and GEJ carcinomas differ from those used in breast carcinomas. This review discusses what is currently known about the patterns of HER2 expression in gastric and GEJ adenocarcinomas, summarizes the findings of the ToGA trial and its clinical implications, and provides an overview of the recommended guidelines for the most accurate evaluation of HER2 status in gastric and GEJ cancer.

  18. Mycoplasmal lipoprotein p37 binds human protein HER2.

    Science.gov (United States)

    Wu, Jun; Wu, Lijuan; Fang, Cheng; Nie, Rong; Wang, Jiamou; Wang, Xuan; Liu, Wenbin

    2016-11-01

    Mycoplasmas are a group of microbes that can cause human diseases. The mycoplasmal lipoprotein p37 promotes cancer metastasis, at least in part, by interacting with EGFR. In this study, we show that the p37 lipoprotein binds another member of the EGFR family, HER2, through the HER2 extracellular domain. The binding of p37-HER2 promotes phosphorylation of HER2 and activates the downstream signaling molecule Erk1/2. Because the HER2 signaling pathway contributes to breast tumor metastasis, our results imply that the mycoplasmal lipoprotein p37 may also be involved in breast cancer metastasis. This study contributes to our understanding of mycoplasmal lipoprotein p37 function and its potential involvement in tumorigenesis. Copyright © 2016. Published by Elsevier GmbH.

  19. Tumor targeting using anti-her2 immunoliposomes.

    Science.gov (United States)

    Park, J W; Kirpotin, D B; Hong, K; Shalaby, R; Shao, Y; Nielsen, U B; Marks, J D; Papahadjopoulos, D; Benz, C C

    2001-07-06

    We have generated anti-HER2 (ErbB2) immunoliposomes (ILs), consisting of long circulating liposomes linked to anti-HER2 monoclonal antibody (MAb) fragments, to provide targeted drug delivery to HER2-overexpressing cells. Immunoliposomes were constructed using a modular strategy in which components were optimized for internalization and intracellular drug delivery. Parameters included choice of antibody construct, antibody density, antibody conjugation procedure, and choice of liposome construct. Anti-HER2 immunoliposomes bound efficiently to and internalized in HER2-overexpressing cells in vitro as determined by fluorescence microscopy, electron microscopy, and quantitative analysis of fluorescent probe delivery. Delivery via ILs in HER2-overexpressing cells yielded drug uptake that was up to 700-fold greater than with non-targeted sterically stabilized liposomes. In vivo, anti-HER2 ILs showed extremely long circulation as stable constructs in normal adult rats after a single i.v. dose, with pharmacokinetics that were indistinguishable from sterically stabilized liposomes. Repeat administrations revealed no increase in clearance, further confirming that ILs retain the long circulation and non-immunogenicity of sterically stabilized liposomes. In five different HER2-overexpressing xenograft models, anti-HER2 ILs loaded with doxorubicin (dox) showed potent anticancer activity, including tumor inhibition, regressions, and cures (pathologic complete responses). ILs were significantly superior vs. all other treatment conditions tested: free dox, liposomal dox, free MAb (trastuzumab), and combinations of dox+MAb or liposomal dox+MAb. For example, ILs produced significantly superior antitumor effects vs. non-targeted liposomes (P values from experiments). In a non-HER2-overexpressing xenograft model (MCF7), ILs and non-targeted liposomal dox produced equivalent antitumor effects. Detailed studies of tumor localization indicated a novel mechanism of drug delivery for anti-HER

  20. Disulfiram targets cancer stem-like properties and the HER2/Akt signaling pathway in HER2-positive breast cancer.

    Science.gov (United States)

    Kim, Ji Young; Cho, Youngkwan; Oh, Eunhye; Lee, Nahyun; An, Hyunsook; Sung, Daeil; Cho, Tae-Min; Seo, Jae Hong

    2016-08-28

    HER2-positive breast tumors are known to harbor cancer stem-like cell populations and are associated with an aggressive tumor phenotype and poor clinical outcomes. Disulfiram (DSF), an anti-alcoholism drug, is known to elicit cytotoxicity in many cancer cell types in the presence of copper (Cu). The objective of the present study was to investigate the mechanism of action responsible for the induction of apoptosis by DSF/Cu and its effect on cancer stem cell properties in HER2-positive breast cancers in vitro and in vivo. DSF/Cu treatment induced apoptosis, associated with a marked decrease in HER2, truncated p95HER2, phospho-HER2, HER3, phospho-HER3 and phospho-Akt levels, and p27 nuclear accumulation. This was accompanied by the eradication of cancer stem-like populations, concomitant with the suppression of aldehyde dehydrogenase 1 (ALDH1) activity and mammosphere formation. DSF administration resulted in a significant reduction in tumor growth and an enhancement of apoptosis, as well as HER2 intracellular domain (ICD) and ALDH1A1 downregulation. Our results demonstrate that DSF/Cu induces apoptosis and eliminates cancer stem-like cells via the suppression of HER2/Akt signaling, suggesting that DSF may be potentially effective for the treatment of HER2-positive cancers.

  1. Long-term hazard of recurrence in HER2+ breast cancer patients untreated with anti-HER2 therapy

    DEFF Research Database (Denmark)

    Strasser-Weippl, Kathrin; Horick, Nora; Smith, Ian E

    2015-01-01

    INTRODUCTION: Worldwide, many patients with HER2+ (human epidermal growth factor receptor 2-positive) early breast cancer (BC) do not receive adjuvant trastuzumab. Hazards of recurrence of these patients with respect to hormone receptor status of the primary tumor have not been described. METHODS......: Using data from 1,260 patients randomized to placebo in the adjuvant TEACH trial, we report 10-year annual hazards of recurrence in HER2+ patients not treated with anti-HER2 therapy. RESULTS: Disease-free survival (DFS) was 75% after 5 and 61% after 10 years, respectively. Patients with HER2+ hormone...... to that seen in HER2+ HR+ patients in years 6 to 10 (hazard ratio 0.97, P=0.92 for years 6 to 10). CONCLUSIONS: Our results show that outcomes in HER2+ patients with early BC not receiving anti-HER2 therapy strongly depend on HR expression. The very high early risk of relapse seen in HER2+ HR- patients...

  2. Targeting GPR110 in HER2-Overexpressing Breast Cancers

    Science.gov (United States)

    2015-10-01

    models. To understand whether GPR110 overexpression is a common phenomenon in anti-HER2 therapy resistance, we first interrogated the RNAseq data...selected resistant models, prioritized based on the RNAseq data. We have found that GPR110 mRNA levels were significantly higher in LR, TR, and...HER2’resistant’deriva9ves’vs.’parental’cells’ by’ RNAseq ." A" total" of" 9" an+,HER2" resistant"models" that" included" lapa+nib" (L),resistant" (LR

  3. HER-2 Targeted Nanoparticle-Affibody Bioconjugates for Cancer Therapy

    Science.gov (United States)

    Alexis, Frank; Basto, Pamela; Levy-Nissenbaum, Etgar; Radovic-Moreno, Aleksandar F.; Zhang, Liangfang; Pridgen, Eric; Wang, Adrew Z.; Marein, Shawn L.; Westerhof, Katrina; Molnar, Linda K.; Farokhzad, Omid C.

    2010-01-01

    Affibodies are a class of polypeptide ligands that are potential candidates for cell- or tissue-specific targeting of drug-encapsulated controlled release polymeric nanoparticles (NPs). Here we report the development of drug delivery vehicles comprised of polymeric NPs that are surface modified with Affibody ligands that bind to the extracellular domain of the trans-membrane human epidermal growth factor receptor 2 (HER-2) for targeted delivery to cells which over express the HER-2 antigen. NPs lacking the anti-HER-2 Affibody did not show significant uptake by these cells. Using paclitaxel encapsulated NP-Affibody (1 wt% drug loading), we demonstrated increased cytotoxicity of these bioconjugates in SK-BR-3 and SKOV-3 cell lines. These targeted, drug encapsulated NPAffibody bioconjugates may be efficacious in treating HER-2 expressing carcinoma. PMID:19012296

  4. HER2-Overexpressing Breast Cancers Amplify FGFR Signaling upon Acquisition of Resistance to Dual Therapeutic Blockade of HER2.

    Science.gov (United States)

    Hanker, Ariella B; Garrett, Joan T; Estrada, Mónica Valeria; Moore, Preston D; Ericsson, Paula González; Koch, James P; Langley, Emma; Singh, Sharat; Kim, Phillip S; Frampton, Garrett M; Sanford, Eric; Owens, Philip; Becker, Jennifer; Groseclose, M Reid; Castellino, Stephen; Joensuu, Heikki; Huober, Jens; Brase, Jan C; Majjaj, Samira; Brohée, Sylvain; Venet, David; Brown, David; Baselga, José; Piccart, Martine; Sotiriou, Christos; Arteaga, Carlos L

    2017-08-01

    Purpose: Dual blockade of HER2 with trastuzumab and lapatinib or pertuzumab has been shown to be superior to single-agent trastuzumab. However, a significant fraction of HER2-overexpressing (HER2(+)) breast cancers escape from these drug combinations. In this study, we sought to discover the mechanisms of acquired resistance to the combination of lapatinib + trastuzumab.Experimental Design: HER2(+) BT474 xenografts were treated with lapatinib + trastuzumab long-term until resistance developed. Potential mechanisms of acquired resistance were evaluated in lapatinib + trastuzumab-resistant (LTR) tumors by targeted capture next-generation sequencing. In vitro experiments were performed to corroborate these findings, and a novel drug combination was tested against LTR xenografts. Gene expression and copy-number analyses were performed to corroborate our findings in clinical samples.Results: LTR tumors exhibited an increase in FGF3/4/19 copy number, together with an increase in FGFR phosphorylation, marked stromal changes in the tumor microenvironment, and reduced tumor uptake of lapatinib. Stimulation of BT474 cells with FGF4 promoted resistance to lapatinib + trastuzumab in vitro Treatment with FGFR tyrosine kinase inhibitors reversed these changes and overcame resistance to lapatinib + trastuzumab. High expression of FGFR1 correlated with a statistically shorter progression-free survival in patients with HER2(+) early breast cancer treated with adjuvant trastuzumab. Finally, FGFR1 and/or FGF3 gene amplification correlated with a lower pathologic complete response in patients with HER2(+) early breast cancer treated with neoadjuvant anti-HER2 therapy.Conclusions: Amplification of FGFR signaling promotes resistance to HER2 inhibition, which can be diminished by the combination of HER2 and FGFR inhibitors. Clin Cancer Res; 23(15); 4323-34. ©2017 AACR. ©2017 American Association for Cancer Research.

  5. Differences in radiosensitivity between three HER2 overexpressing cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Steffen, Ann-Charlott; Tolmachev, Vladimir; Stenerloew, Bo [Uppsala University, Unit of Biomedical Radiation Sciences, Department of Oncology, Radiology and Clinical Immunology, Rudbeck Laboratory, Uppsala (Sweden); Goestring, Lovisa [Affibody AB, Bromma (Sweden); Palm, Stig [Sahlgrenska Academy at Goeteborg University, Department of Radiation Physics, Goeteborg (Sweden); Carlsson, Joergen [Uppsala University, Unit of Biomedical Radiation Sciences, Department of Oncology, Radiology and Clinical Immunology, Rudbeck Laboratory, Uppsala (Sweden); Rudbeck Laboratory, Biomedical Radiation Sciences, Uppsala (Sweden)

    2008-06-15

    HER2 is a potential target for radionuclide therapy, especially when HER2 overexpressing breast cancer cells are resistant to Herceptin {sup registered} treatment. Therefore, it is of interest to analyse whether HER2 overexpressing tumour cells have different inherent radiosensitivity. The radiosensitivity of three often used HER2 overexpressing cell lines, SKOV-3, SKBR-3 and BT-474, was analysed. The cells were exposed to conventional photon irradiation, low linear energy transfer (LET), to characterise their inherent radiosensitivity. The analysis was made with clonogenic survival and growth extrapolation assays. The cells were also exposed to alpha particles, high LET, from {sup 211}At decays using the HER2-binding affibody molecule {sup 211}At-(Z{sub HER2:4}){sub 2} as targeting agent. Assays for studies of internalisation of the affibody molecule were applied. SKOV-3 cells were most radioresistant, SKBR-3 cells were intermediate and BT-474 cells were most sensitive as measured with the clonogenic and growth extrapolation assays after photon irradiation. The HER2 dependent cellular uptake of {sup 211}At was qualitatively similar for all three cell lines. However, the sensitivity to the alpha particles from {sup 211}At differed; SKOV-3 was most resistant, SKBR-3 intermediate and BT-474 most sensitive. These differences were unexpected because it is assumed that all types of cells should have similar sensitivity to high-LET radiation. The sensitivity to alpha particle exposure correlated with internalisation of the affibody molecule and with size of the cell nucleus. There can be differences in radiosensitivity, which, if they also exist between patient breast cancer cells, are important to consider for both conventional radiotherapy and for HER2-targeted radionuclide therapy. (orig.)

  6. Does Lapatinib Work against HER2-negative Breast Cancers?

    Science.gov (United States)

    Mayer, Ingrid A.; Arteaga, Carlos L.

    2012-01-01

    Aberrant growth factor receptor signaling can augment or suppress estrogen receptor (ER) function in hormone-dependent breast cancer cells and lead to escape from anti-estrogen therapy. Interruption of HER2/ER cross-talk with lapatinib can restore sensitivity to anti-estrogens and thus, should be investigated in combination with endocrine therapy in patients with ER+/HER2−negative breast cancers. PMID:20179241

  7. HER-2/neu Testing and Therapy in Gastroesophageal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Cathy B. Moelans

    2011-01-01

    Full Text Available Despite ongoing advances in the treatment of gastroesophageal cancer, prognosis remains poor. The best promise to improve this poor survival is provided by new targeted agents. Of these, human epidermal growth factor receptor 2 (HER2 is currently in the spotlight. In this review, we provide an overview of recent developments in HER2 testing and results of clinical trials targeting HER2 in gastroesophageal adenocarcinoma. Based on the encouraging ToGA trial findings it is now expected that routine HER2 testing will be included in the diagnostic work-up of patients with advanced gastric cancer. With regard to this testing, overexpression of the HER2 protein seems to possess the best predictive properties. However, HER2 immunohistochemistry (IHC is subject to assay and interobserver variability, so standardization and internal and external proficiency testing is an absolute prerequisite, especially as the IHC scoring system in gastric cancer is different from that of breast cancer. Further study is needed to investigate the clinical meaning of the significant heterogeneity observed in both gene amplification and protein overexpression in gastroesophageal cancer. Highly effective therapies for gastroesophageal cancer can only be accomplished by a multi-targeted approach, considering crosstalk between pathways and continuing to optimize chemotherapy.

  8. Production and Characterization of Anti-Her2 Monoclonal Antibodies

    Directory of Open Access Journals (Sweden)

    A.S. Tabatabaei-Panah

    2008-01-01

    Full Text Available Objective: Breast cancer is the most common cancer among women in the world.Early diagnosis of this cancer is a key element for its treatment. One of the approachesfor diagnosis of breast cancer is detection of its tumour-associated markers. Hence,Her2 has been the main focus of the researches in the field.Materials and Methods: For diagnosis of Her2 overexpression, monoclonalantibodies (mAb reacting against Her2 were produced in this study. For thispurpose, two peptides from extracellular domain of Her2 were selected and themAbs reacting against them were produced by hybrodoma technology. Reactivityof these antibodies were then evaluated in different immunological assays includingELISA, Immunoflurescence (IF, western blot (WB and immunoprecipitation (IP.Results: Total of 5 clones were produced from two separate fusions, and antibodyisotyping revealed that all clones were IgM. These mAbs showed appropriatereactivities in the following assays: ELISA, immunofluresence by staining of breastcancer cell line (SKBR3, WB and IP by detecting the 185 KD band of Her2.Conclusion: In conclusion, it seems that the mAbs are useful diagnostic tools fordetection of Her2 expression in patients with breast cancer.

  9. Stability of the HER2 gene after primary chemotherapy in advanced breast cancer.

    Science.gov (United States)

    Varga, Zsuzsanna; Caduff, Rosmarie; Pestalozzi, Bernhard

    2005-02-01

    We investigated whether alterations of the Her2 gene could be detected in breast cancer samples following primary chemotherapy in advanced breast cancer. The prospective study involved 23 patients with stage-II, -III or -IV breast cancer. All patients were treated with two to six cycles of fluorouracil-epirubicin and/or cyclophosphamid/epi-docetaxel. The Her2 protein and gene were assessed both on core needle biopsies prior to and on surgical specimens after completing chemotherapy using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) methods. Estrogen and progesterone receptors (ER/PR) were also determined on both samples using IHC. Her2 status was modified in eight patients using IHC (35%) and in three patients using FISH (13%). Changes in ER/PR expression were detected in seven patients (30%). Our data suggest that alterations of the Her2 gene can occur, although not usually after primary or neoadjuvant chemotherapy. However, changes in ER/PR status seem to be a more common event; thus, both can lead to different therapeutic options. Intratumoral heterogeneity as well as sampling variations can contribute to modification of the Her2 status after primary chemotherapy.

  10. Docosahexaenoic Acid Modulates a HER2-Associated Lipogenic Phenotype, Induces Apoptosis, and Increases Trastuzumab Action in HER2-Overexpressing Breast Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Graziela Rosa Ravacci

    2015-01-01

    Full Text Available In breast cancer, lipid metabolic alterations have been recognized as potential oncogenic stimuli that may promote malignancy. To investigate whether the oncogenic nature of lipogenesis closely depends on the overexpression of HER2 protooncogene, the normal breast cell line, HB4a, was transfected with HER2 cDNA to obtain HER2-overexpressing HB4aC5.2 cells. Both cell lines were treated with trastuzumab and docosahexaenoic acid. HER2 overexpression was accompanied by an increase in the expression of lipogenic genes involved in uptake (CD36, transport (FABP4, and storage (DGAT of exogenous fatty acids (FA, as well as increased activation of “de novo” FA synthesis (FASN. We further investigate whether this lipogenesis reprogramming might be regulated by mTOR/PPARγ pathway. Inhibition of the mTORC1 pathway markers, p70S6 K1, SREBP1, and LIPIN1, as well as an increase in DEPTOR expression (the main inhibitor of the mTOR was detected in HB4aC5.2. Based on these results, a PPARγ selective antagonist, GW9662, was used to treat both cells lines, and the lipogenic genes remained overexpressed in the HB4aC5.2 but not HB4a cells. DHA treatment inhibited all lipogenic genes (except for FABP4 in both cell lines yet only induced death in the HB4aC5.2 cells, mainly when associated with trastuzumab. Neither trastuzumab nor GW9662 alone was able to induce cell death. In conclusion, oncogenic transformation of breast cells by HER2 overexpression may require a reprogramming of lipogenic genetic that is independent of mTORC1 pathway and PPARγ activity. This reprogramming was inhibited by DHA.

  11. A Conjugate Based on Anti-HER2 Diaffibody and Auristatin E Targets HER2-Positive Cancer Cells

    Science.gov (United States)

    Serwotka-Suszczak, Anna M.; Sochaj-Gregorczyk, Alicja M.; Pieczykolan, Jerzy; Krowarsch, Daniel; Jelen, Filip; Otlewski, Jacek

    2017-01-01

    Antibody-drug conjugates (ADCs) have recently emerged as efficient and selective cancer treatment therapeutics. Currently, alternative forms of drug carriers that can replace monoclonal antibodies are under intensive investigation. Here, a cytotoxic conjugate of an anti-HER2 (Human Epidermal Growth Factor Receptor 2) diaffibody with monomethyl-auristatin E (MMAE) is proposed as a potential anticancer therapeutic. The anti-HER2 diaffibody was based on the ZHER2:4 affibody amino acid sequence. The anti-HER2 diaffibody has been expressed as a His-tagged protein in E. coli and purified by Ni-nitrilotriacetyl (Ni-NTA) agarose chromatography. The molecule was properly folded, and the high affinity and specificity of its interaction with HER2 was confirmed by surface plasmon resonance (SPR) and flow cytometry, respectively. The (ZHER2:4)2DCS-MMAE conjugate was obtained by coupling the maleimide group linked with MMAE to cysteines, which were introduced in a drug conjugation sequence (DCS). Cytotoxicity of the conjugate was evaluated using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide MTT assay and the xCELLigence Real-Time Cell Analyzer. Our experiments demonstrated that the conjugate delivered auristatin E specifically to HER2-positive tumor cells, which finally led to their death. These results indicate that the cytotoxic diaffibody conjugate is a highly potent molecule for the treatment of various types of cancer overexpressing HER2 receptors. PMID:28216573

  12. Targeting HER2-positive cancer using multifunctional nanoparticles

    DEFF Research Database (Denmark)

    Juul, Christian Ammitzbøll

    efficiency, is thoroughly reviewed. Chapter 4 encompasses a comprehensive manuscript, which describes the in vitro and in vivo evaluation of a novel liposomal delivery platform designed to target the HER2 receptor on cancer cells and be activated by enzyme activity in the tumor. In Chapter 5, an alternative...... HER2-targeted liposome formulation was assessed in vitro. Rather than being enzyme-sensitive, these liposomes were responsive to reducing conditions. Such conditions are found in several cancers due to hypoxia as well as in endocytic compartments. The progressive in vitro optimization of a complex....... The final study, described in Chapter 7, comprises an in vivo evaluation of the potential benefits of combining enzyme-sensitive liposomal oxaliplatin with the HER2-targeted antibody trastuzumab. As concluded in the final comments in Chapter 8, the extensive in vitro and in vivo data reported in this thesis...

  13. Segregation of naturally occurring mitochondrial DNA variants in a mini-pig model

    Science.gov (United States)

    Within cells and tissues, the maternally inherited mitochondrial genome (mtDNA) is present in multimeric form and can harbour naturally occurring variants. Whilst high variant load can cause mitochondrial disease, naturally occurring mtDNA variants likely persist at low levels across generations of ...

  14. Prognostic impact of HER-2 Subclonal Amplification in breast cancer.

    Science.gov (United States)

    Di Oto, Enrico; Brandes, Alba A; Cucchi, Maria C; Foschini, Maria P

    2017-06-02

    The presence of a limited number of cells with HER-2 amplification (Subclonal Amplification) in breast carcinomas is occasionally encountered, but its prognostic impact is poorly known. The purpose of this study is to evaluate the prognostic impact of HER-2 Subclonal Amplification in a retrospective series of breast cancers. Accordingly, 81 consecutive breast carcinomas showing HER-2 Subclonal Amplification were obtained from the histology files (case series). These cases were subdivided into two groups: (a) those cases in which the HER-2 Subclonal Amplification was consonant to the accepted criteria for amplification, showing clusters of amplified cells, and (b) those cases with rare HER-2 Subclonal Amplification that did not reflect the accepted criteria for amplification, showing scattered amplified cells only. The incidence of metastases and late recurrences of the case series was compared with a series composed of 109 consecutive cases, being HER-2 homogeneous (comprising 14 Amplified and 95 Non-Amplified cases), matched for grade and stage (control series). It appeared that cases showing Subclonal Amplification had an incidence of metastases intermediate between the cases Amplified and Non-Amplified. Specifically, Subclonal Amplification with clustered cells had a lower incidence of metastases than Amplified cases (12.9 versus 21.4%). On the contrary, Subclonal Amplification with scattered cells showed an incidence of metastases higher than Non-Amplified cases (14 versus 9.47%). In addition, patients Subclonal Amplification with clustered cells, who were treated with the specific monoclonal antibody, had a lower incidence of metastases than patients showing Subclonal Amplification with scattered cells, who did not receive target therapy. These data, together with those recently published, indicate that Subclonal Amplification has an impact on prognosis and should be taken into consideration to correctly plan the treatment of breast cancer patients.

  15. EVALUATION OF IMMUNOHISTOCHEMISTRY (IHC MARKER HER2 IN BREAST CANCER

    Directory of Open Access Journals (Sweden)

    Prasanna G. Shete

    2016-08-01

    Full Text Available The paper discusses a novel approach involving algorithm implementation and hardware Devkit processing for estimating the extent of cancer in a breast tissue sample. The process aims at providing a reliable, repeatable, and fast method that could replace the traditional method of manual examination and estimation. Immunohistochemistry (IHC and Fluorescence in situ Hybridization (FISH are the two main methods used to detect the marker status in clinical practice. FISH is though more reliable than IHC, but IHC is widely used as it is cheaper, convenient to operate and conserve, the morphology is clear. The IHC markers are Estrogen receptor (ER, Progesterone receptor (PR, Human Epidermal Growth Factor (HER2 that give clear indications of the presence of cancer cells in the tissue sample. HER2 remains the most reliable marker for the detection of breast cancer. The Human Epidermal Growth Factor Receptor (HER2 markers are discussed in the paper, as it gives clear indications of the presence of cancer cells in the tissue sample. HER2 is identified based on the color and intensity of the cell membrane staining. The color and intensity is obviously based on the thresholding for classifying the cancerous cells into severity levels in terms of score to estimate the extent of spread of cancer in breast tissue. For HER2 evaluation, the percentage of staining is calculated in terms of ratio of stain pixel count to the total pixel count. The evaluation of HER2 is obtained through simulation software (MATLAB using intensity based algorithm and same is run on embedded processor evaluation board Devkit 8500. The results are validated with doctors.

  16. HER2 Phosphorylates and Destabilizes Pro-Apoptotic PUMA, Leading to Antagonized Apoptosis in Cancer Cells

    OpenAIRE

    Carpenter, Richard L.; Woody Han; Ivy Paw; Hui-Wen Lo

    2013-01-01

    HER2 is overexpressed in 15-20% of breast cancers. HER2 overexpression is known to reduce apoptosis but the underlying mechanisms for this association remain unclear. To elucidate the mechanisms for HER2-mediated survival, we investigated the relationship between HER2 and p53 upregulated modulator of apoptosis (PUMA), a potent apoptosis inducer. Our results showed that HER2 interacts with PUMA, which was independent of HER2 activation. In addition, we observed that HER2 interacted with PUMA i...

  17. Technologically Enhanced Naturally Occurring Radioactive Materials (TENORM) in the Oil and Gas Industry: A Review.

    Science.gov (United States)

    Doyi, Israel; Essumang, David Kofi; Dampare, Samuel; Glover, Eric Tetteh

    Radiation is part of the natural environment: it is estimated that approximately 80 % of all human exposure comes from naturally occurring or background radiation. Certain extractive industries such as mining and oil logging have the potential to increase the risk of radiation exposure to the environment and humans by concentrating the quantities of naturally occurring radiation beyond normal background levels (Azeri-Chirag-Gunashli 2004).

  18. Tailoring DNA vaccines: designing strategies against HER2 positive cancers

    Directory of Open Access Journals (Sweden)

    Cristina eMarchini

    2013-05-01

    Full Text Available The crucial role of HER2 in epithelial transformation and its selective overexpression on cancer tissues makes it an ideal target for cancer immunotherapies such as passive immunotherapy with Trastuzumab. There are, however, a number of concerns regarding the use of monoclonal antibodies which include resistance, repeated treatments, considerable costs and side effects that make active immunotherapies against HER2 desirable alternative approaches. The efficacy of anti-HER2 DNA vaccination has been widely demonstrated in transgenic cancer-prone mice, which recapitulate several features of human breast cancers. Nonetheless, the rational design of a cancer vaccine able to trigger a long lasting immunity, and thus prevent tumor recurrence in patients, would require the understanding of how tolerance and immunosuppression regulate antitumor immune responses and, at the same time, the identification of the most immunogenic portions of the target protein. We herein retrace the findings that led to our most promising DNA vaccines that, by encoding human/rat chimeric forms of HER2, are able to circumvent peripheral tolerance. Preclinical data obtained with these chimeric DNA vaccines have provided the rationale for their use in an ongoing phase I clinical trial (EudraCT 2011-001104-34.

  19. An Acquired HER2 T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer.

    Science.gov (United States)

    Hanker, Ariella B; Red Brewer, Monica; Sheehan, Jonathan H; Koch, James P; Sliwoski, Gregory R; Nagy, Rebecca; Lanman, Richard; Berger, Michael F; Hyman, David M; Solit, David B; He, Jie; Miller, Vincent; Cutler, Richard E; Lalani, Alshad S; Cross, Darren; Lovly, Christine M; Meiler, Jens; Arteaga, Carlos L

    2017-03-08

    We report a HER2T798I gatekeeper mutation in a patient with HER2L869R-mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that HER2L869R is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3E928G, also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, HER2T798I was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2T798I reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2L869R but not HER2L869R/T798I. In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2L869R/T798I-induced signaling and cell growth. Acquisition of HER2T798I upon development of resistance to neratinib in a breast cancer with an initial activating HER2 mutation suggests HER2L869R is a driver mutation. HER2T798I-mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib.

  20. Serum HER 2 extracellular domain level is correlated with tissue HER 2 status in metastatic gastric or gastro-oesophageal junction adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Shu-Qin Dai

    Full Text Available BACKGROUND: To explore the association between serum human epidermal growth factor receptor 2 (HER 2 extracellular domain (ECD levels and tissue HER 2 status in metastatic gastric cancer. PATIENTS AND METHODS: HER 2 status was retrospectively analyzed in 219 advanced gastric or gastroesophageal junction (GEJ patients. Serum HER 2 ECD was measured by chemiluminescent assay and tissue HER 2 was assessed by fluorescent in situ hybridisation (FISH and immunohistochemistry (IHC assay. RESULTS: Significant associations were found between serum HER 2 ECD levels and tissue HER 2 status. Twenty-four patients had HER 2 ECD levels >16.35 ng/mL, which has a sensitivity of 51.4% and a specificity of 97.3% to predict tissue HER 2 status. When the cut-off value was increased to 22 ng/mL, then all 12 patients with serum HER 2 ECD levels>22 ng/mL were tissue HER 2 positive, corresponding to a specificity of 100% and a sensitivity of 32.4%. High serum HER 2 ECD levels were strongly associated with the intestinal histological type (Lauren's classification, liver metastasis, multiple metastasis (>2 and increased LDH levels, but not with overall survival. CONCLUSIONS: The high specificity of the serum HER 2 ECD assay in predicting tissue HER 2 status suggests its potential as a surrogate marker of the HER 2 status in gastric cancer.

  1. Serum HER-2 predicts response and resistance to trastuzumab treatment in breast cancer

    DEFF Research Database (Denmark)

    Petersen, Eva Rabing Brix; Sørensen, Patricia Diana; Jakobsen, Erik Hugger;

    2013-01-01

    Serum HER2 (S-HER2) was approved in 2003 by the US Food and Drug Administration (FDA) for monitoring trastuzumab treatment in tissue HER2 positive breast cancer patients. Information of the value of S-HER2 is scarce. We hypothesised that S-HER2 would reflect the clinical effect of trastuzumab....

  2. H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation via heregulin production and activation of HER3

    Science.gov (United States)

    Chakrabarty, Anindita; Rexer, Brent N.; Wang, Shizhen Emily; Cook, Rebecca S.; Engelman, Jeffrey A.; Arteaga, Carlos, L.

    2010-01-01

    Hyperactivation of phosphatidylinositol-3 kinase (PI3K) can occur as a result of somatic mutations in PIK3CA, the gene encoding the p110α subunit of PI3K. The HER2 oncogene is amplified in 25% of all breast cancers and some of these tumors also harbor PIK3CA mutations. We examined mechanisms by which mutant PI3K can enhance transformation and confer resistance to HER2-directed therapies. We introduced the PI3K mutations E545K and H1047R in MCF10A human mammary epithelial cells that also overexpress HER2. Both mutants conferred a gain of function to MCF10A/HER2 cells. Expression of H1047R PI3K but not E545K PI3K markedly upregulated the HER3/HER4 ligand heregulin (HRG). HRG siRNA inhibited growth of H1047R but not E545K-expressing cells and synergized with the HER2 inhibitors trastuzumab and lapatinib. The PI3K inhibitor BEZ235 markedly inhibited HRG and pAKT levels and, in combination with lapatinib, completely inhibited growth of cells expressing H1047R PI3K. These observations suggest that PI3K mutants enhance HER2-mediated transformation by amplifying the ligand-induced signaling output of the ErbB network. This also counteracts the full effect of therapeutic inhibitors of HER2. These data also suggest that mammary tumors that contain both HER2 gene amplification and PIK3CA mutations should be treated with a combination of HER2 and PI3K inhibitors. PMID:20581867

  3. A single-domain antibody-linked Fab bispecific antibody Her2-S-Fab has potent cytotoxicity against Her2-expressing tumor cells.

    Science.gov (United States)

    Li, Aifen; Xing, Jieyu; Li, Li; Zhou, Changhua; Dong, Bin; He, Ping; Li, Qing; Wang, Zhong

    2016-12-01

    Her2, which is frequently overexpressed in breast cancer, is one of the most studied tumor-associated antigens for cancer therapy. Anti-HER2 monoclonal antibody, trastuzumab, has achieved significant clinical benefits in metastatic breast cancer. In this study, we describe a novel bispecific antibody Her2-S-Fab targeting Her2 by linking a single domain anti-CD16 VHH to the trastuzumab Fab. The Her2-S-Fab antibody can be efficiently expressed and purified from Escherichia coli, and drive potent cancer cell killing in HER2-overexpressing cancer cells. In xenograft model, the Her2-S-Fab suppresses tumor growth in the presence of human immune cells. Our results suggest that the bispecific Her2-S-Fab may provide a valid alternative to Her2 positive cancer therapy.

  4. Quantitative detection of HER2 protein concentration in breast cancer tissue does not increase the number of patients eligible for adjuvant HER2-targeted therapy

    DEFF Research Database (Denmark)

    Bechmann, Troels; Olsen, Dorte Aalund; Jakobsen, Erik Hugger;

    2013-01-01

    Human epidermal growth factor receptor-2 (HER2) is overexpressed in 15-20% of breast cancer patients and is associated with an aggressive tumor and a poor prognosis. Currently, patients are selected for adjuvant HER2-targeted therapy based on HER2 status by immunohistochemistry (IHC...... by Centaur, but not treated with adjuvant HER2-targeted therapy, compared to patients defined as HER2-positive by IHC/FISH and therefore treated with adjuvant HER2-targeted therapy. Tumor tissue was obtained at primary surgery from 415 breast cancer patients between 2004 and 2010. HER2 status was determined...... by quantitative immunoassay of fresh-frozen tissue and by IHC/FISH of corresponding paraffin-embedded tissue. We compared the clinical outcome in four groups of patients defined by tissue HER2 status and adjuvant HER2-targeted therapy. The final analysis included 379 patients after a median follow-up of 3.9 years...

  5. Detection of Naturally Occurring Gear and Bearing Faults in a Helicopter Drivetrain

    Science.gov (United States)

    2014-01-01

    Annual Forum, Montreal, Canada, 2002. 3. Samuel, P. D.; Pines, D. J. A Review of Vibration Based Techniques for Helicopter Transmission Diagnostics...Detection of Naturally Occurring Gear and Bearing Faults in a Helicopter Drivetrain by Kelsen E. LaBerge, Eric C. Ames, and Brian D. Dykas...5066 ARL-TR-6795 January 2014 Detection of Naturally Occurring Gear and Bearing Faults in a Helicopter Drivetrain Kelsen E. LaBerge

  6. Concentrations of the naturally occurring radionucleides Pb-210, Po-210, and Ra-226 in aquatic fauna

    Science.gov (United States)

    Holtzman, R. B.

    1969-01-01

    Study reveals naturally occurring radionuclides are ubiquitous and contribute a substantial fraction of the natural radiation dose to humans and various biota. Measurements may be useful in ecological and other biological problems such as tracing food chains of animals and study of the metabolism of these elements.

  7. Mechanisms of resistance to HER2 target therapy.

    Science.gov (United States)

    Tortora, Giampaolo

    2011-01-01

    In the past years, several agents targeting signaling proteins critical for breast cancer growth and dissemination entered clinical evaluation. They include drugs directed against the HER/ErbB family of receptor tyrosine kinases, especially HER2; several downstream signal transducers; and proteins involved in tumor angiogenesis and dissemination. Unfortunately, resistance to targeted agents is a quite common feature, and understanding of the molecular mechanisms predicting response or failure has become a crucial issue to optimize treatment and select patients who are the best candidates to respond. The neoadjuvant setting offers unique opportunities allowing tumor sampling and search for molecular determinants of response. A variety of tumor and host factors may account for the onset of resistance. Major progress has been made in the understanding of the mechanisms involved in the primary and acquired resistance to targeted agents, especially the anti-HER2 drugs, which play a pivotal role in the weaponry against breast cancer.

  8. The Clinical Importance of the Heterogeneity of HER2 neu

    Directory of Open Access Journals (Sweden)

    Enrique Davila

    2010-07-01

    Full Text Available We report on a patient with breast cancer in whom there were areas of the tumor that were 3+ positive and negative for HER2 neu by immunohistochemistry, adjacent to each other. Depending on the area tested the results were completely different. The clinical implications are important. We recommend retesting a large portion of the tumor in all cases of initially negative test results.

  9. Encapsulation of piceatannol, a naturally occurring hydroxylated analogue of resveratrol, by natural and modified cyclodextrins.

    Science.gov (United States)

    Matencio, Adrián; García-Carmona, Francisco; López-Nicolás, José Manuel

    2016-05-18

    In this work, an in-depth study of the interaction between piceatannol (a type of stilbene with high biological activity) and different natural and modified cyclodextrins (CDs) is made, using steady state fluorescence. This bioactive molecule forms a 1 : 1 complex with all the natural (α-CD, β-CD and γ-CD) and modified (HP-β-CD, HE-β-CD and M-β-CD) CDs tested. Among natural CDs, the interaction of piceatannol with β-CD was the most efficient. However, the modified CDs showed higher encapsulation constants (KF) than β-CD, except M-β-CD; the highest KF being found for HP-β-CD (14 048 ± 702 M(-1)). The encapsulation of piceatannol in the internal cavity of CDs showed a strong dependence on pH and temperature. The interaction between HP-β-CD and piceatannol was less effective in the pH region where the stilbene begins to suffer the deprotonation of its hydroxyl group. Moreover, the values of KF decreased as the system temperature increased. To obtain information on the mechanism involved in the piceatannol affinity for CD, the thermodynamic parameters of the complexation (ΔH°, ΔS° and ΔG°) were studied, the results showed a negative entropy (-3.7 ± 0.2 J mol(-1) K(-1)), enthalpy (-24.6 ± 1.2 kJ mol(-1)) and Gibbs free energy change at 25 °C (-23.5 ± 1.2 J mol(-1)). Finally, molecular docking calculations provided further insights into how the different interactions influence the complexation constant. A high degree of correlation was observed between the computed scores and experimental values.

  10. Predicting Emotions in Facial Expressions from the Annotations in Naturally Occurring First Encounters

    DEFF Research Database (Denmark)

    Navarretta, Costanza

    2014-01-01

    This paper deals with the automatic identification of emotions from the manual annotations of the shape and functions of facial expressions in a Danish corpus of video recorded naturally occurring first encounters. More specifically, a support vector classified is trained on the corpus annotation...... to it are reliable and can be used to model and test emotional behaviours in emotional cognitive infocommunicative systems.......This paper deals with the automatic identification of emotions from the manual annotations of the shape and functions of facial expressions in a Danish corpus of video recorded naturally occurring first encounters. More specifically, a support vector classified is trained on the corpus annotations...... to identify emotions in facial expressions. In the classification experiments, we test to what extent emotions expressed in naturally-occurring conversations can be identified automatically by a classifier trained on the manual annotations of the shape of facial expressions and co-occurring speech tokens. We...

  11. Trastuzumab as a preoperative monotherapy does not inhibit HER2 downstream signaling in HER2-positive breast cancer

    Science.gov (United States)

    Lion, Maëva; Harlé, Alexandre; Salleron, Julia; Ramacci, Carole; Campone, Mario; Merlin, Jean-Louis

    2016-01-01

    Human epidermal growth factor 2 (HER2) is overexpressed in 15–20% of breast carcinomas. The overexpression of HER2 was previously associated with a poor prognosis until the development of the first anti-HER2 therapy, trastuzumab, which drastically improves the prognosis of HER2-overexpressing breast cancers. However, its mechanism of action remains not fully understood. Several studies have proposed that the behavior and mechanism of action of trastuzumab may be drastically altered in vitro and in vivo. The present study assesses the ability of trastuzumab to inhibit the phosphorylation of the key-proteins of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin and Ras/Raf/mitogen-activated protein kinase (MAPK) signaling pathways in vitro, in breast cancer cell lines and in tumor biopsies obtained from patients treated with trastuzumab preoperative monotherapy as part of the Unicancer GEP04 RADHER phase II clinical trial. HER2-positive SKBR3 and HER2-negative MCF-7 cell lines were exposed to trastuzumab for 72 h. In total, 41 patients received trastuzumab alone for 6 weeks of preoperative treatment. Biopsies were collected at the baseline and at surgery. A total of 19 pairs of associated baseline and surgery tumor specimens were eligible for protein extraction and comparative phosphoprotein expression analysis, prior to and subsequent to treatment. The expression of phosphoproteins was quantitatively assessed using a multiplex immunoassay. In the SKBR3 cell line, a statistically significant decrease of the expression level of phosphorylated (p-)AKT, p-ribosomal protein S6 kinase B1, p-extracellular signal regulated kinase 1/2 and p-mitogen-activated protein kinase kinase 1 was observed after exposure to trastuzumab. In contrast, no statistically significant variations for levels expression of these phosphoproteins were observed in patients following treatment. The lack of downregulation of PI3K and MAPK pathways could probably

  12. HER2 Oncogenic Function Escapes EGFR Tyrosine Kinase Inhibitors via Activation of Alternative HER Receptors in Breast Cancer Cells

    Science.gov (United States)

    Kong, Anthony; Calleja, Véronique; Leboucher, Pierre; Harris, Adrian; Parker, Peter J.; Larijani, Banafshé

    2008-01-01

    Background The response rate to EGFR tyrosine kinase inhibitors (TKIs) may be poor and unpredictable in cancer patients with EGFR expression itself being an inadequate response indicator. There is limited understanding of the mechanisms underlying this resistance. Furthermore, although TKIs suppress the growth of HER2-overexpressing breast tumor cells, they do not fully inhibit HER2 oncogenic function at physiological doses. Methodology and Principal Findings Here we have provided a molecular mechanism of how HER2 oncogenic function escapes TKIs' inhibition via alternative HER receptor activation as a result of autocrine ligand release. Using both Förster Resonance Energy Transfer (FRET) which monitors in situ HER receptor phosphorylation as well as classical biochemical analysis, we have shown that the specific tyrosine kinase inhibitors (TKIs) of EGFR, AG1478 and Iressa (Gefitinib) decreased EGFR and HER3 phosphorylation through the inhibition of EGFR/HER3 dimerization. Consequent to this, we demonstrate that cleavage of HER4 and dimerization of HER4/HER2 occur together with reactivation of HER3 via HER2/HER3, leading to persistent HER2 phosphorylation in the now resistant, surviving cells. These drug treatment–induced processes were found to be mediated by the release of ligands including heregulin and betacellulin that activate HER3 and HER4 via HER2. Whereas an anti-betacellulin antibody in combination with Iressa increased the anti-proliferative effect in resistant cells, ligands such as heregulin and betacellulin rendered sensitive SKBR3 cells resistant to Iressa. Conclusions and Significance These results demonstrate the role of drug-induced autocrine events leading to the activation of alternative HER receptors in maintaining HER2 phosphorylation and in mediating resistance to EGFR tyrosine kinase inhibitors (TKIs) in breast cancer cells, and hence specify treatment opportunities to overcome resistance in patients. PMID:18682844

  13. Treatment of oral squamous cell carcinoma using anti-HER2 immunonanoshells

    Directory of Open Access Journals (Sweden)

    Fekrazad R

    2011-11-01

    Full Text Available Reza Fekrazad2, Neda Hakimiha3, Enice Farokhi3, Mohammad Javad Rasaee4, Mehdi Shafiee Ardestani5, Katayoun AM Kalhori2, Farzaneh Sheikholeslami1 1Research & Development Department, Production and Research Division of the Pasteur Institute of Iran, Karaj, Iran; 2Dental Department, AJA University of Medical Sciences, Laser Research Center, Dental Faculty, Tehran University of Medical Sciences; 3Dentistry Department, Faculty of Dentistry, Shahed University, Tehran, Iran; 4Department of Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; 5Hepatitis and AIDS Department, Pasteur Institute of Iran, Tehran Background: Worldwide, oral squamous cell carcinoma (potentially mediated by HER2 is recognized as the most commonly occurring malignant neoplasm of the oral cavity. Anti-HER2 nanobodies conjugated to gold-silica nanoshells and used as photothermal treatment for oral squamous cell carcinoma may provide a novel therapeutic alternative to current treatment for this disease. Methods: KB epithelial or HeLaS3 cell cultures (controls were exposed to these immunonanoshells, and plasmon resonance electron initiation specific to gold was employed to burn the tumor cells. Results: Following this treatment, significant cell death occurred in the KB tumor cell cultures while there was no evidence of cellular damage or death in the HeLaS3 cell cultures. Conclusion: These findings suggest that photothermal treatment of oral squamous cell carcinoma has considerable advantages. Keywords: anti-HER2 immunonanoshells, gold-silica nanoshells, photothermal treatment, oral squamous cell carcinoma

  14. Degradation of HER2/ neu by apigenin induces apoptosis through cytochrome c release and caspase-3 activation in HER2/ neu-overexpressing breast cancer cells

    National Research Council Canada - National Science Library

    Way, Tzong-Der; Kao, Ming-Ching; Lin, Jen-Kun

    2005-01-01

    We have shown that exposure of the HER2/ neu ‐overexpressing breast cancer cells to apigenin resulted in induction of apoptosis by depleting HER2/ neu protein and, in turn, suppressing the signaling of the HER2/HER3‐PI3K/Akt pathway...

  15. Naturally occurring radionuclides in pasture soil, feed ingredients and milk of dairy cattle

    Energy Technology Data Exchange (ETDEWEB)

    Turtiainen, T.; Kostiainen, E.; Solatie, D. [STUK-Radiation and Nuclear Safety Authority (Finland)

    2014-07-01

    Naturally occurring radionuclides are generally considered being respective part of the environment and hence no statutory monitoring of their levels are required in food products. Therefore, limited data are available on the naturally occurring radionuclides in food. Dairy products constitute a significant portion of Finnish diet (400-500 g/d) and hence it is reasonable to study radionuclide levels in milk in more detail. Contrary to caesium, strontium and iodine, few transfer coefficients are available in the literature for naturally occurring radionuclide transfer to cow's milk. The renaissance of mining industry in Finland has raised a question among the public about the baseline values of naturally occurring radionuclides in Finnish agricultural products. The objective of this study was to investigate naturally occurring radionuclides in the components of dairy cattle diet and milk and calculate their transfer to milk. This information is needed for regulating the permitted discharges to the environment and for setting up monitoring programs if any unplanned discharges are released. In modern dairy farming, cattle are fed a precise diet in order to maximize milk production and quality and to achieve cost-effectiveness. Therefore, several different components are found in dairy cattle's diet and pasture grass concentrations are not sufficient for calculating radionuclide transfer to cow's milk. In this study, we carried out comprehensive sampling at four dairy farms each representing different areas of natural radiation background. The pasture soils were characterized and measured for natural radioactivity. Samples were taken from cattle's total diet (including e.g. pasture grass, water, silage, mineral forage) and milk. Document available in abstract form only. (authors)

  16. The encounter and analysis of naturally occurring radionuclides in gas and oil production and processing

    Energy Technology Data Exchange (ETDEWEB)

    Hartog, F.A.; Jonkers, G.; Knaepen, W.A.I. [Shell Research and Technology Centre, Amsterdam, (Netherlands)

    1996-12-31

    As a result of oil and gas production, radioactive daughter elements from the uranium and thorium decay series can be mobilized and transported away from the reservoir. Due to changes in flow regime, temperature, pressure or chemical environment NORs (Naturally Occurring Radionuclides) may build up in products, by-products or waste streams from gas and oil production and processing facilities. Products containing NORs are commonly denoted by the acronym NORM (Naturally Occurring Radioactive Materials). Main topics of this paper are: E and P (Exploration and Production) NORM characteristics; incentives for NORM analysis; NORM analysis; interlaboratory test programme; analysis techniques; results and conclusions of the test programme. 4 figs., 2 tabs.

  17. Genotoxic activity in vivo of the naturally occurring glucoside, cycasin, in the Drosophila wing spot test.

    Science.gov (United States)

    Kawai, K; Furukawa, H; Hirono, I

    1995-03-01

    Cycasin, methylazoxymethanol-beta-glucoside, is a naturally occurring carcinogenic compound. The genotoxicity of cycasin was assayed in the Drosophila wing spot test. Cycasin induced small single and large single spots on feeding at 10 mumol/g medium. The presence of these spots indicates that cycasin is genotoxic in Drosophila melanogaster. Microorganisms which showed beta-glucosidase activity for cleaving cycasin to toxic aglycon were isolated from gut flora of the Drosophila larvae. Consequently, the Drosophila wing spot test would be useful for mutagenicity screening of other naturally occurring glucosides.

  18. A systematic review of trastuzumab and lapatinib in the treatment of women with brain metastases from HER2-positive breast cancer

    DEFF Research Database (Denmark)

    Larsen, Pia Bükmann; Kümler, Iben; Nielsen, Dorte Lisbet

    2013-01-01

    Patients with HER2-positive breast cancer are living still longer and increasingly experiencing brain metastases. Current HER2-targeted therapies have limited potential to cross the blood-brain-barrier. We performed a systematic review to investigate data on HER2-targeting therapies in the treatm......Patients with HER2-positive breast cancer are living still longer and increasingly experiencing brain metastases. Current HER2-targeted therapies have limited potential to cross the blood-brain-barrier. We performed a systematic review to investigate data on HER2-targeting therapies...... retrospective thus possibly biasing data. Only three studies were identified comparing trastuzumab to lapatinib. Conclusively, no solid data exist on how to treat patients with HER2-positive disease and brain metastases. Although continuous HER2-blockade is recommended by international consensus guidelines......, it is still not evident which HER2-targeting agent should be preferred when brain metastases occur. The choice of chemotherapy to accompany the blockade is not obvious and we do not know if dual is better than single blockade. Further clinical trials are urgently needed....

  19. A library screening approach identifies naturally occurring RNA sequences for a G-quadruplex binding ligand.

    Science.gov (United States)

    Mirihana Arachchilage, Gayan; Morris, Mark J; Basu, Soumitra

    2014-02-07

    An RNA G-quadruplex library was synthesised and screened against kanamycin A as the ligand. Naturally occurring G-quadruplex forming sequences that differentially bind to kanamycin A were identified and characterized. This provides a simple and effective strategy for identification of potential intracellular G-quadruplex targets for a ligand.

  20. Existence of long-lived isomeric states in naturally-occurring neutron-deficient Th isotopes

    CERN Document Server

    Marinov, A; Kashiv, Y; Halicz, L; Segal, I; Pape, A; Gentry, R V; Miller, H W; Kolb, D; Brandt, R

    2006-01-01

    Evidence for the existence of long-lived neutron-deficient isotopes has been found in a study of naturally-occurring Th using iductively coupled plasma-sector field mass spectrometry. They are interpreted as belonging to the recently discovered class of long-lived high spin super- and hyperdeformed isomers.

  1. BIOCONVERSION OF NATURALLY-OCCURRING PRECURSORS AND RELATED SYNTHETIC COMPOUNDS USING PLANT-CELL CULTURES

    NARCIS (Netherlands)

    PRAS, N

    1992-01-01

    The nearly unlimited enzymatic potential of cultured plant cells can basically be employed for bioconversion purposes. Plant enzymes are able to catalyze regio- and stereospecific reactions and can therefore be applied to the production of compounds of pharmaceutical interest. Naturally occurring as

  2. Naturally occurring products of proglucagon 111-160 in the porcine and human small intestine

    DEFF Research Database (Denmark)

    Buhl, T; Thim, L; Kofod, Hans

    1988-01-01

    Recent studies have revealed that the glucagon gene is expressed in the mammalian intestine. Here it codes for "glicentin" (proglucagon 1-69) and a glucagon-like peptide, proglucagon 78-107, recently isolated from porcine intestine. We studied the fate of the remaining COOH-terminal part of progl...... that this is the structure of the naturally occurring human peptide....

  3. Therapeutic Recreation in the Naturally Occurring Retirement Community (NORC): Benefitting "Aging in Place."

    Science.gov (United States)

    Kunstler, Robin

    2002-01-01

    Describes how therapeutic recreation in naturally occurring retirement communities (neighborhoods where most residents are older) can promote healthy lifestyles, presenting a case report of an in-home therapeutic recreation program offered in conjunction with nursing and social services in a such a community and discussing implications for…

  4. Silencing of the HER2/neu Gene by siRNA Inhibits Proliferation and Induces Apoptosis in HER2/neu-Overexpressing Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Timo Faltus

    2004-11-01

    Full Text Available In eukaryotes, double-stranded (ds RNA induces sequence-specific inhibition of gene expression referred to as RNA interference (RNAi. We exploited RNAi to define the role of HER2/neu in the neoplastic proliferation of human breast cancer cells. We transfected SK-BR-3, BT-474, MCF-7, and MDA-MB-468 breast cancer cells with short interfering RNA (siRNA targeted against human HER2/neu and analyzed the specific inhibition of HER2/neu expression by Northern and Western blots. Transfection with HER2/neu-specific siRNA resulted in a sequence-specific decrease in HER2/neu mRNA and protein levels. Moreover, transfection with HER2/neu siRNA caused cell cycle arrest at G0/G1 in the breast cancer cell lines SKBR-3 and BT-474, consistent with a powerful RNA silencing effect. siRNA treatment resulted in an antiproliferative and apoptotic response in cells overexpressing HER2/neu, but had no influence in cells with almost no expression of HER2/neu proteins like MDA-MB-468 cells. These data indicate that HER2/neu function is essential for the proliferation of HER2/neuoverexpressing breast cancer cells. Our observations suggest that siRNA targeted against human HER2/neu may be valuable tools as anti proliferative agents that display activity against neoplastic cells at very low doses.

  5. Telomerase and HER-2/neu as targets of genetic cancer vaccines in dogs.

    Science.gov (United States)

    Peruzzi, Daniela; Mesiti, Giuseppe; Ciliberto, Gennaro; La Monica, Nicola; Aurisicchio, Luigi

    2010-02-03

    Pet dogs represent a valuable pre-clinical model to assess the efficacy of oncology drugs. Additionally, canine cancers occur with an incidence similar to that of humans and share many features with human malignancies including histological appearance, tumor genetics, biological behavior and response to conventional therapies. The telomerase reverse transcriptase (TERT) is reactivated in most of human and dog tumors. Similarly, HER-2/neu oncoprotein is overexpressed in a proportion of canine breast cancers. Therefore, TERT and HER-2/neu can constitute valid tumor associated antigens (TAA), suitable targets for translational cancer immunotherapy in dogs. In this study, we have evaluated the ability of DNA electroporation (DNA-EP) and Adenovirus serotype 6 (Ad6) to induce immune responses against dog TERT (dTERT) and HER-2/neu in healthy dogs. Vaccination was effective in all treated animals and the adaptive immune response remained detectable and long-lasting in the absence of autoimmunity or other side-effects. Our results show that DNA-EP/Ad6-based cancer vaccine induces adaptive immune responses against TAA in canine subjects and support further evaluation of this approach in cancer dog patients.

  6. Predicting Emotions in Facial Expressions from the Annotations in Naturally Occurring First Encounters

    DEFF Research Database (Denmark)

    Navarretta, Costanza

    2014-01-01

    This paper deals with the automatic identification of emotions from the manual annotations of the shape and functions of facial expressions in a Danish corpus of video recorded naturally occurring first encounters. More specifically, a support vector classified is trained on the corpus annotations...... to identify emotions in facial expressions. In the classification experiments, we test to what extent emotions expressed in naturally-occurring conversations can be identified automatically by a classifier trained on the manual annotations of the shape of facial expressions and co-occurring speech tokens. We...... also investigate the relation between emotions and the communicative functions of facial expressions. Both emotion labels and their values in a three dimensional space are identified. The three dimensions are Pleasure, Arousal and Dominance. The results of our experiments indicate that the classifiers...

  7. Sensitivity, child regulatory processes, and naturally occurring declines in antisocial behavior across childhood.

    Science.gov (United States)

    Buck, Katharine Ann

    2014-12-01

    Despite considerable research on why antisocial behavior develops and interventions that reduce it, aspects of everyday family processes that may promote naturally occurring declines in antisocial behavior or that may result from such declines in most children without intervention are poorly understood. The current study explored family processes that may enable children to replace antisocial tendencies and the effects that declines in antisocial behavior may have on parenting and child regulatory processes. Longitudinal data from 1,022 children (54 months-6th grade) from the NICHD Study of Early Child Care and Youth Development were examined. Findings demonstrated that naturally occurring declines in antisocial behavior both predicted and were predicted by maternal sensitivity, emotion regulation, and social skills. These declines predicted but were not predicted by declines in hostile attributions. The data revealed multiple indirect paths, which highlight the complex nature of these variables across development.

  8. Deposits of naturally occurring radioactivity in production of oil and natural gas; Radioaktive avleiringer i olje- og gassproduksjon

    Energy Technology Data Exchange (ETDEWEB)

    Strand, T.; Lysebo, I.; Kristensen, D.; Birovljev, A.

    1997-01-01

    Deposits of naturally occurring radioactive materials is an increasing problem in Norwegian oil and gas production. Activity concentration in solid-state samples and production water, and doses to workers involved in different operations off-shore, have been measured. The report also includes a discussion of different methods of monitoring and alternatives for final disposal of wastes. 154 refs.

  9. A FISH-based method for assessment of HER-2 amplification status in breast cancer circulating tumor cells following CellSearch isolation

    Directory of Open Access Journals (Sweden)

    Frithiof H

    2016-11-01

    Full Text Available Henrik Frithiof,1 Kristina Aaltonen,1 Lisa Rydén2,3 1Division of Oncology and Pathology, 2Division of Surgery, Department of Clinical Sciences Lund, Lund University, Lund, 3Department of Surgery, Skåne University Hospital, Malmö, Sweden Introduction: Amplification of the HER-2/neu (HER-2 proto-oncogene occurs in 10%–15% of primary breast cancer, leading to an activated HER-2 receptor, augmenting growth of cancer cells. Tumor classification is determined in primary tumor tissue and metastatic biopsies. However, malignant cells tend to alter their phenotype during disease progression. Circulating tumor cell (CTC analysis may serve as an alternative to repeated biopsies. The Food and Drug Administration-approved CellSearch system allows determination of the HER-2 protein, but not of the HER-2 gene. The aim of this study was to optimize a fluorescence in situ hybridization (FISH-based method to quantitatively determine HER-2 amplification in breast cancer CTCs following CellSearch-based isolation and verify the method in patient samples. Methods: Using healthy donor blood spiked with human epidermal growth factor receptor 2 (HER-2-positive breast cancer cell lines, SKBr-3 and BT-474, and a corresponding negative control (the HER-2-negative MCF-7 cell line, an in vitro CTC model system was designed. Following isolation in the CellSearch system, CTC samples were further enriched and fixed on microscope slides. Immunocytochemical staining with cytokeratin and 4',6-diamidino-2'-phenylindole dihydrochloride identified CTCs under a fluorescence microscope. A FISH-based procedure was optimized by applying the HER2 IQFISH pharmDx assay for assessment of HER-2 amplification status in breast cancer CTCs. Results: A method for defining the presence of HER-2 amplification in single breast cancer CTCs after CellSearch isolation was established using cell lines as positive and negative controls. The method was validated in blood from breast cancer patients

  10. Is it necessary to raise awareness about technologically enhanced naturally occurring radioactive materials?

    Science.gov (United States)

    Michalik, Bogusław

    2009-10-01

    Since radiation risks are usually considered to be related to nuclear energy, the majority of research on radiation protection has focused on artificial radionuclides in radioactive wastes, spent nuclear fuel or global fallout caused by A-bomb tests and nuclear power plant failures. Far less attention has been paid to the radiation risk caused by exposure to ionizing radiation originating from natural radioactivity enhanced due to human activity, despite the fact that technologically enhanced naturally occurring radioactive materials are common in many branches of the non-nuclear industry. They differ significantly from "classical" nuclear materials and usually look like other industrial waste. The derived radiation risk is usually associated with risk caused by other pollutants and can not be controlled by applying rules designed for pure radioactive waste. Existing data have pointed out a strong need to take into account the non-nuclear industry where materials containing enhanced natural radioactivity occur as a special case of radiation risk and enclose them in the frame of the formal control. But up to now there are no reasonable and clear regulations in this matter. As a result, the non-nuclear industries of concern are not aware of problems connected with natural radioactivity or they would expect negative consequences in the case of implementing radiation protection measures. The modification of widely comprehended environmental legislation with requirements taken from radiation protection seems to be the first step to solve this problem and raise awareness about enhanced natural radioactivity for all stakeholders of concern.

  11. Interaction of flavonoids, the naturally occurring antioxidants with different media: A UV-visible spectroscopic study

    Science.gov (United States)

    Naseem, Bushra; Shah, S. W. H.; Hasan, Aurangzeb; Sakhawat Shah, S.

    2010-04-01

    Quantitative parameters for interaction of flavonoids—the naturally occurring antioxidants, with solvents and surfactants are determined using UV-visible absorption spectroscopy. The availability of flavonoids; kaempferol, apigenin, kaempferide and rhamnetin in micelles of sodium dodecyl sulfate (SDS) is reflected in terms of partition coefficient, Kc. Thermodynamic calculations show that the process of transfer of flavonoid molecules to anionic micelles of SDS is energy efficient. A distortion in flavonoid's morphology occurs in case of kaempferol and apigenin in surfactant and water, exhibited in terms of a new band in the UV region of electronic spectra of these flavonoids. The partition coefficients of structurally related flavonoids are correlated with their antioxidant activities.

  12. A Review on the Phytochemistry, Pharmacology, and Pharmacokinetics of Amentoflavone, a Naturally-Occurring Biflavonoid

    Directory of Open Access Journals (Sweden)

    Sheng Yu

    2017-02-01

    Full Text Available Amentoflavone (C30H18O10 is a well-known biflavonoid occurring in many natural plants. This polyphenolic compound has been discovered to have some important bioactivities, including anti-inflammation, anti-oxidation, anti-diabetes, and anti-senescence effects on many important reactions in the cardiovascular and central nervous system, etc. Over 120 plants have been found to contain this bioactive component, such as Selaginellaceae, Cupressaceae, Euphorbiaceae, Podocarpaceae, and Calophyllaceae plant families. This review paper aims to profile amentoflavone on its plant sources, natural derivatives, pharmacology, and pharmacokinetics, and to highlight some existing issues and perspectives in the future.

  13. Trastuzumab for HER-2-Positive Advanced Salivary Gland Cancer

    Directory of Open Access Journals (Sweden)

    Yi-Tsung Yang

    2014-12-01

    Full Text Available Salivary gland adenocarcinoma is a rare type of head and neck cancer and often has aggressive behavior with propensity to recur and metastasize. Currently, there are no standard treatment guidelines. Surgery is however, the mainstay of treatment in resectable disease and radiation is also considered for most patients after surgery. Systemic chemotherapy is reserved for metastatic cases, but its results are often disappointing. Recent development of molecular biology has shown that salivary gland caner has several molecular changes which may guide potential therapeutic targets. Here, we report a 67 year-old man diagnosed to have metastasized minor salivary gland adenocarcinoma with diffuse human epidermal growth factor receptor-2 (HER-2-positive, by the immunohistochemical (IHC stain. He was treated with a trastuzumab-containing chemotherapeutic regimen with encouraging results.

  14. Mammakarzinom: Spezifische Aspekte der Therapie kleiner HER2-positiver Tumore

    Directory of Open Access Journals (Sweden)

    Bartsch R

    2012-01-01

    Full Text Available Im vorliegenden Artikel präsentieren wir den Fall einer 52jährigen Patientin, bei der ein Mammakarzinom im Frühstadium diagnostiziert worden war. Nach brusterhaltender Operation fand sich in der histopathologischen Untersuchung eine Mikrometastase in einem von zwei entnommenen Sentinellymphknoten, was jedoch nach aktueller Interpretation keine Indikation zur axillären Dissektion darstellt. Auf Grund der geringen Tumorgröße (8 mm, pT1b würde üblicherweise auf eine Chemotherapie verzichtet werden, bei positivem HER2- Status muss jedoch von einer aggressiven Erkrankung ausgegangen werden, weshalb eine adjuvante Chemo-Immuntherapie gerechtfertigt erschien. Weiters ergab sich bei Zustand nach brusterhaltender Operation die Indikation zur adjuvanten Radiatio, wobei zusätzlich die Indikation zur Boostbestrahlung mittels Brachytherapie gestellt wurde.

  15. Prospective trial of metronomic chlorambucil chemotherapy in dogs with naturally occurring cancer.

    Science.gov (United States)

    Leach, T N; Childress, M O; Greene, S N; Mohamed, A S; Moore, G E; Schrempp, D R; Lahrman, S R; Knapp, D W

    2012-06-01

    The purpose of this study was to assess the toxicoses and antitumor activity of metronomic chlorambucil at a dosage of 4 mg m(-2) daily in dogs with naturally occurring cancer. Thirty-six dogs were enrolled in the study. The protocol was well tolerated with no grade 3 or 4 toxicoses noted. Complete remission was achieved, and lasted over 35 weeks in three dogs (mast cell tumour, soft tissue sarcoma and thyroid carcinoma). Partial remission was noted in 1 dog with histiocytic sarcoma (39 weeks duration) for an overall remission rate of 11% (4 of 36). Stable disease was noted in 17 dogs (47%) with various other cancers. The median progression-free interval was 61 days, and the median survival time was 153 days. Chlorambucil given in a metronomic protocol showed antitumor activity in dogs with a variety of naturally occurring cancers.

  16. Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease

    DEFF Research Database (Denmark)

    Höllmer, M.; Willesen, J. L.; Tolver, A.

    2017-01-01

    of cardiac compensation. Left atrial function in dogs with naturally occurring MMVD remains largely unexplored. The objective of this study was to evaluate LA volume and function in dogs with naturally occurring MMVD. ANIMALS: This prospective study included 205 client-owned dogs of different breeds, 114...... healthy dogs, and 91 dogs with MMVD of different disease severities. METHODS: Using two-dimensional echocardiography, the biplane area-length method was applied to assess LA volume and calculate volumetric indices of LA reservoir, conduit, and contractile function. RESULTS: Left atrial volume and LA...... stroke volume increased, whereas LA reservoir and contractile function decreased with increasing disease severity. A maximal LA volume dogs with chronic MMVD with a sensitivity of 96% and a specificity of 100...

  17. Monitoring of increased natural occuring radiation exposure; Arbeitsplatzueberwachung bei erhoehter natuerlicher Strahlenexposition

    Energy Technology Data Exchange (ETDEWEB)

    Guhr, Andreas [ALTRAC Radon-Messtechnik, Berlin (Germany); Leissring, Nick [Bergtechnisches Ingenieurbuero GEOPRAX, Chemnitz (Germany)

    2015-07-01

    The radiation exposure due to natural occurring sources is a special challenge for the health and safety protection at workplaces. The monitoring of the radon exposure of employees in mines, radon-spa and in water works is regulated by prescription of radiation protection. The relevant compounds of the radiation exposure are the inhalation of radon and radon daughter products; terrestrial irradiation; ingestion of radioactive contaminated materials and the inhalation of contaminated dust. The monitoring of the radiation workers is realized essentially by measurements by radiation safety officer of the performing company, by an external engineering firm as well as by control measurements of experts of local authorities. The experiences in the practice have shown that in the field of operational radiation protection only a combination of personal- and operational dosimetry is suitable to avoid health hazards by work in fields with increased natural occurring radiation exposures.

  18. Extraction and characterization of naturally occurring bioactive peptides from different tissues from Salmon (Salmo salar)

    DEFF Research Database (Denmark)

    Falkenberg, Susan Skanderup; Nielsen, Henrik Hauch

    2011-01-01

    is therefore to extract and identify naturally occurring bioactive peptides from different tissues from salmon. A number of aqueous extracts were made from gills, skin and belly flap. In order to preserve the bioactivity of the peptides mild extraction procedures as acidic, basic and aqueous solutions were...... number of bio-components such as bioactive peptides for this purpose. Tissue and proteins from e.g. fish gills, skin and viscera could be a new source of peptides that could have a nutritional and pharmaceutical value, and be used in health and functional foods and thereby increasing the value adding...... of secondary marine products. Only few naturally occurring bioactive peptides have been characterized such as the antimicrobial polypeptide piscidines from gills. It is therefore hypothesized, that fish tissue also contains numerous other peptides with other bioactive properties. The approach in this project...

  19. Recombinant feline leukemia virus genes detected in naturally occurring feline lymphosarcomas.

    OpenAIRE

    Sheets, R L; Pandey, R.; Jen, W C; Roy-Burman, P

    1993-01-01

    Using a polymerase chain reaction strategy aimed at detecting recombinant feline leukemia virus (FeLV) genomes with 5' env sequences originating from an endogenous source and 3' env sequences resulting from FeLV subgroup A (FeLV-A), we detected recombinant proviruses in approximately three-fourths of naturally occurring thymic and alimentary feline lymphosarcomas (LSAs) and one-third of the multicentric LSAs from cats determined to be FeLV capsid antigen positive by immunofluorescence assay. ...

  20. Natural occurring 2-(2-phenylethyl) chromones, structure elucidation and biological activities.

    Science.gov (United States)

    Ibrahim, Sabrin R M; Mohamed, Gamal A

    2015-01-01

    2-(2-Phenylethyl) chromone (PEC), an uncommon class of chromones, possesses a phenylethyl substituent at the C2 position. They have been isolated from a few plant species. They have promising biological activities such as neuro-protective, cytotoxic, acetylcholinesterase inhibitory, antibacterial and anti-inflammatory. This review focuses on the naturally occurring PEC derivatives, their sources, physical and spectral data, as well as biological activities.

  1. Inhibition of the Corrosion of Mild Steel in Acid Media by Naturally Occurring Acacia Senegal

    Directory of Open Access Journals (Sweden)

    Urvija Garg

    2010-01-01

    Full Text Available The inhibition of corrosion of mild steel in HCl solution by naturally occurring Acacia Senegal has been studied in relation to the concentration of inhibitor and concentration of corrosive medium. It has been observed that the Acacia Senegal alcoholic extract acts as a good corrosion inhibitor in hydrochloric acid solution and the adsorption of the extract provides a good protection against mild steel corrosion.

  2. A database of naturally occurring human urinary peptides and proteins for use in clinical applications

    OpenAIRE

    Petra Zürbig; Joshua Coon; Hartwig Bauer; Georg Behrens; Mohammed Dakna; Anna Dominiczak; Stephane Decramer; Jochen Ehrich; Danilo Fliser; Moritz Frommberger; Arnold Ganser; Mark Giolami; Igor Golovko; David Good; Wilfried Gwinner

    2007-01-01

    Owing to its availability, ease of collection and correlation with (patho-) physiology, urine is an attractive source for clinical proteomics. However, the lack of comparable datasets from large cohorts has greatly hindered development in this field. Here we report the establishment of a high resolution proteome database of naturally occurring human urinary peptides and proteins - ranging from 800-17,000 Da - from over 3,600 individual samples using capillary electrophoresis coupled to mass s...

  3. Apigenin induces apoptosis through proteasomal degradation of HER2/neu in HER2/neu-overexpressing breast cancer cells via the phosphatidylinositol 3-kinase/Akt-dependent pathway.

    Science.gov (United States)

    Way, Tzong-Der; Kao, Ming-Ching; Lin, Jen-Kun

    2004-02-06

    Apigenin is a low toxicity and non-mutagenic phytopolyphenol and protein kinase inhibitor. It exhibits anti-proliferating effects on human breast cancer cells. Here we examined several human breast cancer cell lines having different levels of HER2/neu expression and found that apigenin exhibited potent growth-inhibitory activity in HER2/neu-overexpressing breast cancer cells but was much less effective for those cells expressing basal levels of HER2/neu. Induction of apoptosis was also observed in HER2/neu-overexpressing breast cancer cells in a dose- and time-dependent manner. However, the one or more molecular mechanisms of apigenin-induced apoptosis in HER2/neu-overexpressing breast cancer cells remained to be elucidated. A cell survival pathway involving phosphatidylinositol 3-kinase (PI3K), and Akt is known to play an important role in inhibiting apoptosis in response to HER2/neu-overexpressing breast cancer cells, which prompted us to investigate whether this pathway plays a role in apigenin-induced apoptosis in HER2/neu-overexpressing breast cancer cells. Our results showed that apigenin inhibits Akt function in tumor cells in a complex manner. First, apigenin directly inhibited the PI3K activity while indirectly inhibiting the Akt kinase activity. Second, inhibition of HER2/neu autophosphorylation and transphosphorylation resulting from depleting HER2/neu protein in vivo was also observed. In addition, apigenin inhibited Akt kinase activity by preventing the docking of PI3K to HER2/HER3 heterodimers. Therefore, we proposed that apigenin-induced cellular effects result from loss of HER2/neu and HER3 expression with subsequent inactivation of PI3K and AKT in cells that are dependent on this pathway for cell proliferation and inhibition of apoptosis. This implies that the inhibition of the HER2/HER3 heterodimer function provided an especially effective strategy for blocking the HER2/neu-mediated transformation of breast cancer cells. Our results also

  4. Serum canine pancreatic lipase immunoreactivity in experimentally induced and naturally occurring canine monocytic ehrlichiosis (Ehrlichia canis).

    Science.gov (United States)

    Mylonakis, Mathios E; Xenoulis, Panagiotis G; Theodorou, Konstantina; Siarkou, Victoria I; Steiner, Jörg M; Harrus, Shimon; Leontides, Leonidas; Rallis, Timoleon; Suchodolski, Jan S; Koutinas, Christos K; Koutinas, Alexander F

    2014-03-14

    Ehrlichia canis infection causes multisystemic disease in dogs (canine monocytic ehrlichiosis, CME) which is associated with variable morbidity and mortality. Atypical clinical manifestations, including gastrointestinal signs, may occasionally occur in CME and approximately 10-15% of dogs are presented with historical or clinical evidence of vomiting, diarrhea, and/or abdominal discomfort. The objective of this study was to investigate if there are any alterations in serum canine pancreatic lipase immunoreactivity (cPLI) in dogs with experimentally induced or naturally occurring monocytic ehrlichiosis. Serum samples from 10 Beagle dogs experimentally infected with E. canis and two healthy uninfected Beagles were serially examined; samples from 20 naturally infected dogs (10 with non-myelosuppressive [NME] and 10 with myelosuppressive [ME] ehrlichiosis) were also examined at a given point in time (cross-sectional sampling). None of the experimentally infected Beagles showed gastrointestinal signs or increased cPLI concentrations prior to or following the artificial infection. Three naturally infected dogs with NME and one with ME demonstrated serum cPLI concentrations in the diagnostic range for pancreatitis (>400 μg/L) without showing gastrointestinal signs. The results of the present study indicated that 4/20 (20%) of dogs naturally infected with E. canis demonstrated increased serum cPLI concentrations consistent with mild and clinically inapparent pancreatitis.

  5. The HER2 amplicon includes several genes required for the growth and survival of HER2 positive breast cancer cells — A data description

    Directory of Open Access Journals (Sweden)

    Vesa Hongisto

    2014-12-01

    Full Text Available A large number of breast cancers are characterized by amplification and overexpression of the chromosome segment surrounding the HER2 (ERBB2 oncogene. As the HER2 amplicon at 17q12 contains multiple genes, we have systematically explored the role of the HER2 co-amplified genes in breast cancer cell growth and their relation to trastuzumab resistance. We integrated array comparative genomic hybridization (aCGH data of the HER2 amplicon from 71 HER2 positive breast tumors and 10 cell lines with systematic functional RNA interference analysis of 23 core amplicon genes with several phenotypic endpoints in a panel of trastuzumab responding and non-responding HER2 positive breast cancer cells. In this Data in Brief we give a detailed description of the experimental procedures and the data analysis methods used in the study (1.

  6. Phenotypic changes of p53, HER2, and FAS system in multiple normal tissues surrounding breast cancer.

    Science.gov (United States)

    Mottolese, Marcella; Nádasi, Edit A; Botti, Claudio; Cianciulli, Anna M; Merola, Roberta; Buglioni, Simonetta; Benevolo, Maria; Giannarelli, Diana; Marandino, Ferdinando; Donnorso, Raffaele Perrone; Venturo, Irene; Natali, Pier Giorgio

    2005-07-01

    To determine whether phenotypic field changes occur in tissues adjacent to carcinoma, we assayed, by immunohistochemistry, the expression of HER-2, p53, Fas, and FasL in 72 breast cancers (BC) and multiple autologous peritumoral tissues (PTTs) sampled up to 5 cm distance and in 44 benign breast tumors (BBTs). About 5% and 3% of the PTTs and 4.5% and 6.8% of BBTs showed alterations in HER2 and p53 expression, respectively. Of interest, gene amplification was observed in 50% of HER2 positive PTTs, but not in any HER2 positive BBTs. Fas, highly expressed in BBTs and downregulated in BC, maintained its expression in PTTs, whereas FasL, usually negative in BBTs, was upregulated in BC as well as in the PTTs closest (1 cm) to the invasive lesion. Our data suggest that FasL could be a potential novel biomarker of transformation, which may identify, along with HER2 and p53, precursor lesions in a genetically altered breast tissue.

  7. Effect of neoadjuvant chemotherapy on breast cancer phenotype, ER/PR and HER2 expression - Implications for the practising oncologist.

    Science.gov (United States)

    Gahlaut, Renu; Bennett, Aneliese; Fatayer, Hiba; Dall, Barbara J; Sharma, Nisha; Velikova, Galina; Perren, Tim; Dodwell, David; Lansdown, Mark; Shaaban, Abeer M

    2016-06-01

    To assess the effect of neoadjuvant chemotherapy (NACT) on breast cancer characteristics, hormone receptors and human epidermal growth factor receptor 2 (HER2) expression and whether testing should be repeated on residual tumours. Patients with primary operable breast cancer who received NACT at a single United Kingdom tertiary referral centre were included. Tumour type, grade (including details of mitotic grade, tubule formation and pleomorphism), oestrogen receptor (ER), progesterone receptor (PR) and HER2 status were compared between pre-treatment and post-treatment residual samples using tissue microarrays. A control group of paired core and excision tumours from patients who did not receive NACT was also assessed. Two hundred forty-six cases and 113 controls were included. Pathological complete response (path CR) was achieved in 21.5% of patients. In those patients failing to achieve a path CR, a change in the histological type was noted in 29 out of 178 cases (16.3%, pnegative to positive status for ER and from positive to negative status for HER2. Further alterations in expression levels were also noted. Minimal changes in the low ER/PR expressors and the HER2 2+ tumours were found in the control group. Significant changes in tumour morphology, grade, hormone receptors and HER2 status occur following NACT. We recommend testing on residual invasive carcinoma. A switch from negative to positive status warrants offering endocrine/trastuzumab-based therapy to this group of patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Is the skin a sanctuary for breast cancer cells during treatment with anti-HER2 antibodies?

    Science.gov (United States)

    Graziano, Vincenzo; Scognamiglio, Maria Teresa; Zilli, Marinella; Giampietro, Jamara; Vici, Patrizia; Natoli, Clara; Grassadonia, Antonino

    2015-01-01

    The occurrence of skin metastases is a common event in patients affected by advanced breast cancer, usually associated with systemic disease progression. Here we describe 2 cases of diffuse cutaneous metastases from HER2-overexpressing breast cancer occurring despite a dramatic response in liver and bone, respectively, during treatment with anti-HER2 antibodies Trastuzumab and Pertuzumab. We discuss the reasons for this discrepancy and suggest a possible implication of impaired immune response in the skin. Future research should provide strategies to overcome the induction of immune privilege in the skin in order to avoid discontinuation of effective treatments.

  9. HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials.

    Science.gov (United States)

    Richman, Susan D; Southward, Katie; Chambers, Philip; Cross, Debra; Barrett, Jennifer; Hemmings, Gemma; Taylor, Morag; Wood, Henry; Hutchins, Gordon; Foster, Joseph M; Oumie, Assa; Spink, Karen G; Brown, Sarah R; Jones, Marc; Kerr, David; Handley, Kelly; Gray, Richard; Seymour, Matthew; Quirke, Philip

    2016-03-01

    HER2 overexpression/amplification is linked to trastuzumab response in breast/gastric cancers. One suggested anti-EGFR resistance mechanism in colorectal cancer (CRC) is aberrant MEK-AKT pathway activation through HER2 up-regulation. We assessed HER2-amplification/overexpression in stage II-III and IV CRC patients, assessing relationships to KRAS/BRAF and outcome. Pathological material was obtained from 1914 patients in the QUASAR stage II-III trial and 1342 patients in stage IV trials (FOCUS and PICCOLO). Tissue microarrays were created for HER2 immunohistochemistry. HER2-amplification was assessed using FISH and copy number variation. KRAS/BRAF mutation status was assessed by pyrosequencing. Progression-free survival (PFS) and overall survival (OS) data were obtained for FOCUS/PICCOLO and recurrence and mortality for QUASAR; 29/1342 (2.2%) stage IV and 25/1914 (1.3%) stage II-III tumours showed HER2 protein overexpression. Of the HER2-overexpressing cases, 27/28 (96.4%) stage IV tumours and 20/24 (83.3%) stage II-III tumours demonstrated HER2 amplification by FISH; 41/47 (87.2%) also showed copy number gains. HER2-overexpression was associated with KRAS/BRAF wild-type (WT) status at all stages: in 5.2% WT versus 1.0% mutated tumours (p < 0.0001) in stage IV and 2.1% versus 0.2% in stage II-III tumours (p = 0.01), respectively. HER2 was not associated with OS or PFS. At stage II-III, there was no significant correlation between HER2 overexpression and 5FU/FA response. A higher proportion of HER2-overexpressing cases experienced recurrence, but the difference was not significant. HER2-amplification/overexpression is identifiable by immunohistochemistry, occurring infrequently in stage II-III CRC, rising in stage IV and further in KRAS/BRAF WT tumours. The value of HER2-targeted therapy in patients with HER2-amplified CRC must be tested in a clinical trial. © 2015 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society

  10. Resveratrol chemosensitizes HER-2-overexpressing breast cancer cells to docetaxel chemoresistance by inhibiting docetaxel-mediated activation of HER-2-Akt axis.

    Science.gov (United States)

    Vinod, B S; Nair, H H; Vijayakurup, V; Shabna, A; Shah, S; Krishna, A; Pillai, K S; Thankachan, S; Anto, R J

    2015-01-01

    As breast cancer cells often develop chemoresistance, better therapeutic options are in search to circumvent it. Here we demonstrate that human epidermal growth factor receptor-2 (HER-2)-overexpressing breast cancer cells resist docetaxel-induced cytotoxicity by upregulating HER-2 and its activity downstream, through Akt and mitogen-activated protein kinase (MAPK) pathways. We observed that introducing resveratrol as a chemosensitizer in docetaxel chemotherapy blocks upregulation and activation of HER-2 in addition to blocking downstream signaling pathways such as Akt. Resveratrol and docetaxel combination results in the synergistic induction of cell death in HER-2-overexpressing SK-BR-3 cells, whereas introduction of wild-type HER-2 in MDA-MD-231 cells increased the resistance to docetaxel. Dominant-negative HER-2 sensitizes SK-BR-3 cells to docetaxel. Our study identified a new synergistic therapeutic combination that targets HER-2-induced breast cancer resistance and might help to overcome therapeutic resistance during breast cancer therapy. The synergism of docetaxel and resveratrol was maximum in SK-BR-3, which is unique among the cell lines studied, due to its high expression status of HER-2, a receptor known to dictate the signaling environment of breast cancer cells. Docetaxel could further induce HER-2 activity in these cells, which was downregulated on resveratrol treatment. Transfection of DN-HER-2 in SK-BR-3 cells inhibits the synergism as the transfection itself sensitizes these cells to docetaxel, leaving no role for resveratrol, whereas ectopic expression of HER-2 introduces the synergism in MDA-MB-231, the triple-negative cell line, in which the synergism was minimum, attesting the crucial role of HER-2 in suppressing the sensitivity to docetaxel. Single-agent docetaxel induced HER-2-mediated resistance to cell death, which was blocked by resveratrol. Resveratrol also downregulated docetaxel-induced activation of MAPK and Akt, survival signaling

  11. Phytohormonal basis for the plant growth promoting action of naturally occurring biostimulators.

    Science.gov (United States)

    Kurepin, Leonid V; Zaman, Mohammad; Pharis, Richard P

    2014-07-01

    There is increasing interest in the use of naturally occurring 'biostimulators' for enhancing the growth of agricultural and horticultural crops. Bacteria, fungi and protozoa, as well as marine algae-based seaweed extracts, can produce or contain biostimulators. The activity of biostimulators to promote plant growth is often attributed to their ability to directly or indirectly provide mineral nutrients (mostly N, but also P, S and other macro- and micro-nutrients) to plants. Alternatively, biostimulators are postulated to increase the plant's ability to assimilate these mineral nutrients, often in return for photo-assimilates (as occurs with certain bacteria and fungi associations). Although optimal growth of plants depends on the availability of adequate mineral nutritients, that growth (and also development, including reproduction) is also regulated by plant hormones (phytohormones), including gibberellins, auxins and cytokinins. This review describes and discusses the evidence that the presence or application of biostimulators also increases plant growth directly via phytohormone action and also influences the plant's ability to control its own hormone biosynthesis and homeostasis. Finally, it discusses the need for a better understanding of the role(s) that are played by the naturally occurring biostimulators associated with the plant in the crop field. It is suggested that better understanding will allow for optimal crop yield returns, since disruptions of phytohormone homeostasis in plant organs and tissues can yield either beneficial or sub-optimal outcomes.

  12. Differentiation of naturally-occurring vs. artificial hydrocarbons in a landfill groundwater investigation

    Energy Technology Data Exchange (ETDEWEB)

    Beaver, J.L.; Hartness, J.A.; Breeding, L.B.; Buchanan, D.M. [Law Environmental, Inc., Kennesaw, GA (United States)

    1994-12-31

    Interpretation of groundwater sampling data at a large municipal/industrial landfill indicates contamination by both artificial and naturally-occurring hydrocarbons. Site hydrogeology consists of three different water bearing zones. The uppermost (shallow) aquifer is an unconfined unit consisting of silt, clay, and sand deposits. An intermediate depth semiconfined aquifer underlies the unconfined unit, and consists of a chert rubble zone and the upper portion of a fractured and solution-enhanced limestone formation. A regionally-extensive organic-rich shale underlies the semiconfined aquifer and separates it from the deep confined aquifer, which also consists of limestone. Groundwater investigations at the landfill have detected chlorinated and non-chlorinated hydrocarbons in the different aquifer intervals. Chlorinated hydrocarbons detected include tetrachloroethene, dichloroethene, and vinyl chloride and occur almost exclusively in the shallow aquifer. Aromatic hydrocarbons detected include benzene, toluene, ethylbenzene, and xylene (BTEX) and-occur in the intermediate and deep aquifers. The landfill was originally interpreted as the source of the contaminants. The observation of free-phase liquid hydrocarbons in the intermediate aquifer at the site, and high dissolved BTEX levels in the deep and intermediate aquifers upgradient of the landfill suggest that the aromatics were derived from a source other than the landfill. A potential source of BTEX contamination may be abandoned (pre-1930) natural gas wells located near the landfill. An additional BTEX source may be the organic-rich shale formation (a documented petroleum source rock).

  13. Naturally occurring arsenic in the groundwater at the Kansas City Plant

    Energy Technology Data Exchange (ETDEWEB)

    Korte, N.E.

    1990-12-01

    This report describes an investigation concerning the presence of arsenic in concentrations exceeding 0.4 mg/L in the groundwater under the Department of Energy's Kansas City Plant (KCP). The study consisted of four distinct phases: a thorough review of the technical literature, a historical survey of arsenic use at the facility, a laboratory study of existing techniques for determining arsenic speciation, and a field program including water, soil, and sediment sampling. The historical survey and literature review demonstrated that plant activities had not released significant quantities of arsenic to the environment but that similar occurrences of arsenic in alluvial groundwater are widespread in the midwestern United States. Laboratory studies showed that a chromatographic separation technique was necessary to accurately determine arsenic speciation for the KCP groundwater samples. Field studies revealed that naturally occurring reducing conditions prevalent in the subsurface are responsible for dissolving arsenic previously sorbed by iron oxides. Indeed, the data demonstrated that the bulk arsenic concentration of site subsoils and sediments is {approximately}7 mg/kg, whereas the arsenic content of iron oxide subsamples is as high as 84 mg/kg. Literature showed that similar concentrations of arsenic in sediments occur naturally and are capable of producing the levels of arsenic found in groundwater monitoring wells at the KCP. The study concludes, therefore, that the arsenic present in the KCP groundwater is the result of natural phenomena. 44 refs., 8 figs., 14 tabs.

  14. Biological activity of some naturally occurring resins, gums and pigments against in vitro LDL oxidation.

    Science.gov (United States)

    Andrikopoulos, Nikolaos K; Kaliora, Andriana C; Assimopoulou, Andreana N; Papapeorgiou, Vassilios P

    2003-05-01

    Naturally occurring gums and resins with beneficial pharmaceutical and nutraceutical properties were tested for their possible protective effect against copper-induced LDL oxidation in vitro. Chiosmastic gum (CMG) (Pistacia lentiscus var. Chia resin) was the most effective in protecting human LDL from oxidation. The minimum and maximum doses for the saturation phenomena of inhibition of LDL oxidation were 2.5 mg and 50 mg CMG (75.3% and 99.9%, respectively). The methanol/water extract of CMG was the most effective compared with other solvent combinations. CMG when fractionated in order to determine a structure-activity relationship showed that the total mastic essential oil, collofonium-like residue and acidic fractions of CMG exhibited a high protective activity ranging from 65.0% to 77.8%. The other natural gums and resins (CMG resin 'liquid collection', P. terebinthus var. Chia resin, dammar resin, acacia gum, tragacanth gum, storax gum) also tested as above, showed 27.0%-78.8% of the maximum LDL protection. The other naturally occurring substances, i.e. triterpenes (amyrin, oleanolic acid, ursolic acid, lupeol, 18-a-glycyrrhetinic acid) and hydroxynaphthoquinones (naphthazarin, shikonin and alkannin) showed 53.5%-78.8% and 27.0%-64.1% LDL protective activity, respectively. The combination effects (68.7%-76.2% LDL protection) of ursolic-, oleanolic- and ursodeoxycholic- acids were almost equal to the effect (75.3%) of the CMG extract in comparable doses.

  15. HER2: An emerging biomarker in non-breast and non-gastric cancers

    Directory of Open Access Journals (Sweden)

    Norhayati Omar

    2015-08-01

    Conclusion: Moving forward, the rigorous evaluation of HER2 (protein and genomic status as a predictive biomarker will be necessary to bring anti-HER2 therapeutics for non-breast and non-gastric cancers to the clinic.

  16. Comparison of Thoracic Radiography and Computed Tomography in Calves with Naturally Occurring Respiratory Disease

    Directory of Open Access Journals (Sweden)

    Jennifer Fowler

    2017-07-01

    Full Text Available ObjectiveTo evaluate the severity and extent of lung disease using thoracic computed radiography (CR compared to contrast-enhanced multi-detector computed tomography (MDCT of the thorax in calves with naturally occurring respiratory disease and to evaluate the feasibility and safety of performing contrast-enhanced thoracic multi-detector MDCT examinations in sedated calves. Furthermore, to evaluate if combining CR or MDCT with respiratory scoring factors will improve prediction of the chronicity of pulmonary disease in calves.AnimalsThirty Jersey heifer calves ranging in age between 25 and 89 days with naturally occurring respiratory disease.ProceduresAll calves were evaluated via thoracic CR and contrast-enhanced MDCT. All calves were euthanized immediately following thoracic MDCT and submitted for necropsy. Imaging and histopathology results were compared with each other.ResultsThoracic MDCT was superior for evaluation of pneumonia in calves due to the lack of summation in all areas of the lungs. Intravenously administered sedation provided an adequate plane of sedation for acquiring MDCT images of diagnostic quality, without the need for re-scanning. A diagnosis of pneumonia was made with equal rate on both thoracic CR and MDCT. Although mild differences in classification of lung pattern and extent of lung disease were seen when comparing an experienced and a less experienced evaluator, the overall differences were not statistically significant. The best intra- and inter-observer agreement was noted when evaluating the cranioventral aspects of the lungs in either modality. Clinical respiratory scoring is inadequate for diagnosing chronicity of pneumonia in calves with naturally occurring pneumonia.Conclusion and clinical importanceBoth imaging modalities allowed diagnosis of pneumonia in calves. The cranial ventral aspects of the lungs were most commonly affected. Thoracic CR and MDCT provided similar diagnostic effectiveness in diagnosing

  17. Articular Osteochondrosis: A Comparison of Naturally-Occurring Human and Animal Disease

    Science.gov (United States)

    McCoy, Annette M; Toth, Ferenc; Dolvik, Nils I; Ekman, Stina; Ellermann, Jutta; Olstad, Kristin; Ytrehus, Bjornar; Carlson, Cathy S

    2013-01-01

    Background Osteochondrosis (OC) is a common developmental orthopedic disease affecting both humans and animals. Despite increasing recognition of this disease among children and adolescents, its pathogenesis is incompletely understood because clinical signs are often not apparent until lesions have progressed to end-stage, and examination of cadaveric early lesions is not feasible. In contrast, both naturally-occurring and surgically-induced animal models of disease have been extensively studied, most notably in horses and swine, species in which OC is recognized to have profound health and economic implications. The potential for a translational model of human OC has not been recognized in the existing human literature. Objective The purpose of this review is to highlight the similarities in signalment, predilection sites and clinical presentation of naturally-occurring OC in humans and animals and to propose a common pathogenesis for this condition across species. Study Design Review Methods The published human and veterinary literature for the various manifestations of OC was reviewed. Peer-reviewed original scientific articles and species-specific review articles accessible in PubMed (US National Library of Medicine) were eligible for inclusion. Results A broad range of similarities exists between OC affecting humans and animals, including predilection sites, clinical presentation, radiographic/MRI changes, and histological appearance of the end stage lesion, suggesting a shared pathogenesis across species. Conclusion This proposed shared pathogenesis for OC between species implies that naturally-occurring and surgically-induced models of OC in animals may be useful in determining risk factors and for testing new diagnostic and therapeutic interventions that can be used in humans. PMID:23954774

  18. HER-2阳性炎性乳腺癌的靶向治疗进展%Progress in molecular targeted therapy for HER-2 positive inflammatory breast cancer

    Institute of Scientific and Technical Information of China (English)

    汪泽兴

    2013-01-01

    Human epidermal growth factor receptor-2( HER-2) positive inflammatory breast cancer is a very aggressive type of inflammatory breast cancer(IBC) with HER-2 over-expression or amplified. Clinically, such cancer is more aggressive and characterized by rapid local and systemic progression and overlying skin inflammation or discoloration without ulceration. With poor prognosis, but, combinations of neo-adjuvant systemic chemotherapy, surgery and radiation therapy, especially molecular targeted therapy can drastically alter the natural course of this disease. This article reviews the progress in molecular targeted therapy for HER-2 positive IBC in recent years.%原癌基因人类表皮生长因子受体2 (HER-2)阳性炎性乳腺癌是指HER-2过表达或扩增的炎性乳腺癌.临床上以乳房表面皮肤呈炎性改变而没有溃疡形成、局部及全身快速进展为特点,表现出更高的侵袭性.尽管炎性乳腺癌预后差,但新辅助化疗、手术及放疗等多学科综合治疗,尤其是分子靶向治疗显著改变了本病的自然进程.本文就近年来HER-2阳性炎性乳腺癌的分子靶向治疗进展作一综述.

  19. Interaction of flavonoids, the naturally occurring antioxidants with different media: a UV-visible spectroscopic study.

    Science.gov (United States)

    Naseem, Bushra; Shah, S W H; Hasan, Aurangzeb; Sakhawat Shah, S

    2010-04-01

    Quantitative parameters for interaction of flavonoids-the naturally occurring antioxidants, with solvents and surfactants are determined using UV-visible absorption spectroscopy. The availability of flavonoids; kaempferol, apigenin, kaempferide and rhamnetin in micelles of sodium dodecyl sulfate (SDS) is reflected in terms of partition coefficient, K(c). Thermodynamic calculations show that the process of transfer of flavonoid molecules to anionic micelles of SDS is energy efficient. A distortion in flavonoid's morphology occurs in case of kaempferol and apigenin in surfactant and water, exhibited in terms of a new band in the UV region of electronic spectra of these flavonoids. The partition coefficients of structurally related flavonoids are correlated with their antioxidant activities. Copyright 2010 Elsevier B.V. All rights reserved.

  20. Biologically active cis-cinnamic acid occurs naturally in Brassica parachinensis

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    The biologically active cis-cinnamic acid (cis-CA) has been perceived as a synthetic plant growth regulator for decades. However, in the present study, we found that cis-CA actually exists as a naturally occurring compound in a Brassica plant. This natural growth- regulating substance presents in both the sunlight-irradiated leaf tissue and the non-irradiated root tissue. The concentrations of cis-CA in both tissues are comparable to the biologically effective levels of those major plant hormones. The presence of cis-CA in root tissue suggests that it may be produced through both light-dependent and -independent path- ways or it can be transported from a plant organ to another.

  1. Naturally occurring variation in Arabidopsis: an underexploited resource for plant genetics.

    Science.gov (United States)

    Alonso-Blanco, C; Koornneef, M

    2000-01-01

    The definition of gene functions requires the phenotypic characterization of genetic variants. Currently, such functional analysis of Arabidopsis genes is based largely on laboratory-induced mutants that are selected in forward and reverse genetic studies. An alternative complementary source of genetic variation is available: the naturally occurring variation among accessions. The multigenic nature of most of this variation has limited its application until now. However, the use of genetic methods developed to map quantitative trait loci, in combination with the characteristics and resources available for molecular biology in Arabidopsis, allow this variation to be exploited up to the molecular level. Here, we describe the current tools available for the forward genetic analysis of this variation, and review the recent progress in the detection and mapping of loci and the cloning of large-effect genes.

  2. Leishmanicidal and cytotoxic activities of extracts and naturally-occurring compounds from two Lauraceae species.

    Science.gov (United States)

    Sánchez-Suárez, Jeysson; Coy-Barrera, Ericsson; Cuca, Luis Enrique; Delgado, Gabriela

    2011-02-01

    The in vitro leishmanicidal effects of ethanolic extracts and fifteen naturally-occurring compounds (five lignans, eight neolignans, a diterpene and a dihydrochalcone), obtained from Pleurothyrium cinereum and Ocotea macrophylla, were evaluated on promastigotes of Leishmania panamensis and L. braziliensis. In addition, in order to determine the selective action on Leishmania species as a safety principle, in vitro cytotoxicity on J774 cells was also evaluated for test compounds and extracts. One extract and seven compounds showed activity against Leishmania parasites at different levels. Dihydroflavokawin B (8) was found to be the most potent antileishmanial compound on both parasites, whilst (+)-otobaphenol (14), was found to be the most selective compound on L. panamensis.

  3. Ectomycorrhizal symbiosis in vitro between Tricholoma matsutake and Pinus densiflora seedlings that resembles naturally occurring 'shiro'.

    Science.gov (United States)

    Yamada, Akiyoshi; Maeda, Ken; Kobayashi, Hisayasu; Murata, Hitoshi

    2006-03-01

    We established an in vitro ectomycorrhizal symbiosis between Tricholoma matsutake and Pinus densiflora. Mycorrhiza formed in a substrate of Modified Norkrans' C medium and granite-based soil had features similar to those observed previously only in naturally occurring mycorrhizal system called 'shiro,' and promoted the growth of plants with smaller root/shoot ratios. The in vitro formation of 'shiro' is essential for the development of T. matsutake system to produce mushrooms and is useful for the propagation and plantation of the mycorrhizal seedlings.

  4. Characterization of naturally-occurring and modified fullerenes by Fourier transform mass spectrometry

    Science.gov (United States)

    Hettich, Robert L.; Jin, Changming; Compton, Robert N.; Buseck, Peter R.; Tsipursky, Semeon J.

    1993-10-01

    Fourier transform mass spectrometry (FTMS) employing both laser desorption/ionization and thermal desorption/electron ionization is useful for the detection and structural characterization of fullerenes and chemically-modified fullerenes. Examination of a carbon-rich shungite rock sample from Russia by transmission electron microscopy and FTMS provided evidence of naturally-occurring fullerenes. Ion-molecule reactions can be studied with FTMS to investigate the electron affinities of modified fullerenes. By monitoring charge exchange reactions, the electron affinities of C60Fx (x=44,46) and C70Fy (y=52,54) were found to be substantially higher than the values for the parent fullerenes.

  5. Naturally occurring bioactive Cyclobutane-containing (CBC) alkaloids in fungi, fungal endophytes, and plants.

    Science.gov (United States)

    Dembitsky, Valery M

    2014-10-15

    This article focuses on the occurrence and biological activities of cyclobutane-containing (CBC) alkaloids obtained from fungi, fungal endophytes, and plants. Naturally occurring CBC alkaloids are of particular interest because many of these compounds display important biological activities and possess antitumour, antibacterial, antimicrobial, antifungal, and immunosuppressive properties. Therefore, these compounds are of great interest in the fields of medicine, pharmacology, medicinal chemistry, and the pharmaceutical industry. Fermentation and production of CBC alkaloids by fungi and/or fungal endophytes is also discussed. This review presents the structures and describes the activities of 98 CBC alkaloids.

  6. Naturally occurring phenanthrene degrading bacteria associated with seeds of various plant species.

    Science.gov (United States)

    Fernet, Jennifer L; Lawrence, John R; Germida, James J

    2016-01-01

    Seeds of 11 of 19 plant species tested yielded naturally occurring phenanthrene degrading bacteria when placed on phenanthrene impression plates. Seed associated phenanthrene degrading bacteria were mostly detected on caragana, Canada thistle, creeping red fescue, western wheatgrass, and tall wheat grass. Based on 16S rRNA analysis the most common bacteria isolated from these seeds were strains belonging to the genera Enterobacteria, Erwinia, Burkholderia, Pantoea, Pseudomonas, and Sphingomonas. These plants may provide an excellent source of pre-adapted bacterial-plant associations highly suitable for use in remediation of contaminated soil environments.

  7. Occupational exposure due to naturally occurring radionuclide material in granite quarry industry.

    Science.gov (United States)

    Ademola, J A

    2012-02-01

    The potential occupational exposure in granite quarry industry due to the presence of naturally occurring radioactive material (NORM) has been investigated. The activity concentrations of (40)K, (226)Ra and (232)Th were determined using gamma-ray spectroscopy method. The annual effective dose of workers through different exposure pathways was determined by model calculations. The total annual effective dose varied from 21.48 to 33.69 μSv y(-1). Inhalation dose contributes the highest to the total effective dose. The results obtained were much lower than the intervention exemption levels (1.0 mSv y(-1)) given in the International Commission on Radiological Protection Publication 82.

  8. The new IAEA reference material: IAEA-434 technologically enhanced naturally occurring radioactive materials (TENORM) in phosphogypsum

    Energy Technology Data Exchange (ETDEWEB)

    Shakhashiro, A., E-mail: A.Shakhashiro@iaea.or [International Atomic Energy Agency, Agency' s Laboratories, Vienna International Center, PO Box 100, A-1400 Vienna (Austria); Sansone, U. [International Atomic Energy Agency, Agency' s Laboratories, Vienna International Center, PO Box 100, A-1400 Vienna (Austria); Wershofen, H. [Environmental Radioactivity, PTP, Braunschweig (Germany); Bollhoefer, A. [Environmental Radioactivity, Department of the Environment and Heritage, Darwin (Australia); Kim, C.K. [International Atomic Energy Agency, Agency' s Laboratories, Vienna International Center, PO Box 100, A-1400 Vienna (Austria); Kim, C.S. [Department of Environmental Radioactivity Assessment, Korea Institute of Nuclear Safety, Daejeon, Republic of Korea (Former collaborator) (Korea, Republic of); Kis-Benedek, G. [International Atomic Energy Agency, Agency' s Laboratories, Vienna International Center, PO Box 100, A-1400 Vienna (Austria); Korun, M. [Jozef Stefan Institute, Ljubljana (Slovenia); Moune, M. [LNE-LNHB, Laboratoire National Henri Becquerel, Gif-sur-Yvette Cedex (France); Lee, S.H. [Korea Research Institute of Standards and Science, Daejeon (Korea, Republic of); Tarjan, S. [Central Radiological Laboratory, Hungarian Agricultural Authority, Budapest (Hungary); Al-Masri, M.S. [Atomic Energy Commission of Syria, Damascus (Syrian Arab Republic)

    2011-01-15

    A reliable determination of Technologically Enhanced Naturally Occurring Radioactive Materials in phosphogypsum is necessary to comply with radiation protection and environmental regulations. In this respect, a new phosphogypsum reference material was produced and certified to assist in the validation of analytical methods and the quality assurance of produced analytical results. This paper presents the sample preparation methodology, material homogeneity assessment, characterization campaign results and assignment of property values, and associated uncertainties. The reference values and associated uncertainties for Pb-210, Ra-226, Th-230, U-234 and U-238 were established based on consensus values calculated from analytical results reported by three National Metrology Institutes and five expert laboratories.

  9. Activity measurements of technically enhanced naturally occurring radionuclides (TENORM) in phosphogypsum

    Energy Technology Data Exchange (ETDEWEB)

    Luca, A. [Horia Hulubei National Institute of Physics and Nuclear Engineering (IFIN-HH), 407 Atomistilor Street, P.O. Box MG-6, Postcode 077125, Magurele, Ilfov County (Romania)], E-mail: aluca@ifin.nipne.ro; Margineanu, R.; Sahagia, M.; Waetjen, A.C. [Horia Hulubei National Institute of Physics and Nuclear Engineering (IFIN-HH), 407 Atomistilor Street, P.O. Box MG-6, Postcode 077125, Magurele, Ilfov County (Romania)

    2009-05-15

    Phosphogypsum is a by-product of the phosphoric acid based fertilizer industry; it can be used in agriculture and to make building materials. Phosphogypsum is radioactive due to the presence of technically enhanced naturally occurring radionuclides (TENORM) and its environmental impact is a major concern of the public authorities. The Radionuclide Metrology Laboratory from IFIN-HH participated at the IAEA-CU-2007-06-CCRI(II)-S5 Supplementary Comparison for the Determination of TENORM in phosphogypsum. The measurement procedures and the discussion of results and problems encountered are presented.

  10. Bibliography of reports, papers, and presentations on naturally occurring radioactive material (NORM) in petroleum industry wastes

    Energy Technology Data Exchange (ETDEWEB)

    Smith, K.P.; Wilkey, M.L.; Hames, R.D.

    1997-07-01

    This bibliography was created to support projects conducted by Argonne National Laboratory (ANL) addressing issues related to naturally occurring radioactive material (NORM) in petroleum industry wastes. The bibliography provides citations for many of the available published reports, papers, articles, and presentations on petroleum industry NORM. In the past few years, the rapid expansion of NORM treatment and disposal technologies, the efforts to characterize NORM wastes and their associated potential risks, and the promulgation of state-level NORM regulatory programs have been well-documented in project reports and in papers presented at technical conferences and symposia. There are 221 citations.

  11. The new IAEA reference material: IAEA-434 technologically enhanced naturally occurring radioactive materials (TENORM) in phosphogypsum.

    Science.gov (United States)

    Shakhashiro, A; Sansone, U; Wershofen, H; Bollhöfer, A; Kim, C K; Kim, C S; Kis-Benedek, G; Korun, M; Moune, M; Lee, S H; Tarjan, S; Al-Masri, M S

    2011-01-01

    A reliable determination of Technologically Enhanced Naturally Occurring Radioactive Materials in phosphogypsum is necessary to comply with radiation protection and environmental regulations. In this respect, a new phosphogypsum reference material was produced and certified to assist in the validation of analytical methods and the quality assurance of produced analytical results. This paper presents the sample preparation methodology, material homogeneity assessment, characterization campaign results and assignment of property values, and associated uncertainties. The reference values and associated uncertainties for Pb-210, Ra-226, Th-230, U-234 and U-238 were established based on consensus values calculated from analytical results reported by three National Metrology Institutes and five expert laboratories.

  12. Activity measurements of technically enhanced naturally occurring radionuclides (TENORM) in phosphogypsum.

    Science.gov (United States)

    Luca, A; Margineanu, R; Sahagia, M; Wätjen, A C

    2009-05-01

    Phosphogypsum is a by-product of the phosphoric acid based fertilizer industry; it can be used in agriculture and to make building materials. Phosphogypsum is radioactive due to the presence of technically enhanced naturally occurring radionuclides (TENORM) and its environmental impact is a major concern of the public authorities. The Radionuclide Metrology Laboratory from IFIN-HH participated at the IAEA-CU-2007-06-CCRI(II)-S5 Supplementary Comparison for the Determination of TENORM in phosphogypsum. The measurement procedures and the discussion of results and problems encountered are presented.

  13. Synthesis and anti-cancer activity of naturally occurring 2,5-diketopiperazines.

    Science.gov (United States)

    Mollica, Adriano; Costante, Roberto; Fiorito, Serena; Genovese, Salvatore; Stefanucci, Azzurra; Mathieu, Veronique; Kiss, Robert; Epifano, Francesco

    2014-10-01

    Three naturally occurring oxyprenylated diketopiperazines were synthesized and preliminarily tested as growth inhibitory agents in vitro against various cancer cell lines. The compounds were tested on six human cancer cell lines with different sensitivity to proapoptotic stimuli using the MTT colorimetric assay. The data revealed that of the chemicals under study only deoxymicelianamide (11) displayed the highest activity, recording mean IC50 growth inhibitory values ranging from 2 to 23 μM. A comparative study with the non-geranylated saturated derivative of (11) revealed the importance of the presence of the geranyloxy side chain and the exocyclic 2,5-DPK double bond moiety for the observed activity.

  14. Her2+ and b-HCG Producing Undifferentiated Gastric Adenocarcinoma.

    Science.gov (United States)

    Eivaz-Mohammadi, Sahar; Gonzalez-Ibarra, Fernando; Abdul, Waheed; Tarar, Omer; Malik, Khurram; Syed, Amer K

    2014-01-01

    A 25-year-old Hispanic female with a history of anemia, schizoaffective disorder, and psychosis was admitted for anemia associated with fatigue, weakness, shortness of breath, night sweats, weight loss, and abdominal and lower back pain for the past two months. On routine management, she was found to have a positive serum b-HCG of 80.4 (0-5 mIU/mL) but the patient denied any sexual activity in her life. During her admission, U/S of the pelvis was noncontributory. CT angiogram of the chest was significant for prominent mediastinal and hilar lymph nodes, diffusely thickened stomach suggesting gastric malignancy with multiple hypoenhancing lesions in the liver and diffuse lytic lesions in the spine and sacrum suspicious for metastatic disease. The MRI of the abdomen confirmed the CT angiogram findings. After these findings, EGD was performed which showed lesions in the antrum, body of the stomach, fundus, and cardia on the lesser curvature of the stomach body correlating with carcinoma. The biopsy was positive for Her2, b-HCG producing poorly differentiated gastric adenocarcinoma. Patient underwent one successful round of chemotherapy with Taxotene, Cisplatin, and 5-FU for Stage IV gastric adenocarcinoma.

  15. Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer.

    LENUS (Irish Health Repository)

    Mohd Sharial, M S N

    2012-12-01

    Approximately 15%-23% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), which leads to the activation of signaling pathways that stimulate cell proliferation and survival. HER2-targeted therapy has substantially improved outcomes in patients with HER2-positive breast cancer. However, both de novo and acquired resistance are observed.

  16. Clinicopathologic significance of HER-2/neu protein expression and gene amplification in gastric carcinoma

    Institute of Scientific and Technical Information of China (English)

    Shi-Yan Yan; Ying Hu; Jian-Gao Fan; Guo-Quan Tao; Yong-Ming Lu; Xu Cai; Bao-Hua Yu; Yi-Qun Du

    2011-01-01

    AIM: To study the HER-2/neu protein expression and gene amplification in gastric carcinoma and their relation. METHODS: One hundred and forty-five formalin-fixed and paraffin- embedded tumor tissue samples from Chinese gastric carcinoma patients were studied with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) methods. Clinicopathologic data about all patients were collected. RESULTS: The levels of HER-2 3+, HER-2 2+ and HER2 1+ were measurable in 6.9%, 8.3% and 17.2% of the samples, respectively. No HER-2 was stained in 67.6% of the samples. FISH showed that HER-2 gene was amplified in 18 samples, 10 HER-2 3+ samples, 5 HER-2 2+ samples, and 3 HER-2 1+ samples with IHC staining. HER-2 status was not correlated with the sex and age of patients, and tumor size, location or differentiation, but with the depth of invasion, TNM stage, lymph node and distant metastasis as well as histopathological classification of gastric cancer (P < 0.05). CONCLUSION: All samples with IHC as HER-2 expression should be analyzed with FISH. Detection of HER-2 gene amplification can assess the malignant biological behaviors and prognosis of gastric cancer.

  17. Why is this effective HSP90 inhibitor not being developed in HER2+ breast cancer?

    Science.gov (United States)

    Arteaga, Carlos L

    2011-08-01

    Inhibition of the HSP90 chaperone leads to degradation of the HER2 receptor. The HSP90 inhibitor tanespimycin in combination with trastuzumab is active in patients with HER2-overexpressing metastatic breast cancer. This combination is one of several HER2-targeted therapies that will significantly improve the outcome of patients with this subtype of breast cancer.

  18. Prolyl isomerase Pin1 is highly expressed in Her2-positive breast cancer and regulates erbB2 protein stability

    Directory of Open Access Journals (Sweden)

    Lu Kun

    2008-12-01

    Full Text Available Abstract Overexpression of HER-2/Neu occurs in about 25–30% of breast cancer patients and is indicative of poor prognosis. While Her2/Neu overexpression is primarily a result of erbB2 amplification, it has recently been recognized that erbB2 levels are also regulated on the protein level. However, factors that regulate Her2/Neu protein stability are less well understood. The prolyl isomerase Pin1 catalyzes the isomerization of specific pSer/Thr-Pro motifs that have been phosphorylated in response to mitogenic signaling. We have previously reported that Pin1-catalyzed post-phosphorylational modification of signal transduction modulates the oncogenic pathways downstream from c-neu. The goal of this study was to examine the expression of prolyl isomerase Pin1 in human Her2+ breast cancer, and to study if Pin1 affects the expression of Her2/Neu itself. Methods Immunohistochemistry for Her2 and Pin1 were performed on two hundred twenty-three human breast cancers, with 59% of the specimen from primary cancers and 41% from metastatic sites. Pin1 inhibition was achieved using siRNA in Her2+ breast cancer cell lines, and its effects were studied using cell viability assays, immunoblotting and immunofluorescence. Results Sixty-four samples (28.7% stained positive for Her2 (IHC 3+, and 54% (122/223 of all breast cancers stained positive for Pin1. Of the Her2-positive cancers 40 (62.5% were also Pin1-positive, based on strong nuclear or nuclear and cytoplasmic staining. Inhibition of Pin1 via RNAi resulted in significant suppression of Her2-positive tumor cell growth in BT474, SKBR3 and AU565 cells. Pin1 inhibition greatly increased the sensitivity of Her2-positive breast cancer cells to the mTOR inhibitor Rapamycin, while it did not increase their sensitivity to Trastuzumab, suggesting that Pin1 might act on Her2 signaling. We found that Pin1 interacted with the protein complex that contains ubiquitinated erbB2 and that Pin1 inhibition accelerated erbB2

  19. Lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, downregulates thymidylate synthase by inhibiting the nuclear translocation of EGFR and HER2.

    Directory of Open Access Journals (Sweden)

    Hwang-Phill Kim

    Full Text Available BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI has been shown to exert a synergistic antitumor effect when combined with fluoropyrimidine. This synergy may be attributable to the downregulation of thymidylate synthase (TS, which is frequently overexpressed in fluoropyrimidine-resistant cancer cells. However, the molecular mechanism underlying the downregulation of TS has yet to be clearly elucidated. METHODOLOGY AND PRINCIPAL FINDINGS: In this study, we demonstrate that lapatinib, a dual TKI of EGFR and HER2 downregulates TS via inhibition of the nuclear translocation of EGFR and HER2. From our cDNA microarray experiments, we determined that a variety of nucleotide synthesis-related genes, including TS, were downregulated with lapatinib, and this was apparent in HER2-amplified cells. Targeted and pharmacologic inhibition assays confirmed that the dual inhibition of EGFR and HER2 is required for the more effective reduction of TS as compared to what was observed with gefitinib or trasutuzumab alone. Additionally, we determined that co-transfected EGFR and HER2 activate the TS gene promoter more profoundly than do either EGFR or HER2 alone. The translocation of EGFR and HER2 into the nucleus and the subsequent activation of the TS promoter were inhibited by lapatinib. CONCLUSIONS AND SIGNIFICANCE: These results demonstrate that lapatinib inhibits the nuclear translocation of EGFR and HER2 and downregulates TS, thus sensitizing cancer cells to fluoropyrimidine.

  20. Extracellular Matrix/Integrin Signaling Promotes Resistance to Combined Inhibition of HER2 and PI3K in HER2(+) Breast Cancer.

    Science.gov (United States)

    Hanker, Ariella B; Estrada, Mónica Valeria; Bianchini, Giampaolo; Moore, Preston D; Zhao, Junfei; Cheng, Feixiong; Koch, James P; Gianni, Luca; Tyson, Darren R; Sánchez, Violeta; Rexer, Brent N; Sanders, Melinda E; Zhao, Zhongming; Stricker, Thomas P; Arteaga, Carlos L

    2017-06-15

    PIK3CA mutations are associated with resistance to HER2-targeted therapies. We previously showed that HER2(+)/PIK3CA(H1047R) transgenic mammary tumors are resistant to the HER2 antibodies trastuzumab and pertuzumab but respond to PI3K inhibitor buparlisib (TPB). In this study, we identified mechanisms of resistance to combined inhibition of HER2 and PI3K. TPB-resistant tumors were generated by treating HER2(+)/PIK3CA(H1047R) tumor-bearing mice long term with the drug combination. RNA sequencing of TPB-resistant tumors revealed that extracellular matrix and cell adhesion genes, including collagen II (Col2a1), were markedly upregulated, accompanied by activation of integrin β1/Src. Cells derived from drug-resistant tumors were sensitive to TBP when grown in vitro, but exhibited resistance when plated on collagen or when reintroduced into mice. Drug resistance was partially reversed by the collagen synthesis inhibitor ethyl-3,4-dihydroxybenzoate. Inhibition of integrin β1/Src blocked collagen-induced resistance to TPB and inhibited growth of drug-resistant tumors. High collagen II expression was associated with significantly lower clinical response to neoadjuvant anti-HER2 therapy in HER2(+) breast cancer patients. Overall, these data suggest that upregulation of collagen/integrin/Src signaling contributes to resistance to combinatorial HER2 and PI3K inhibition. Cancer Res; 77(12); 3280-92. ©2017 AACR. ©2017 American Association for Cancer Research.

  1. AAV-mediated cone rescue in a naturally occurring mouse model of CNGA3-achromatopsia.

    Directory of Open Access Journals (Sweden)

    Ji-jing Pang

    Full Text Available Achromatopsia is a rare autosomal recessive disorder which shows color blindness, severely impaired visual acuity, and extreme sensitivity to bright light. Mutations in the alpha subunits of the cone cyclic nucleotide-gated channels (CNGA3 are responsible for about 1/4 of achromatopsia in the U.S. and Europe. Here, we test whether gene replacement therapy using an AAV5 vector could restore cone-mediated function and arrest cone degeneration in the cpfl5 mouse, a naturally occurring mouse model of achromatopsia with a CNGA3 mutation. We show that gene therapy leads to significant rescue of cone-mediated ERGs, normal visual acuities and contrast sensitivities. Normal expression and outer segment localization of both M- and S-opsins were maintained in treated retinas. The therapeutic effect of treatment lasted for at least 5 months post-injection. This study is the first demonstration of substantial, relatively long-term restoration of cone-mediated light responsiveness and visual behavior in a naturally occurring mouse model of CNGA3 achromatopsia. The results provide the foundation for development of an AAV5-based gene therapy trial for human CNGA3 achromatopsia.

  2. HIV-1 Tat and Viral Latency: What We Can Learn from Naturally Occurring Sequence Variations

    Science.gov (United States)

    Kamori, Doreen; Ueno, Takamasa

    2017-01-01

    Despite the effective use of antiretroviral therapy, the remainder of a latently HIV-1-infected reservoir mainly in the resting memory CD4+ T lymphocyte subset has provided a great setback toward viral eradication. While host transcriptional silencing machinery is thought to play a dominant role in HIV-1 latency, HIV-1 protein such as Tat, may affect both the establishment and the reversal of latency. Indeed, mutational studies have demonstrated that insufficient Tat transactivation activity can result in impaired transcription of viral genes and the establishment of latency in cell culture experiments. Because Tat protein is one of highly variable proteins within HIV-1 proteome, it is conceivable that naturally occurring Tat mutations may differentially modulate Tat functions, thereby influencing the establishment and/or the reversal of viral latency in vivo. In this mini review, we summarize the recent findings of Tat naturally occurring polymorphisms associating with host immune responses and we highlight the implication of Tat sequence variations in relation to HIV latency.

  3. Naturally occurring hybrids of coral reef butterflyfishes have similar fitness compared to parental species

    Science.gov (United States)

    Hobbs, Jean-Paul A.; Pratchett, Morgan S.; Bay, Line K.; van Herwerden, Lynne

    2017-01-01

    Hybridisation can produce evolutionary novelty by increasing fitness and adaptive capacity. Heterosis, or hybrid vigour, has been documented in many plant and animal taxa, and is a notable consequence of hybridisation that has been exploited for decades in agriculture and aquaculture. On the contrary, loss of fitness in naturally occurring hybrid taxa has been observed in many cases. This can have negative consequences for the parental species involved (wasted reproductive effort), and has raised concerns for species conservation. This study evaluates the relative fitness of previously documented butterflyfish hybrids of the genus Chaetodon from the Indo-Pacific suture zone at Christmas Island. Histological examination confirmed the reproductive viability of Chaetodon hybrids. Examination of liver lipid content showed that hybrid body condition was not significantly different from parent species body condition. Lastly, size at age data revealed no difference in growth rates and asymptotic length between hybrids and parent species. Based on the traits measured in this study, naturally occurring hybrids of Chaetodon butterflyfishes have similar fitness to their parental species, and are unlikely to supplant parental species under current environmental conditions at the suture zone. However, given sufficient fitness and ongoing genetic exchange between the respective parental species, hybrids are likely to persist within the suture zone. PMID:28257492

  4. AAV-mediated cone rescue in a naturally occurring mouse model of CNGA3-achromatopsia.

    Science.gov (United States)

    Pang, Ji-jing; Deng, Wen-Tao; Dai, Xufeng; Lei, Bo; Everhart, Drew; Umino, Yumiko; Li, Jie; Zhang, Keqing; Mao, Song; Boye, Sanford L; Liu, Li; Chiodo, Vince A; Liu, Xuan; Shi, Wei; Tao, Ye; Chang, Bo; Hauswirth, William W

    2012-01-01

    Achromatopsia is a rare autosomal recessive disorder which shows color blindness, severely impaired visual acuity, and extreme sensitivity to bright light. Mutations in the alpha subunits of the cone cyclic nucleotide-gated channels (CNGA3) are responsible for about 1/4 of achromatopsia in the U.S. and Europe. Here, we test whether gene replacement therapy using an AAV5 vector could restore cone-mediated function and arrest cone degeneration in the cpfl5 mouse, a naturally occurring mouse model of achromatopsia with a CNGA3 mutation. We show that gene therapy leads to significant rescue of cone-mediated ERGs, normal visual acuities and contrast sensitivities. Normal expression and outer segment localization of both M- and S-opsins were maintained in treated retinas. The therapeutic effect of treatment lasted for at least 5 months post-injection. This study is the first demonstration of substantial, relatively long-term restoration of cone-mediated light responsiveness and visual behavior in a naturally occurring mouse model of CNGA3 achromatopsia. The results provide the foundation for development of an AAV5-based gene therapy trial for human CNGA3 achromatopsia.

  5. Naturally Occurring Human Urinary Peptides for Use in Diagnosis of Chronic Kidney Disease*

    Science.gov (United States)

    Good, David M.; Zürbig, Petra; Argilés, Àngel; Bauer, Hartwig W.; Behrens, Georg; Coon, Joshua J.; Dakna, Mohammed; Decramer, Stéphane; Delles, Christian; Dominiczak, Anna F.; Ehrich, Jochen H. H.; Eitner, Frank; Fliser, Danilo; Frommberger, Moritz; Ganser, Arnold; Girolami, Mark A.; Golovko, Igor; Gwinner, Wilfried; Haubitz, Marion; Herget-Rosenthal, Stefan; Jankowski, Joachim; Jahn, Holger; Jerums, George; Julian, Bruce A.; Kellmann, Markus; Kliem, Volker; Kolch, Walter; Krolewski, Andrzej S.; Luppi, Mario; Massy, Ziad; Melter, Michael; Neusüss, Christian; Novak, Jan; Peter, Karlheinz; Rossing, Kasper; Rupprecht, Harald; Schanstra, Joost P.; Schiffer, Eric; Stolzenburg, Jens-Uwe; Tarnow, Lise; Theodorescu, Dan; Thongboonkerd, Visith; Vanholder, Raymond; Weissinger, Eva M.; Mischak, Harald; Schmitt-Kopplin, Philippe

    2010-01-01

    Because of its availability, ease of collection, and correlation with physiology and pathology, urine is an attractive source for clinical proteomics/peptidomics. However, the lack of comparable data sets from large cohorts has greatly hindered the development of clinical proteomics. Here, we report the establishment of a reproducible, high resolution method for peptidome analysis of naturally occurring human urinary peptides and proteins, ranging from 800 to 17,000 Da, using samples from 3,600 individuals analyzed by capillary electrophoresis coupled to MS. All processed data were deposited in an Structured Query Language (SQL) database. This database currently contains 5,010 relevant unique urinary peptides that serve as a pool of potential classifiers for diagnosis and monitoring of various diseases. As an example, by using this source of information, we were able to define urinary peptide biomarkers for chronic kidney diseases, allowing diagnosis of these diseases with high accuracy. Application of the chronic kidney disease-specific biomarker set to an independent test cohort in the subsequent replication phase resulted in 85.5% sensitivity and 100% specificity. These results indicate the potential usefulness of capillary electrophoresis coupled to MS for clinical applications in the analysis of naturally occurring urinary peptides. PMID:20616184

  6. Oocyst Discharge, Rumen Metabolism and Performance of Early Weaned Lambs with Naturally Occurring Coccidiosis Fed Monensin

    Science.gov (United States)

    Horton, G. M. J.; Stockdale, P. H. G.

    1981-01-01

    Ninety-six 9.5 kg early-weaned lambs with naturally occurring coccidiosis were fed monensin either at 0, 11, 22, or 33 mg/kg of feed for 105 days. Fecal oocyst discharge during the first three days was highest with monensin 22 mg, lowest with monensin 33 mg and averaged 149.6 × 103 oocysts per gram feces for all lambs. Monensin at 22 mg/kg of feed reduced Eimeria ninakohlyakimovae and E. ahsata oocyst discharge. Organic matter and crude protein digestibilities were highest (P ≤ 0.05) in lambs fed monensin 22 mg/kg of feed. Monensin increased (P ≤ 0.01) rumen ammonia and propionic acid and decreased (P ≤ 0.01) acetic acid. Feeding monensin 33 mg decreased (P ≤ 0.05) feed intake by 5% and had no effect on gain or feed efficiency. Optimal responses were observed with monensin at 11 mg, feed consumption was not affected, gains were 8% higher (P ≤ 0.05) and feed was utilized 9% more efficiently (P ≤ 0.05) than the controls. In conclusion, monensin was an effective therapeutic agent against naturally occurring coccidial infections in early weaned lambs. Performance responses were largest with monensin fed at the rate of 11 mg/kg of feed. PMID:7197187

  7. Harnessing naturally occurring tumor immunity: a clinical vaccine trial in prostate cancer.

    Directory of Open Access Journals (Sweden)

    Mayu O Frank

    Full Text Available BACKGROUND: Studies of patients with paraneoplastic neurologic disorders (PND have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC vaccine. METHODS AND FINDINGS: We have modeled PND tumor immunity in a clinical trial in which apoptotic allogeneic prostate tumor cells were used to generate an apoptotic tumor-autologous dendritic cell vaccine. Twenty-four prostate cancer patients were immunized in a Phase I, randomized, single-blind, placebo-controlled study to assess the safety and immunogenicity of this vaccine. Vaccinations were safe and well tolerated. Importantly, we also found that the vaccine was immunogenic, inducing delayed type hypersensitivity (DTH responses and CD4+ and CD8+ T cell proliferation, with no effect on FoxP3+ regulatory T cells. A statistically significant increase in T cell proliferation responses to prostate tumor cells in vitro (p = 0.002, decrease in prostate specific antigen (PSA slope (p = 0.016, and a two-fold increase in PSA doubling time (p = 0.003 were identified when we compared data before and after vaccination. CONCLUSIONS: An apoptotic cancer cell vaccine modeled on naturally occurring tumor immune responses in PND patients provides a safe and immunogenic tumor vaccine. TRIAL REGISTRATION: ClinicalTrials.gov NCT00289341.

  8. Inhibition of N-nitrosodiethylamine carcinogenesis in mice by naturally occurring organosulfur compounds and monoterpenes.

    Science.gov (United States)

    Wattenberg, L W; Sparnins, V L; Barany, G

    1989-05-15

    Naturally occurring compounds belonging to two chemical groups were studied for their capacities to inhibit N-nitrosodiethylamine (NDEA)-induced carcinogenesis in female A/J mice. One group consists of organosulfur compounds found in Allium species, including garlic, onions, leeks, and shallots, and the other, two monoterpenes, i.e., D-limonene and D-carvone. In an initial experiment, in which organosulfur compounds were investigated, diallyl disulfide, allyl mercaptan, and allyl methyl disulfide were found to produce a marked inhibition of NDEA-induced neoplasia of the forestomach when the test compounds were administered p.o. 96 and 48 h prior to NDEA. The most potent was diallyl disulfide which reduced forestomach tumor formation by more than 90%. Pulmonary adenoma formation also was inhibited but to a considerably lesser extent, i.e., about 30%. In three additional experiments, test compounds were given p.o. either 15 min or 1 h prior to NDEA. Under these conditions diallyl disulfide and allyl mercaptan again inhibited forestomach tumor formation substantially, i.e., greater than 75%, and pulmonary adenoma formation marginally, i.e., less than 20%. In these experiments D-limonene and D-carvone were tested and reduced forestomach tumor formation by slightly over 60% and pulmonary adenoma formation by about 35%. The results of these studies provide evidence of an increasing diversity of naturally occurring compounds having the capacity to inhibit nitrosamine carcinogenesis.

  9. High diversity of the fungal community structure in naturally-occurring Ophiocordyceps sinensis.

    Directory of Open Access Journals (Sweden)

    Yongjie Zhang

    Full Text Available BACKGROUND: Ophiocordyceps sinensis (syn. Cordyceps sinensis, which is a parasite of caterpillars and is endemic to alpine regions on the Tibetan Plateau, is one of the most valuable medicinal fungi in the world. "Natural O. sinensis specimens" harbor various other fungi. Several of these other fungi that have been isolated from natural O. sinensis specimens have similar chemical components and/or pharmaceutical effects as O. sinensis. Nevertheless, the mycobiota of natural O. sinensis specimens has not been investigated in detail. METHODOLOGY/PRINCIPAL FINDINGS: Based on the technique of PCR-single-strand conformation polymorphism (PCR-SSCP, the mycobiota of three different sections (stromata, sclerotia, and mycelial cortices from natural O. sinensis specimens were investigated using both culture-dependent and -independent methods. For the culture-dependent method, 572 fungal strains were isolated, and 92 putative operational taxonomic units (OTUs were identified from 226 sequenced strains with the threshold of 97%. For the culture-independent method, 490 fungal clones were identified from about 3000 clones of ITS fragments from the whole-community DNA; based on PCR-SSCP analyses, 266 of these clones were selected to be sequenced, and 118 putative OTUs were detected. The overwhelming majority of isolates/clones and OTUs were detected from mycelial cortices; only a few were detected from stromata and sclerotia. The most common OTUs detected with both methods belonged to Ascomycota; however, only 13 OTUs were detected simultaneously by both methods. Potential novel lineages were detected by each of the two methods. CONCLUSIONS/SIGNIFICANCE: A great number of fungal species present in the mycobiota of naturally-occurring O. sinensis specimens were detected, and many of them may represent undescribed lineages. That only a few of the same OTUs were detected by both methods indicated that different methods should be used. This study increased our

  10. Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression.

    Science.gov (United States)

    Li, Dan; Williams, Jon I; Pietras, Richard J

    2002-04-25

    Angiogenesis is important for growth and progression of ovarian cancers. Squalamine is a natural antiangiogenic sterol, and its potential role in treatment of ovarian cancers with or without standard cisplatin chemotherapy was assessed. Since HER-2 gene overexpression is associated with cisplatin resistance in vitro and promotion of tumor angiogenesis in vivo, the response of ovarian cancer cells with or without HER-2 gene overexpression to squalamine and cisplatin was evaluated both in tumor xenograft models and in tissue culture. Ovarian cancer cells with or without HER-2 overexpression were grown as subcutaneous xenografts in nude mice. Animals were treated by intraperitoneal injection with control vehicle, cisplatin, squalamine or cisplatin combined with squalamine. At the end of the experiment, tumors were assessed for tumor growth inhibition and for changes in microvessel density and apoptosis. Additional in vitro studies evaluated effects of squalamine on tumor and endothelial cell growth and on signaling pathways in human endothelial cells. Profound growth inhibition was elicited by squalamine alone and by combined treatment with squalamine and cisplatin for both parental and HER-2-overexpressing ovarian tumor xenografts. Immunohistochemical evaluation of tumors revealed decreased microvessel density and increased apoptosis. Although HER-2-overexpressing tumors had more angiogenic and less apoptotic activity than parental cancers, growth of both tumor types was similarly suppressed by treatment with squalamine combined with cisplatin. In in vitro studies, we found that squalamine does not directly affect proliferation of ovarian cells. However, squalamine significantly blocked VEGF-induced activation of MAP kinase and cell proliferation in human vascular endothelial cells. The results suggest that squalamine is anti-angiogenic for ovarian cancer xenografts and appears to enhance cytotoxic effects of cisplatin chemotherapy independent of HER-2 tumor status.

  11. Neuroanatomical distribution of abnormal prion protein in naturally occurring atypical scrapie cases in Great Britain.

    Science.gov (United States)

    Moore, Sarah Jo; Simmons, Marion; Chaplin, Melanie; Spiropoulos, John

    2008-11-01

    Scrapie belongs to a group of diseases known as the transmissible spongiform encephalopathies or prion diseases. Two different categories of naturally occurring scrapie have been identified: classical scrapie, which was first recorded around 1750, and atypical scrapie or 'Nor-98', which was first identified in Norway in 1998. The molecular characteristics of atypical scrapie have been well defined, but detailed descriptions of the neuropathological phenotype are rare since the majority of cases have been detected through active surveillance programmes where only brainstem and cerebellum are collected for statutory diagnosis. In order to characterise the neuropathology of naturally occurring atypical scrapie in sheep, we examined multiple brain levels from 15 whole brains from field cases of atypical scrapie, both clinical suspects and fallen stock, collected in Great Britain between 2004 and 2006. We found that the distribution of disease-associated prion protein (PrP(Sc)) and vacuolation in atypical scrapie cases are very different to both classical scrapie and experimental bovine spongiform encephalopathy in sheep. Immunolabelling for PrP(Sc) is mild and restricted at the obex and more intense and widespread rostrally, particularly in the cerebellum, substantia nigra, thalamus and basal nuclei. Intracellular immunolabelling types are not seen, but distinctive white matter immunolabelling is widespread. Vacuolation associated with PrP(Sc) deposits was not observed in the brainstem neuroanatomical areas commonly affected in classical scrapie and bovine spongiform encephalopathy, but was instead most prominent in the cerebellar cortex and neocortex. This is the largest comprehensive descriptive study of atypical scrapie pathology to date, and provides baseline data against which other natural or experimental cases can be compared. It also reinforces the current recommendation to collect cerebellum in addition to brainstem to enable confident confirmation of this

  12. Unravelling a 'miner's myth' that environmental contamination in mining towns is naturally occurring.

    Science.gov (United States)

    Kristensen, Louise Jane; Taylor, Mark Patrick

    2016-08-01

    Australia has a long history of metal mining and smelting. Extraction and processing have resulted in elevated levels of toxic metals surrounding mining operations, which have adverse health effects, particularly to children. Resource companies, government agencies and employees often construct 'myths' to down play potential exposure risks and responsibility arising from operating emissions. Typical statements include: contaminants are naturally occurring, the wind blows emissions away from residential areas, contaminants are not bioavailable, or the problem is a legacy issue and not related to current operations. Evidence from mining and smelting towns shows that such 'myths' are exactly that. In mining towns, the default and primary defence against contamination is that elevated metals in adjacent urban environments are from the erosion and weathering of the ore bodies over millennia-hence 'naturally occurring'. Not only is this a difficult argument to unravel from an evidence-based perspective, but also it causes confusion and delays remediation work, hindering efforts to reduce harmful exposures to children. An example of this situation is from Broken Hill, New South Wales, home to one of the world's largest lead-zinc-silver ore body, which has been mined continuously for over 130 years. Environmental metal concentration and lead isotopic data from soil samples collected from across Broken Hill are used to establish the nature and timing of lead contamination. We use multiple lines of evidence to unravel a 'miner's myth' by evaluating current soil metal concentrations and lead isotopic compositions, geological data, historical environmental assessments and old photographic evidence to assess the impacts from early smelting along with mining to the surface soils in the city.

  13. Fourier–transform infrared spectroscopic characterization of naturally occurring glassy fulgurites

    Indian Academy of Sciences (India)

    B J Saikia; G Parthasarathy; N C Sarmah; G D Baruah

    2008-04-01

    We report here for the first time the spectroscopic characterization of natural fulgurites of Garuamukh. On April 22, 2005 at 04 : 00 local time, large amounts of black-brown colour of colloidal solution came out from below the earth’s surface at Garuamukh near Nagaon town (latitude 26°20′39″N, longitude 92°41′39″E, Assam, India) with fire and smoke. This colloidal solution got transformed into fulgurites, glassy material, within a few hours. We present here the characterization of the fulgurites by Fourier transform infrared (FTIR) absorption, X-ray diffraction and X-ray fluorescence methods. The amorphous nature of the substance has been confirmed by Fourier transform infrared spectra of the fulgurites, which exhibit prominent absorption band in the region 400–1200 cm-1, the basic component of amorphous silica. The present study might have significant implications in understanding the thermodynamic properties of naturally occurring glasses, which are formed by shock metamorphism.

  14. Estrogen, progesterone and HER2 receptor expression in breast tumors of patients, and their usage of HER2-targeted therapy, in a tertiary care centre in India

    Directory of Open Access Journals (Sweden)

    J Ghosh

    2011-01-01

    Full Text Available Background: This study was undertaken to document the pattern of expression of estrogen (ER, progesterone (PR and human epidermal growth factor receptor-2 (HER2 and the usage of HER2-targeted therapy in a large tertiary care hospital in India in the year 2008. Materials and Methods: The histopathology reports of all breast cancer patients registered in the hospital in 2008 were extracted from the electronic medical record system. All the cases were immunohistochemically evaluated for estrogen and progesterone receptor status (ER and PR, and c-erbB-2 protein (HER2 expression using standard immunoperoxidase method. The use of HER2-targeted therapies was evaluated by extracting relevant information from the database of the hospital pharmacy and case charts of patients enrolled in ongoing approved trials. Results: A total of 2001 new patients of invasive breast cancers with available pathology reports were registered in the hospital in the year 2008. ER and/or PR expression was positive in tumors of 1025 (51.2% patients. HER2 3+ expression by immunohistochemistry (IHC was found in 335 (16.7% and HER2 2+ in 163 (8.1%. The triple negative phenotype was found in 596 (29.8% patients. An estimated 441 patients were eligible to receive HER2-targeted therapy based on their HER2 status. Of these 38 (8.6% patients received some form of HER2-targeted therapy; 20 patients (4.5% as part of ongoing clinical trials and 18 (4.1% as part of routine care. Conclusions: The overwhelming majority of patients eligible for HER2-targeted therapy in our institution are unable to receive it because of financial constraints and limited access to health insurance. There is a higher fraction of patients with the triple negative phenotype compared to the Western population.

  15. HER2 phosphorylates and destabilizes pro-apoptotic PUMA, leading to antagonized apoptosis in cancer cells.

    Science.gov (United States)

    Carpenter, Richard L; Han, Woody; Paw, Ivy; Lo, Hui-Wen

    2013-01-01

    HER2 is overexpressed in 15-20% of breast cancers. HER2 overexpression is known to reduce apoptosis but the underlying mechanisms for this association remain unclear. To elucidate the mechanisms for HER2-mediated survival, we investigated the relationship between HER2 and p53 upregulated modulator of apoptosis (PUMA), a potent apoptosis inducer. Our results showed that HER2 interacts with PUMA, which was independent of HER2 activation. In addition, we observed that HER2 interacted with PUMA in both mitochondrial and non-mitochondrial compartments. We next examined whether HER2 phosphorylates PUMA. Notably, PUMA tyrosine phosphorylation has never been reported. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life. To identify which of the three tyrosines within PUMA are targeted by HER2, we generated three PUMA non-phosphorylation mutants each with a single Tyr→Phe substitution. Results indicated that each PUMA single mutant had lost some, but not all phosphorylation by HER2 indicating that HER2 targets all three tyrosines. Consequently, we created an additional PUMA mutant with all three tyrosines mutated (TM-PUMA) that could not be phosphorylated by HER2. Importantly, TM-PUMA was found to have a longer half-life than PUMA. An inverse association was observed between HER2 and PUMA in 93 invasive breast carcinoma samples. We further found that TM-PUMA suppressed growth of breast cancer cells to a greater degree than PUMA. Also, TM-PUMA had a stronger propensity to induce apoptosis than PUMA. Together, our results demonstrate, for the first time, that PUMA can be tyrosine phosphorylated and that HER2-mediated phosphorylation destabilizes PUMA protein. The HER2-PUMA interplay represents a novel mechanism by which PUMA is regulated and a new molecular basis for HER2

  16. High-density SNP arrays improve detection of HER2 amplification and polyploidy in breast tumors

    DEFF Research Database (Denmark)

    Hansen, Thomas V. O.; Vikesaa, Jonas; Buhl, Sine S

    2015-01-01

    ) arrays can provide additional diagnostic power to assess HER2 gene status. METHODS: DNA from 65 breast tumor samples previously diagnosed by HER2 IHC and FISH analysis were blinded and examined for HER2 copy number variation employing SNP array analysis. RESULTS: SNP array analysis identified 24 (37......%) samples with selective amplification or imbalance of the HER2 region in the q-arm of chromosome 17. In contrast, only 15 (23%) tumors were found to have HER2 amplification by IHC and FISH analysis. In total, there was a discrepancy in 19 (29%) samples between SNP array and IHC/FISH analysis. In 12...

  17. Validation of a Fully Automated HER2 Staining Kit in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Cathy B. Moelans

    2010-01-01

    Full Text Available Background: Testing for HER2 amplification and/or overexpression is currently routine practice to guide Herceptin therapy in invasive breast cancer. At present, HER2 status is most commonly assessed by immunohistochemistry (IHC. Standardization of HER2 IHC assays is of utmost clinical and economical importance. At present, HER2 IHC is most commonly performed with the HercepTest which contains a polyclonal antibody and applies a manual staining procedure. Analytical variability in HER2 IHC testing could be diminished by a fully automatic staining system with a monoclonal antibody.

  18. The genomics and therapeutics of HER2-positive gastric cancer—from trastuzumab and beyond

    Science.gov (United States)

    Kelly, Ciara M.

    2016-01-01

    Gastric cancer is a biologically heterogeneous tumor. The identification of human epidermal growth factor receptor-2 (HER2) biomarker overexpression in gastric cancer represented a significant step towards unraveling the molecular complexity of this disease. Trastuzumab in combination with chemotherapy, in the first-line setting of patients with metastatic, HER2-positive gastric and gastroesophageal, represents the first targeted therapeutic to demonstrate improvement in response rate and survival in gastric cancer. However, not all patients with HER2-positive gastric cancer respond to trastuzumab and the majority of patients who do initially benefit from trastuzumab develop resistance to it. Advances in molecular oncology and cancer genomics have helped to classify gastric cancer into molecularly distinct subtypes. This information informs research efforts investigating the etiology of mechanisms of resistance to HER2-directed therapy and guides clinical investigation in methods to overcome this resistance. This article reviews anti-HER2-therapies that are currently used as standard of care in advanced, HER2-positive, breast cancer and are now under investigation as monotherapy and in combination with chemotherapy and/or a second HER2-directed agent in advanced HER2-positive gastric cancer. The future directions of clinical investigation in HER2-positive gastric cancer are also discussed including: novel HER2-directed therapies, the pharmacokinetics and pharmacodynamics of anti-HER2-therapies, the role of functional imaging, the potential of patient derived xenograft preclinical models and the importance of tumor genomic sequencing. PMID:27747089

  19. Quantitative Analysis of HER2 Receptor Expression In Vivo by Near-Infrared Optical Imaging

    Directory of Open Access Journals (Sweden)

    Victor Chernomordik

    2010-07-01

    Full Text Available Human epidermal growth factor receptor 2 (HER2 overexpression in breast cancers is associated with poor prognosis and resistance to therapy. Current techniques for estimating this important characteristic use ex vivo assays that require tissue biopsies. We suggest a novel noninvasive method to characterize HER2 expression in vivo, using optical imaging, based on HER2-specific probes (albumin-binding domain–fused-(ZHER2:3422-Cys Affibody molecules [Affibody AB, Solna, Sweden], labeled with Alexa Fluor 750 [Molecular Probes, Invitrogen, Carlsbad, CA] that could be used concomitantly with HER2-targeted therapy. Subcutaneous tumor xenografts, expressing different levels of HER2, were imaged with a near-infrared fluorescence small-animal imaging system at several times postinjection of the probe. The compartmental ligand-receptor model was used to calculate HER2 expression from imaging data. Correlation between HER2 amplification/overexpression in tumor cells and parameters, directly estimated from the sequence of optical images, was observed (eg, experimental data for BT474 xenografts indicate that initial slope, characterizing the temporal dependence of the fluorescence intensity detected in the tumor, linearly depends on the HER2 expression, as measured ex vivo by an enzyme-linked immunosorbent assay for the same tumor. The results obtained from tumors expressing different levels of HER2 substantiate a similar relationship between the initial slope and HER2 amplification/overexpression. This work shows that optical imaging, combined with mathematical modeling, allows noninvasive monitoring of HER2 expression in vivo.

  20. Affibody-displaying bionanocapsules for specific drug delivery to HER2-expressing cancer cells.

    Science.gov (United States)

    Shishido, Takuya; Mieda, Hiroaki; Hwang, Sang Youn; Nishimura, Yuya; Tanaka, Tsutomu; Ogino, Chiaki; Fukuda, Hideki; Kondo, Akihiko

    2010-10-01

    A novel HER2-targeted carrier was developed using bionanocapsules (BNCs). Bionanocapsules (BNCs) are 100-nm hollow nanoparticles composed of the L-protein of hepatitis B virus surface antigen. An affibody of HER2 was genetically displayed on the BNC surface (Z(HER2)-BNC). For the investigation of binding affinity, Z(HER2)-BNC was incubated with the cancer cell lines SK-BR-3 (HER2 positive), and MDA-MB-231 (HER2 negative). For analysis of HER2 targeting specificity, Z(HER2)-BNC or Z(WT)-BNC (without affibody) was incubated with both SK-BR-3 and MDA-MB-231 cells by time lapse and concentration. For the delivery of encapsulated molecules (calcein), fluorescence of Z(HER2)-BNC mixed with liposomes was also compared with that of Z(WT)-BNC and nude liposomes by incubation with SK-BR-3 cells. As a result, Z(HER2)-BNC-liposome complex demonstrated the delivery to HER2-expressing cells (SK-BR-3) with a high degree of specificity. This indicates that genetically engineered BNCs are promising carrier for cancer treatment.

  1. Effect of p95HER2/611CTF on the response to trastuzumab and chemotherapy.

    Science.gov (United States)

    Parra-Palau, Josep Lluís; Morancho, Beatriz; Peg, Vicente; Escorihuela, Marta; Scaltriti, Maurizio; Vicario, Rocio; Zacarias-Fluck, Mariano; Pedersen, Kim; Pandiella, Atanasio; Nuciforo, Paolo; Serra, Violeta; Cortés, Javier; Baselga, José; Perou, Charles M; Prat, Aleix; Rubio, Isabel T; Arribas, Joaquín

    2014-11-01

    Human epidermal growth factor receptor 2 (HER2)-positive breast cancers are currently treated with trastuzumab, an anti-HER2 antibody. About 30% of these tumors express a group of HER2 fragments collectively known as p95HER2. Our previous work indicated that p95HER2-positive tumors are resistant to trastuzumab monotherapy. However, recent results showed that tumors expressing the most active of these fragments, p95HER2/611CTF, respond to trastuzumab plus chemotherapy. To clarify this discrepancy, we analyzed the response to chemotherapy of cell lines transfected with p95HER2/611CTF and patient-derived xenografts (n = 7 mice per group) with different levels of the fragment. All statistical tests were two-sided. p95HER2/611CTF-negative and positive tumors showed different responses to various chemotherapeutic agents, which are particularly effective on p95HER2/611CTF-positive cells. Furthermore, chemotherapy sensitizes p95HER2/611CTF-positive patient-derived xenograft tumors to trastuzumab (mean tumor volume, trastuzumab alone: 906 mm(3), 95% confidence interval = 1274 to 538 mm(3); trastuzumab+doxorubicin: 259 mm(3), 95% confidence interval = 387 to 131 mm(3); P chemotherapy in p95HER2/611CTF-positive cells. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  2. HER2 Dimerization Inhibitor Pertuzumab - Mode of Action and Clinical Data in Breast Cancer.

    Science.gov (United States)

    Harbeck, Nadia; Beckmann, Matthias W; Rody, Achim; Schneeweiss, Andreas; Müller, Volkmar; Fehm, Tanja; Marschner, Norbert; Gluz, Oleg; Schrader, Iris; Heinrich, Georg; Untch, Michael; Jackisch, Christian

    2013-03-01

    The humanized monoclonal antibody pertuzumab prevents the dimerization of HER2 with other HER receptors, in particular the pairing of the most potent signaling heterodimer HER2/HER3, thus providing a potent strategy for dual HER2 inhibition. It binds to the extracellular domain of HER2 at a different epitope than trastuzumab. Pertuzumab and trastuzumab act in a complementary fashion and provide a more complete blockade of HER2-mediated signal transduction than either agent alone. Phase II studies demonstrated that pertuzumab was generally well tolerated as a single agent or in combination with trastuzumab and/or cytotoxic agents, and implied an improved clinical efficacy of the combination of pertuzumab and trastuzumab in early and advanced HER2-positive breast cancer. Results of the pivotal phase III study CLEOPATRA in patients with HER2-positive metastatic breast cancer demonstrated that the addition of pertuzumab to first-line combination therapy with docetaxel and trastuzumab significantly prolonged progression-free and overall survival without increasing cardiac toxicity. Currently, the combination of both antibodies is being explored in the palliative setting as well as in the treatment of early HER2-positive breast cancer. Dual HER2 inhibition with the HER2 dimerization inhibitor pertuzumab and trastuzumab may change clinical practice in HER2-positive first-line metastatic breast cancer treatment.

  3. Sarcosine induces increase in HER2/neu expression in androgen-dependent prostate cancer cells

    DEFF Research Database (Denmark)

    Dahl, Malin; Bouchelouche, Pierre; Kramer-Marek, Gabriela

    2011-01-01

    epithelial cells. The aim of this work was to investigate the effect of sarcosine on HER2/neu expression in prostate cancer cell lines LNCaP (androgen dependent), PC-3 and DU145 (both androgen independent). Relative amounts of HER2/neu and androgen receptor (AR) transcripts were determined using RT......Increasing evidence suggests that Human epidermal growth factor receptor 2 (HER2/neu) is involved in progression of prostate cancer. Recently, sarcosine was reported to be highly increased during prostate cancer progression, and exogenous sarcosine induces an invasive phenotype in benign prostate......-qPCR. Total expression of HER2/neu was confirmed by Western blot (WB). HER2/neu protein on the surface of living LNCaP cells was visualized by confocal microscopy using a HER2/neu-specific fluorescent probe. Exposure of LNCaP cells to 50 µM sarcosine for 24 h resulted in a 58% increase of the HER2/neu m...

  4. Sarcosine induces increase in HER2/neu expression in androgen-dependent prostate cancer cells

    DEFF Research Database (Denmark)

    Dahl, Malin; Bouchelouche, Pierre; Kramer-Marek, Gabriela

    2011-01-01

    epithelial cells. The aim of this work was to investigate the effect of sarcosine on HER2/neu expression in prostate cancer cell lines LNCaP (androgen dependent), PC-3 and DU145 (both androgen independent). Relative amounts of HER2/neu and androgen receptor (AR) transcripts were determined using RT......Increasing evidence suggests that Human epidermal growth factor receptor 2 (HER2/neu) is involved in progression of prostate cancer. Recently, sarcosine was reported to be highly increased during prostate cancer progression, and exogenous sarcosine induces an invasive phenotype in benign prostate......-qPCR. Total expression of HER2/neu was confirmed by Western blot (WB). HER2/neu protein on the surface of living LNCaP cells was visualized by confocal microscopy using a HER2/neu-specific fluorescent probe. Exposure of LNCaP cells to 50 μM sarcosine for 24 h resulted in a 58% increase of the HER2/neu m...

  5. Clinical Application of Fluorescence in Situ Hybridization (FISH) to Detect HER-2 Gene in Breast Cancer

    Institute of Scientific and Technical Information of China (English)

    Maurie Buehler; Ellie Guardino; Jung Sik Park; Eun Jeong Jang

    2014-01-01

    Objective: To investigate the clinical application of the detection of HER-2 gene by lfuorescence in situ hybridization (FISH) in breast cancer and the correlation between HER-2 gene ampliifcation and clinicopathology of breast cancer. Methods:Parafifn-embedded breast inifltrating ductal carcinoma from 48 patients were detected by FISH and immunohistochemistry (IHC) respectively for comparing the results of two methods. Results: HER-2 protein expressions were classified into three groups (3+/2+/1+ or 0) and the positive rates of HER-2 gene ampliifcation by FISH were 77.8%, 57.1% and 10.5%, respectively. Of the 29 cases with positive axillary lymph node, 12 were with HER-2 gene ampliifcation (P0.05). Conclusion:The false positive and negative rates are higher in HER-2 protein expression by IHC. Compared with IHC, FISH, being more effective and precise, can be applied extensively in clinic. HER-2 gene ampliifcation is concerned with axillary nodes metastases.

  6. Naturally occurring Parelaphostrongylus tenuis-associated choriomeningitis in a guinea pig with neurologic signs.

    Science.gov (United States)

    Southard, T; Bender, H; Wade, S E; Grunenwald, C; Gerhold, R W

    2013-05-01

    An adult male guinea pig (Cavia porcellus) with a 1-month history of hind limb paresis, torticollis, and seizures was euthanized and submitted for necropsy. Gross examination was unremarkable, but histologic examination revealed multifocal eosinophilic and lymphoplasmacytic choriomeningitis and cross sections of nematode parasites within the leptomeninges of the midbrain and diencephalon. Morphologic features of the nematode were consistent with a metastrongyle, and the parasite was identified as Parelaphostrongylus tenuis by polymerase chain reaction testing and nucleotide sequencing. Further questioning of the owner revealed that the guinea pig was fed grass from a yard often grazed by white-tailed deer (Odocoileus virginianus). To the authors' knowledge, this is the first report of a naturally occurring P. tenuis infection in a guinea pig.

  7. Characterization of naturally-occurring and modified fullerenes by Fourier transform mass spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Hettich, R.L.; Jin, C.; Compton, R.N. (Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831-6120 (United States)); Buseck, P.R.; Tsipursky, S.J. (Department of Geology, Arizona State University, Tempe, Arizona 85287 (United States))

    1993-10-10

    Fourier transform mass spectrometry (FTMS) employing both laser desorption/ionization and thermal desorption/electron ionization is useful for the detection and structural characterization of fullerenes and chemically-modified fullerenes. Examination of a carbon-rich shungite rock sample from Russia by transmission electron microscopy and FTMS provided evidence of naturally-occurring fullerenes. Ion-molecule reactions can be studied with FTMS to investigate the electron affinities of modified fullerenes. By monitoring charge exchange reactions, the electron affinities of C[sub 60]F[sub x] (x=44,46) and C[sub 70]F[sub y] (y=52,54) were found to be substantially higher than the values for the parent fullerenes.

  8. Morphologic studies of the pathogenesis of naturally occurring porcine circovirus type 2 diseases in pigs

    DEFF Research Database (Denmark)

    Hansen, Mette Sif

    of an outbreak of naturally occurring PCV2 associated reproductive failure in a Danish herd. In stillborn and Summary VIII mummified foetuses PCV2 was detected mainly in the heart and bone marrow, by IHC, and replication was detected in myocardiocytes, by ISH. The study showed that measurements of total....... • Manuscript IV is an update on the pathology and pathogens present in porcine respiratory disease complex (PRDC) in Danish finishing pigs. Multiple pathogens were detected, including PCV2, confirming the previously reported pathogen profile and multifactorial aetiology of PRDC. The histopathology was very......This Ph.D. thesis presents different aspects of porcine circovirus diseases (PCVDs), based upon work performed at The Faculty of Life Sciences, University of Copenhagen, Denmark and at The National Veterinary Institute, Technical University of Denmark. The introduction, chapter 1, briefly presents...

  9. Systems and methods for facilitating hydrogen storage using naturally occurring nanostructure assemblies

    Science.gov (United States)

    Fliermans; , Carl B.

    2012-08-07

    Some or all of the needs above can be addressed by embodiments of the invention. According to embodiments of the invention, systems and methods for facilitating hydrogen storage using naturally occurring nanostructure assemblies can be implemented. In one embodiment, a method for storing hydrogen can be provided. The method can include providing diatoms comprising diatomaceous earth or diatoms from a predefined culture. In addition, the method can include heating the diatoms in a sealed environment in the presence of at least one of titanium, a transition metal, or a noble metal to provide a porous hydrogen storage medium. Furthermore, the method can include exposing the porous hydrogen storage medium to hydrogen. In addition, the method can include storing at least a portion of the hydrogen in the porous hydrogen storage medium.

  10. Effect of Naturally Occurring nif Reiterations on Symbiotic Effectiveness in Rhizobium phaseoli

    Science.gov (United States)

    Romero, David; Singleton, Paul W.; Segovia, Lorenzo; Morett, Enrique; Bohlool, B. Ben; Palacios, Rafael; Dávila, Guillermo

    1988-01-01

    Most naturally occurring strains of Rhizobium phaseoli possess reiteration of the nif genes. Three regions contain nitrogenase structural genes in strain CFN42. Two of these regions (a and b) have copies of nifH, nifD, and nifK, whereas the third region (c) contains only nifH. Strains containing mutations in either nif region a or nif region b had significantly diminished symbiotic effectiveness compared with the wild-type strain on the basis of nodule mass, total nitrogenase activity per plant, nitrogenase specific activity, total nitrogen in the shoot, and percentage of nitrogen. A strain containing mutations in both nif region a and nif region b was totally ineffective. These data indicate that both nif region a and nif region b are needed for full symbiotic effectiveness in R. phaseoli. PMID:16347593

  11. Some Nutritional Characteristics of a Naturally Occurring Alga (Microcystis sp.) in a Guatemalan Lake

    Science.gov (United States)

    de la Fuente, Gabriel; Flores, Antonio; Molina, Mario R.; Almengor, Leticia; Bressani, Ricardo

    1977-01-01

    The nutritional characteristics of an alga (Microcystis sp.) that occurs naturally in a Guatemalan lake were determined. The sun-dried material proved to have a high protein content (55.6%) and to be a possible good source of calcium and phosphorus (1, 169.1 and 633.4 mg/100 mg, respectively). Amino acid analysis showed that total sulfur amino acids were the most deficient ones, giving a protein score of 42 to the material. The in vitro protein digestibility of the material was 69.5%. Biological trials demonstrated that when the material was offered as the only protein source, very low consumption and a high mortality rate were obtained whether or not the diet was supplemented with 0.4% dl-methionine. However, when the material supplied 25% of the total protein of a corn-algae diet, the protein quality of the cereal was significantly improved (P < 0.05). PMID:16345191

  12. Immunohistochemical detection of Brucella melitensis antigens in cases of naturally occurring abortions in sheep.

    Science.gov (United States)

    Ilhan, Fatma; Yener, Zabit

    2008-11-01

    Brucella melitensis, a worldwide zoonotic pathogen, is a significant cause of abortion in sheep and goats in some countries. The present study was carried out to determine, by immunohistochemistry, the presence of B. melitensis antigens in 110 naturally occurring aborted sheep fetuses. Sections of lung, liver, kidney, and spleen of each fetus were stained with immunoperoxidase to detect Brucella antigens. Brucella melitensis antigens were detected in 33 of 110 fetuses (30%). In the 33 positive cases, Brucella antigens were found in lung (25 [22.7%]), liver (21 [19%]), spleen (13 [11.8%]), and kidney (6 [5.4%]). Microscopic studies demonstrated that Brucella antigens were mainly located in the cytoplasm of macrophages and neutrophils of the lung, and in the cytoplasm of macrophages in the portal infiltrates and Kupffer cells of the liver. It was concluded that immunohistochemistry in formalin-fixed, paraffin-embedded tissues is a useful tool for the diagnosis of spontaneous ovine abortion caused by B. melitensis.

  13. Poly(anhydride-esters) comprised exclusively of naturally occurring antimicrobials and EDTA: antioxidant and antibacterial activities.

    Science.gov (United States)

    Carbone-Howell, Ashley L; Stebbins, Nicholas D; Uhrich, Kathryn E

    2014-05-12

    Carvacrol, thymol, and eugenol are naturally occurring phenolic compounds known to possess antimicrobial activity against a range of bacteria, as well as antioxidant activity. Biodegradable poly(anhydride-esters) composed of an ethylenediaminetetraacetic acid (EDTA) backbone and antimicrobial pendant groups (i.e., carvacrol, thymol, or eugenol) were synthesized via solution polymerization. The resulting polymers were characterized to confirm their chemical composition and understand their thermal properties and molecular weight. In vitro release studies demonstrated that polymer hydrolytic degradation was complete after 16 days, resulting in the release of free antimicrobials and EDTA. Antioxidant and antibacterial assays determined that polymer release media exhibited bioactivity similar to that of free compound, demonstrating that polymer incorporation and subsequent release had no effect on activity. These polymers completely degrade into components that are biologically relevant and have the capability to promote preservation of consumer products in the food and personal care industries via antimicrobial and antioxidant pathways.

  14. The corrosion inhibition of iron and aluminum by various naturally occurring biological molecules

    Energy Technology Data Exchange (ETDEWEB)

    McCafferty, E.; Hansen, D.C. [Naval Research Lab., Washington, DC (United States)

    1995-12-31

    Biological polymers that exhibit a strong affinity for metal surfaces are increasingly becoming the focus of research toward the development of environmentally friendly corrosion inhibitors. This paper deals with the use of various naturally occurring organic molecules as corrosion inhibitors for iron or aluminum. Among the organic molecules considered are catecholate and hydroxamate siderophores isolated from bacteria, the adhesive protein from the blue mussel Mytilus edulis L, and caffeic acid and chlorogenic acid. FTIR analysis, anodic polarization curves, and AC impedance measurements were used to determine the adsorption and effectiveness of the various organic molecules as corrosion inhibitors. Parabactin, a catecholate siderophore, was effective in inhibiting both the corrosion of iron in hydrochloric acid and the pitting of aluminum in 0.1 M sodium chloride. The adhesive protein from the blue mussel was also effective in inhibiting the pitting of aluminum.

  15. The effect of various naturally occurring metal-binding compounds on the electrochemical behavior of aluminum

    Energy Technology Data Exchange (ETDEWEB)

    Hansen, D.C.; McCafferty, E. [Naval Research lab., Washington, DC (United States)

    1996-01-01

    Naturally occurring biological molecules are of considerable interest as possible corrosion inhibitors because of increased attention on the development of environmentally compatible, nonpolluting corrosion inhibitors. A hydroxamate yeast siderophore (rhodotorulic acid), a catecholate bacterial siderophore (parabactin), an adhesive protein from the blue mussel Mytilus edulis, and two metal-binding compounds isolated from the tomato and sunflower roots, namely, chlorogenic and caffeic acid, respectively, were adsorbed from solution onto pure aluminum (99.9995%) and their effect on the critical pitting potential and polarization resistance in deaerated 0.1 M NaCl was measured. These measurements were made using anodic polarization and ac impedance spectroscopy. The catechol-containing siderophore has an inhibitive effect on the critical pitting potential of aluminum in 0.1 M NaCl and increases the polarization resistance of the metal over time. The adhesive protein from the blue mussel is also effective in inhibiting the pitting of aluminum.

  16. Technically enhanced naturally occurring radionuclides (TENORM) in phosphogypsum: Comparison CCRI(II)-S5

    Energy Technology Data Exchange (ETDEWEB)

    Shakhashiro, A.; Sansone, U.; Kim, C.K. [International Atomic Energy Agency, Agency' s Laboratories, Seibersdorf (Austria); Wershofen, H. [Environmental Radioactivity, PTB, Braunschweig (Germany); Bollhofer, A. [Environmental Radioactivity, Department of the Environment and Heritage, Darwin (Australia); Kim, C.S. [Department of Environmental Radioactivity Assessment, Korea Institute of Nuclear Safety, Daejeon (Korea, Republic of); Korun, M. [Jozef Stefan Institute, Ljubljana (Slovenia); Moune, M. [LNE-LNHB, Laboratoire National Henri Becquerel, 91 - Gif-sur-Yvette (France); Lee, S.H. [Korea Research Institute of Standards and Science, Daejeon (Korea, Republic of); Tarjan, S. [Central Radiological Laboratory, Hungarian Agricultural Authority, Budapest (Hungary)

    2010-10-15

    Within the frame of mutual cooperation between the IAEA and the BIPM, the Consultative Committee for Ionizing Radiation Section II-Measurement of Radionuclides accepted an IAEA-organized interlaboratory comparison in 2008 on the determination of technically enhanced naturally occurring radionuclides in phosphogypsum. The study was piloted by the Chemistry Unit at the IAEA's Laboratories in Seibersdorf (Austria). This report presents the methodology applied in conducting this comparison and the results. Activity results for Pb-210, Ra-226, Th-230, U-234, U-235 and U-238 were reported by three national metrology institutes (NMI) and five other expert laboratories or designated institutes. Four different approaches were used to calculate the nominal value of the reported results and associated uncertainties, and the results from each individual participant were evaluated and compared with this nominal reference value. The reported evaluation of the measurement results demonstrated agreement amongst the participating laboratories. (authors)

  17. Extraction and characterization of naturally occurring bioactive peptides from different tissues from Salmon (Salmo salar)

    DEFF Research Database (Denmark)

    Falkenberg, Susan Skanderup; Nielsen, Henrik Hauch

    2011-01-01

    (Free Radical Scavenging assay). A number of extracts showed high ACE inhibiting and anti-oxidative activity. The extracts were then size fractionated by ultrafiltration using a 10 kDa filter, and relevant fractions below 10 kDa from gills, skin and belly flap were further fractionated by gel...... number of bio-components such as bioactive peptides for this purpose. Tissue and proteins from e.g. fish gills, skin and viscera could be a new source of peptides that could have a nutritional and pharmaceutical value, and be used in health and functional foods and thereby increasing the value adding...... is therefore to extract and identify naturally occurring bioactive peptides from different tissues from salmon. A number of aqueous extracts were made from gills, skin and belly flap. In order to preserve the bioactivity of the peptides mild extraction procedures as acidic, basic and aqueous solutions were...

  18. Natural Competence of Xylella fastidiosa Occurs at a High Frequency Inside Microfluidic Chambers Mimicking the Bacterium's Natural Habitats

    Science.gov (United States)

    Kandel, Prem P.; Lopez, Samantha M.; Almeida, Rodrigo P. P.

    2016-01-01

    ABSTRACT Xylella fastidiosa is a xylem-limited bacterium that is the causal agent of emerging diseases in a number of economically important crops. Genetic diversity studies have demonstrated homologous recombination occurring among X. fastidiosa strains, which has been proposed to contribute to host plant shifts. Moreover, experimental evidence confirmed that X. fastidiosa is naturally competent for recombination in vitro. Here, as an approximation of natural habitats (plant xylem vessels and insect mouthparts), recombination was studied in microfluidic chambers (MCs) filled with media amended with grapevine xylem sap. First, different media were screened for recombination in solid agar plates using a pair of X. fastidiosa strains that were previously reported to recombine in coculture. The highest frequency of recombination was obtained with PD3 medium, compared to those with the other two media (X. fastidiosa medium [XFM] and periwinkle wilt [PW] medium) used in previous studies. Dissection of the media components led to the identification of bovine serum albumin as an inhibitor of recombination that was correlated to its previously known effect on inhibition of twitching motility. When recombination was performed in liquid culture, the frequencies were significantly higher under flow conditions (MCs) than under batch conditions (test tubes). The recombination frequencies in MCs and agar plates were not significantly different from each other. Grapevine xylem sap from both susceptible and tolerant varieties allowed high recombination frequency in MCs when mixed with PD3. These results suggest that X. fastidiosa has the ability to be naturally competent in the natural growth environment of liquid flow, and this phenomenon could have implications in X. fastidiosa environmental adaptation. IMPORTANCE Xylella fastidiosa is a plant pathogen that lives inside xylem vessels (where water and nutrients are transported inside the plant) and the mouthparts of insect

  19. Naturally occurring radioactive material (NORM) from a former phosphoric acid processing plant

    Energy Technology Data Exchange (ETDEWEB)

    Beddow, H. [Geoscience Building, School of Human and Environmental Sciences, Whiteknights, PO Box 227, University of Reading, Reading, Berkshire RG6 6AB (United Kingdom)]. E-mail: h.l.beddow@reading.ac.uk; Black, S. [Geoscience Building, School of Human and Environmental Sciences, Whiteknights, PO Box 227, University of Reading, Reading, Berkshire RG6 6AB (United Kingdom); Read, D. [Enterpris Ltd., Whiteknights, University of Reading, Reading, Berkshire RG6 6AB (United Kingdom); Department of Chemistry, University of Aberdeen, Meston Walk, Old Aberdeen AB24 3UE (United Kingdom)

    2006-07-01

    In recent years there has been an increasing awareness of the radiological impact of non-nuclear industries that extract and/or process ores and minerals containing naturally occurring radioactive material (NORM). These industrial activities may result in significant radioactive contamination of (by-) products, wastes and plant installations. In this study, scale samples were collected from a decommissioned phosphoric acid processing plant. To determine the nature and concentration of NORM retained in pipe-work and associated process plant, four main areas of the site were investigated: (1) the 'Green Acid Plant', where crude acid was concentrated; (2) the green acid storage tanks; (3) the Purified White Acid (PWA) plant, where inorganic impurities were removed; and (4) the solid waste, disposed of on-site as landfill. The scale samples predominantly comprise the following: fluorides (e.g. ralstonite); calcium sulphate (e.g. gypsum); and an assemblage of mixed fluorides and phosphates (e.g. iron fluoride hydrate, calcium phosphate), respectively. The radioactive inventory is dominated by {sup 238}U and its decay chain products, and significant fractionation along the series occurs. Compared to the feedstock ore, elevated concentrations ({<=}8.8 Bq/g) of {sup 238}U were found to be retained in installations where the process stream was rich in fluorides and phosphates. In addition, enriched levels ({<=}11 Bq/g) of {sup 226}Ra were found in association with precipitates of calcium sulphate. Water extraction tests indicate that many of the scales and waste contain significantly soluble materials and readily release radioactivity into solution.

  20. Urinary bladder cancer in dogs, a naturally occurring model for cancer biology and drug development.

    Science.gov (United States)

    Knapp, Deborah W; Ramos-Vara, José A; Moore, George E; Dhawan, Deepika; Bonney, Patty L; Young, Kirsten E

    2014-01-01

    Each year more than 65,000 people are diagnosed with urinary bladder cancer, and more than 14,000 people die from the disease in the United States. Studies in relevant animal models are essential to improve the management of bladder cancer. Naturally occurring bladder cancer in dogs very closely mimics human invasive bladder cancer, specifically high-grade invasive transitional cell carcinoma (TCC; also referred to as invasive urothelial carcinoma) in cellular and molecular features; biological behavior, including sites and frequency of metastasis; and response to therapy. Canine bladder cancer complements experimentally induced rodent tumors in regard to animal models of bladder cancer. Results of cellular and molecular studies and -omics analyses in dogs are expected to lead to improved detection of TCC and preneoplastic lesions, earlier intervention, better prediction of patient outcome, and more effective TCC management overall. Studies in dogs are being used to help define heritable risks (through very strong breed-associated risk) and environment risks and to evaluate prevention and treatment approaches that benefit humans as well as dogs. Clinical treatment trials in pet dogs with TCC are considered a win-win scenario by clinician scientists and pet owners. The individual dog benefits from effective treatment, the results are expected to help other dogs, and the findings are expected to ultimately help humans with TCC. This article provides an overview of canine TCC, a summary of the similarities and differences between canine and human invasive TCC, and examples of the types of valuable translational research that can be done using dogs with naturally occurring TCC.

  1. Characterization of naturally-occurring humoral immunity to AAV in sheep.

    Directory of Open Access Journals (Sweden)

    Joseph Tellez

    Full Text Available AAV vectors have shown great promise for clinical gene therapy (GT, but pre-existing human immunity against the AAV capsid often limits transduction. Thus, testing promising AAV-based GT approaches in an animal model with similar pre-existing immunity could better predict clinical outcome. Sheep have long been used for basic biological and preclinical studies. Moreover, we have re-established a line of sheep with severe hemophilia A (HA. Given the impetus to use AAV-based GT to treat hemophilia, we characterized the pre-existing ovine humoral immunity to AAV. ELISA revealed naturally-occurring antibodies to AAV1, AAV2, AAV5, AAV6, AAV8, and AAV9. For AAV2, AAV8, and AAV9 these inhibit transduction in a luciferase-based neutralization assay. Epitope mapping identified peptides that were common to the capsids of all AAV serotypes tested (AAV2, AAV5, AAV8 and AAV9, with each animal harboring antibodies to unique and common capsid epitopes. Mapping using X-ray crystallographic AAV capsid structures demonstrated that these antibodies recognized both surface epitopes and epitopes located within regions of the capsid that are internal or buried in the capsid structure. These results suggest that sheep harbor endogenous AAV, which induces immunity to both intact capsid and to capsid epitopes presented following proteolysis during the course of infection. In conclusion, their clinically relevant physiology and the presence of naturally-occurring antibodies to multiple AAV serotypes collectively make sheep a unique model in which to study GT for HA, and other diseases, and develop strategies to circumvent the clinically important barrier of pre-existing AAV immunity.

  2. Naturally occurring marine brominated indoles are aryl hydrocarbon receptor ligands/agonists.

    Science.gov (United States)

    DeGroot, Danica E; Franks, Diana G; Higa, Tatsuo; Tanaka, Junichi; Hahn, Mark E; Denison, Michael S

    2015-06-15

    The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates the toxic and biological effects of structurally diverse chemicals, including the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). As part of a larger effort to identify the full spectrum of chemicals that can bind to and activate the AhR, we have examined the ability of several naturally occurring marine-derived brominated indoles and brominated (methylthio)indoles (collectively referred to as brominated indoles) to bind to the AhR and stimulate AhR-dependent gene expression. Incubation of mouse, rat, and guinea pig recombinant cell lines containing a stably transfected AhR-responsive luciferase reporter gene with eight brominated indoles revealed that all compounds stimulated luciferase reporter gene activity, although some species-specific differences were observed. All compounds induced significantly more luciferase activity when incubated with cells for 4 h as compared to 24 h, demonstrating that these compounds are transient activators of the AhR signaling pathway. Three of the brominated indoles induced CYP1A1 mRNA in human HepG2 cells in vitro and Cyp1a mRNA in zebrafish embryos in vivo. The identification of the brominated indoles as direct ligands and activators/agonists of the AhR was confirmed by their ability to compete with [(3)H]TCDD for binding to the AhR and to stimulate AhR transformation and DNA binding in vitro. Taken together, these results indicate that marine-derived brominated indoles are members of a new class of naturally occurring AhR agonists.

  3. Naturally-Occurring Marine Brominated Indoles are Aryl Hydrocarbon Receptor Ligands/Agonists

    Science.gov (United States)

    DeGroot, Danica E.; Franks, Diana G.; Higa, Tatsuo; Tanaka, Junichi; Hahn, Mark E.; Denison, Michael S.

    2015-01-01

    The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates the toxic and biological effects of structurally diverse chemicals, including the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). As part of a larger effort to identify the full spectrum of chemicals that can bind to and activate the AhR, we have examined the ability of several naturally-occurring marine-derived brominated indoles and brominated (methylthio)indoles (collectively referred to as “brominated indoles”) to bind to the AhR and stimulate AhR-dependent gene expression. Incubation of mouse, rat and guinea pig recombinant cell lines containing a stably transfected AhR-responsive luciferase reporter gene with eight brominated indoles revealed that all compounds stimulated luciferase reporter gene activity, although some species-specific differences were observed. All compounds induced significantly more luciferase activity when incubated with cells for 4 h as compared to 24 h, demonstrating that these compounds are transient activators of the AhR signaling pathway. Three of the brominated indoles induced CYP1A1 mRNA in human HepG2 cells in vitro and Cyp1a mRNA in zebrafish embryos in vivo. The identification of the brominated indoles as direct ligands and activators/agonists of the AhR was confirmed by their ability to compete with [3H]TCDD for binding to the AhR and to stimulate AhR transformation and DNA binding in vitro. Taken together, these marine-derived brominated indoles are members of a new class of naturally-occurring AhR agonists. PMID:26001051

  4. Naturally occurring triggers that induce apoptosis-like programmed cell death in Plasmodium berghei ookinetes.

    Directory of Open Access Journals (Sweden)

    Medhat Ali

    Full Text Available Several protozoan parasites have been shown to undergo a form of programmed cell death that exhibits morphological features associated with metazoan apoptosis. These include the rodent malaria parasite, Plasmodium berghei. Malaria zygotes develop in the mosquito midgut lumen, forming motile ookinetes. Up to 50% of these exhibit phenotypic markers of apoptosis; as do those grown in culture. We hypothesised that naturally occurring signals induce many ookinetes to undergo apoptosis before midgut traversal. To determine whether nitric oxide and reactive oxygen species act as such triggers, ookinetes were cultured with donors of these molecules. Exposure to the nitric oxide donor SNP induced a significant increase in ookinetes with condensed nuclear chromatin, activated caspase-like molecules and translocation of phosphatidylserine that was dose and time related. Results from an assay that detects the potential-dependent accumulation of aggregates of JC-1 in mitochondria suggested that nitric oxide does not operate via loss of mitochondrial membrane potential. L-DOPA (reactive oxygen species donor also caused apoptosis in a dose and time dependent manner. Removal of white blood cells significantly decreased ookinetes exhibiting a marker of apoptosis in vitro. Inhibition of the activity of nitric oxide synthase in the mosquito midgut epithelium using L-NAME significantly decreased the proportion of apoptotic ookinetes and increased the number of oocysts that developed. Introduction of a nitric oxide donor into the blood meal had no effect on mosquito longevity but did reduce prevalence and intensity of infection. Thus, nitric oxide and reactive oxygen species are triggers of apoptosis in Plasmodium ookinetes. They occur naturally in the mosquito midgut lumen, sourced from infected blood and mosquito tissue. Up regulation of mosquito nitric oxide synthase activity has potential as a transmission blocking strategy.

  5. Analysis of naturally-occurring radionuclides in coal combustion fly ash, gypsum, and scrubber residue samples.

    Science.gov (United States)

    Roper, Angela R; Stabin, Michael G; Delapp, Rossane C; Kosson, David S

    2013-03-01

    Coal combustion residues from coal-fired power plants can be advantageous for use in building and construction materials. These by-products contain trace quantities of naturally occurring radionuclides from the uranium and thorium series, as well as other naturally occurring radionuclides such as K. Analysis was performed on samples of coal fly ash, flue gas desulfurization, gypsum and scrubber sludges, fixated scrubber sludges, and waste water filter cakes sampled from multiple coal-fired power plants in the United States. The radioactive content of U and Th decay series nuclides was determined using gamma photopeaks from progeny Pb at 352 keV and Tl at 583 keV, respectively; K specific activities were determined using the 1,461 keV photopeak. The samples were hermetically sealed to allow for secular equilibrium between the radium parents and the radon and subsequent progeny. Samples were analyzed in a common geometry using two high purity germanium photon detectors with low energy detection capabilities. The specific activities (Bq kg) were compared to results from literature studies including different building materials and fly ash specific activities. Fly ash from bituminous and subbituminous coals had U specific activities varying from 30-217 Bq kg (mean + 1 s.d. 119 ± 45 Bq kg) and 72-209 Bq kg (115 ± 40 Bq kg), respectively; Th specific activities from 10-120 Bq kg (73 ± 26 Bq kg) and 53-110 Bq kg (81 ± 18 Bq kg), respectively; and K specific activities from 177 to 928 Bq kg (569 ± 184 Bq kg) and 87-303 Bq kg (171 ± 69 Bq kg), respectively. Gypsum samples had U, Th, and K specific activities approximately one order of magnitude less than measured for fly ash samples.

  6. Naturally occurring MHR variants in Turkish patients infected with hepatitis B virus.

    Science.gov (United States)

    Sayiner, A Arzu; Ozcan, Ayla; Sengonul, Aylin

    2008-03-01

    Major B-cell epitopes are located at the major hydrophilic region (MHR) of hepatitis B virus (HBV) surface antigen (HBsAg). The genotypes, subtypes, and naturally occurring amino acid (aa) substitutions of MHR were analyzed in 81 Turkish adult patients (41 inactive HBsAg carriers and 40 patients with chronic hepatitis B) by direct sequencing of the S gene fragment. All the isolates were genotype D according to the phylogenetic analysis. The most common HBsAg subtype was ayw2, followed by ayw3 while one isolate specified ayw4 by encoding Leu127. MHR variants were detected in 22 of the 81 (27.2%) isolates. The prevalence was significantly higher in the chronic hepatitis B group (42.5%) compared to inactive HBsAg carriers (12.2%). Twenty-two samples had a total of 26 amino acid substitutions involving 14 positions. The majority of the patients had a single variation. Most of the amino acid substitutions were located at the HBs1 region of the MHR, while 9 of the 26 were in the classic "a" determinant (aa 124-147). When samples with "a" variants were evaluated by two different commercial HBsAg tests, only the isolate with Ser143Leu variation had a decreased reactivity in the assay using monoclonal antibodies for capture and detection. In conclusion, the findings of the study was in accordance with previous studies showing HBV genotype and subtype homogeneity (genotype D/ayw) in Turkey. Naturally occurring MHR and "a" determinant variants were common, especially among chronic hepatitis B patients. The influence of detected "a" variants on diagnostic assays was limited.

  7. Risk and protective factors for cats with naturally occurring chronic kidney disease.

    Science.gov (United States)

    Piyarungsri, Kakanang; Pusoonthornthum, Rosama

    2017-04-01

    Objectives Chronic kidney disease (CKD) is a significant disease in cats. Identifying risk and protective factors may help to prevent this significant disease. Methods An age-matched case-control study was performed to determine the risk factors in cats with naturally occurring CKD. Twenty-nine clinically normal cats aged ⩾5 years and 101 cats with naturally occurring CKD were studied. Risk factors were determined by interviewing cat owners from the Small Animal Hospital, Faculty of Veterinary Science, Chulalongkorn University, and veterinary hospitals in the Bangkok Metropolitan area, through questionnaires completed between June 2004 and November 2014. Univariable and multivariable analyses were performed using two independent proportional test methods and logistic regression analysis with backward elimination. Results Male sex (odd ratios [OR] 2.80, 95% confidence interval [CI] 1.02-8.87; P = 0.02), tap water (OR 3.43, 95% CI 1.08-11.45; P = 0.03) and an outdoor lifestyle (OR 3.77, 95% CI 1.03-17.99; P = 0.04) were associated with an increased risk for CKD. Commercial dry cat food (OR 0.06, 95% CI 0.02-0.17; P = 0.00), filtered water (OR 0.13, 95% CI 0.03-0.52; P = 0.01) and an indoor lifestyle (OR 0.28, 95% CI 0.07-0.98; P = 0.02) were associated with a decreased risk. Logistic regression analysis using backward elimination demonstrated that cats fed commercial dry cat food (OR 0.042, 95% CI 0.01-0.17; P = 0.00) had a decreased risk for CKD compared with cats on other types of diet. Conclusions and relevance Multivariable analysis found only feeding commercial dry cat food to be significant, suggesting that commercial dry cat food may be a potential protective factor for CKD in cats.

  8. Selective internalization of self-assembled artificial oil bodies by HER2/neu-positive cells

    Energy Technology Data Exchange (ETDEWEB)

    Chiang, Chung-Jen; Lin, Che-Chin [Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan (China); Lin, Li-Jen [School of Chinese Medicine, China Medical University, Taichung, Taiwan (China); Chang, Chih-Hsiang; Chao, Yun-Peng, E-mail: cjchiang@mail.cmu.edu.tw, E-mail: ypchao@fcu.edu.tw [Department of Chemical Engineering, Feng Chia University, Taichung, Taiwan (China)

    2011-01-07

    A novel delivery carrier was developed using artificial oil bodies (AOBs). Plant seed oil bodies (OBs) consist of a triacylglycerol matrix surrounded by a monolayer of phospholipids embedded with the storage protein oleosin (Ole). Ole consists of a central hydrophobic domain with two amphiphatic arms that extrude from the surface of OBs. In this study, a bivalent anti-HER2/neu affibody domain (ZH2) was fused with Ole at the C terminus. After overproduction in Escherichia coli, the fusion protein (Ole-ZH2) was recovered to assemble AOBs. The size of self-assembled AOBs was tailored by varying the oil/Ole-ZH2 ratio and pH to reach a nanoscale. Upon co-incubation with tumor cells, the nanoscale AOBs encapsulated with a hydrophobic fluorescence dye were selectively internalized by HER2/neu-overexpressing cells and displayed biocompatibility with the cells. In addition, the ZH2-mediated endosomal entry of AOBs occurred in a time- and AOB dose-dependent manner. The internalization efficiency was as high as 90%. The internalized AOBs disintegrated at the non-permissive pH (e.g. in acidic endosomes) and the cargo dye was released. Results of in vitro study revealed a sustained and prolonged release profile. Taken together, our findings indicate the potential of AOBs as a delivery carrier.

  9. Selective internalization of self-assembled artificial oil bodies by HER2/neu-positive cells

    Science.gov (United States)

    Chiang, Chung-Jen; Lin, Li-Jen; Lin, Che-Chin; Chang, Chih-Hsiang; Chao, Yun-Peng

    2011-01-01

    A novel delivery carrier was developed using artificial oil bodies (AOBs). Plant seed oil bodies (OBs) consist of a triacylglycerol matrix surrounded by a monolayer of phospholipids embedded with the storage protein oleosin (Ole). Ole consists of a central hydrophobic domain with two amphiphatic arms that extrude from the surface of OBs. In this study, a bivalent anti-HER2/neu affibody domain (ZH2) was fused with Ole at the C terminus. After overproduction in Escherichia coli, the fusion protein (Ole-ZH2) was recovered to assemble AOBs. The size of self-assembled AOBs was tailored by varying the oil/Ole-ZH2 ratio and pH to reach a nanoscale. Upon co-incubation with tumor cells, the nanoscale AOBs encapsulated with a hydrophobic fluorescence dye were selectively internalized by HER2/neu-overexpressing cells and displayed biocompatibility with the cells. In addition, the ZH2-mediated endosomal entry of AOBs occurred in a time- and AOB dose-dependent manner. The internalization efficiency was as high as 90%. The internalized AOBs disintegrated at the non-permissive pH (e.g. in acidic endosomes) and the cargo dye was released. Results of in vitro study revealed a sustained and prolonged release profile. Taken together, our findings indicate the potential of AOBs as a delivery carrier.

  10. Reorienting the Fab domains of trastuzumab results in potent HER2 activators.

    Directory of Open Access Journals (Sweden)

    Justin M Scheer

    Full Text Available The structure of the Fab region of antibodies is critical to their function. By introducing single cysteine substitutions into various positions of the heavy and light chains of the Fab region of trastuzumab, a potent antagonist of HER2, and using thiol chemistry to link the different Fabs together, we produced a variety of monospecific F(ab'(2-like molecules with activities spanning from activation to inhibition of breast tumor cell growth. These isomers (or bis-Fabs of trastuzumab, with varying relative spatial arrangements between the Fv-regions, were able to either promote or inhibit cell-signaling activities through the PI3K/AKT and MAPK pathways. A quantitative phosphorylation mapping of HER2 indicated that the agonistic isomers produced a distinct phosphorylation pattern associated with activation. This study suggests that antibody geometric isomers, found both in nature and during synthetic antibody development, can have profoundly different biological activities independent of their affinities for their target molecules.

  11. Ganoderma tsugae Extract Inhibits Growth of HER2-Overexpressing Cancer Cells via Modulation of HER2/PI3K/Akt Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Han-Peng Kuo

    2013-01-01

    Full Text Available Ganoderma, also known as Lingzhi or Reishi, has been used for medicinal purposes in Asian countries for centuries. It is a medicinal fungus with a variety of biological properties including immunomodulatory and antitumor activities. In this study, we investigated the molecular mechanisms by which Ganoderma tsugae (GT, one of the most common species of Ganoderma, inhibits the proliferation of HER2-overexpressing cancer cells. Here, we show that a quality assured extract of GT (GTE inhibited the growth of HER2-overexpressing cancer cells in vitro and in vivo and enhanced the growth-inhibitory effect of antitumor drugs (e.g., taxol and cisplatin in these cells. We also demonstrate that GTE induced cell cycle arrest by interfering with the HER2/PI3K/Akt signaling pathway. Furthermore, GTE curtailed the expression of the HER2 protein by modulating the transcriptional activity of the HER2 gene and the stability/degradation of the HER2 protein. In conclusion, this study suggests that GTE may be a useful adjuvant therapeutic agent in the treatment of cancer cells that highly express HER2.

  12. Intrinsic and Acquired Resistance to HER2-Targeted Therapies in HER2 Gene-Amplified Breast Cancer: Mechanisms and Clinical Implications

    Science.gov (United States)

    Rexer, Brent N.; Arteaga, Carlos L.

    2012-01-01

    Approximately 25% of human breast cancers overexpress the HER2 (ErbB2) proto-oncogene, which confers a more aggressive tumor phenotype and associates with a poor prognosis in patients with this disease. Two approved therapies targeting HER2, the monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib, are clinically active against this type of breast cancer. However, a significant fraction of patients with HER2+ breast cancer treated with these agents eventually relapse or develop progressive disease. This suggests that tumors acquire or possess intrinsic mechanisms of resistance that allow escape from HER2 inhibition. This review focuses on mechanisms of intrinsic and/or acquired resistance to HER2-targeted therapies that have been identified in preclinical and clinical studies. These mechanisms involve alterations to HER2 itself, coexpression or acquisition of bypass signaling through other receptor or intracellular signaling pathways, defects in mechanisms of cell cycle regulation or apoptosis, and host factors that may modulate drug response. Emerging clinical evidence already suggests that combinations of therapies targeting HER2 as well as these resistance pathways will be effective in overcoming or preventing resistance. PMID:22471661

  13. The MTAP-CDKN2A Locus Confers Susceptibility to a Naturally Occurring Canine Cancer

    Science.gov (United States)

    Shearin, Abigail L.; Hedan, Benoit; Cadieu, Edouard; Erich, Suzanne A.; Schmidt, Emmett V.; Faden, Daniel L.; Cullen, John; Abadie, Jerome; Kwon, Erika M.; Gröne, Andrea; Devauchelle, Patrick; Rimbault, Maud; Karyadi, Danielle M.; Lynch, Mary; Galibert, Francis; Breen, Matthew; Rutteman, Gerard R.; André, Catherine; Parker, Heidi G.; Ostrander, Elaine A.

    2012-01-01

    Background Advantages offered by canine population substructure, combined with clinical presentations similar to human disorders, makes the dog an attractive system for studies of cancer genetics. Cancers that have been difficult to study in human families or populations are of particular interest. Histiocytic sarcoma is a rare and poorly understood neoplasm in humans that occurs in 15–25% of Bernese Mountain Dogs (BMD). Methods Genomic DNA was collected from affected and unaffected BMD in North America (NA) and Europe. Both independent and combined genome wide association studies (GWAS) were used to identify cancer-associated loci. Fine mapping and sequencing narrowed the primary locus to a single gene region. Results Both populations shared the same primary locus, which features a single haplotype spanning MTAP and part of CDKN2A and is present in 96% of affected BMD. The haplotype is within the region homologous to human chromosome 9p21, which has been implicated in several types of cancer. Conclusions We present the first GWAS for HS in any species. The data identify an associated haplotype in the highly cited tumor suppressor locus near CDKN2A. These data demonstrate the power of studying distinctive malignancies in highly predisposed dog breeds. Impact Here, we establish a naturally-occurring model of cancer susceptibility due to CDKN2 dysregulation, thus providing insight regarding this cancer-associated, complex, and poorly understood genomic region. PMID:22623710

  14. Enhancing arsenic removal from groundwater at household level with naturally occurring iron

    Directory of Open Access Journals (Sweden)

    Anitha Kumari Sharma

    2016-06-01

    Full Text Available A supply of drinking water low in Arsenic (As prevents arsenic poisoning. The presence of high concentrations of iron (Fe in groundwater under the alluvial plains of the large rivers in Southeast Asia is a prerequisite for the simple removal of As. This study investigated the mechanisms and possibilities for enhancing As removal with naturally occurring Fe in a reliable, low cost and sustainable way. The results of the study show that As removal with Fe is greatly enhanced by the addition of an oxidizing agent (preferably KMnO4 immediately after the pumping of groundwater. Further enhancement of As removal in the presence of Fe can be achieved by adding a small volume of a concentrated basic solution of MnO4- and AlO2-, which has a combined oxidation, coagulation and buffering capacity. Best results were obtained when this solution was mixed with the groundwater immediately after its pumping until a pale pink color appeared. Maximum required reaction time was 10 minutes and subsequent filtration of the water was able to reduce the As concentration to near zero. Concentrations of MnO4- and AlO2- can be varied in the solution to achieve sufficient As removal to suit different Fe/As ratios and the presence of interfering co-occurring anions.

  15. Distribution of naturally occurring radionuclides (U, Th) in Timahdit black shale (Morocco)

    Energy Technology Data Exchange (ETDEWEB)

    Galindo, C. [Institut Pluridisciplinaire Hubert Curien, 23, rue du Loess BP28, 67037 Strasbourg Cedex 2 (France)]. E-mail: Catherine.galindo@ires.in2p3.fr; Mougin, L. [Institut Pluridisciplinaire Hubert Curien, 23, rue du Loess BP28, 67037 Strasbourg Cedex 2 (France); Fakhi, S. [Laboratoire de Radiochimie (LRC), Faculte des Sciences Ben M' sik, Casablanca (Morocco); Nourreddine, A. [Institut Pluridisciplinaire Hubert Curien, 23, rue du Loess BP28, 67037 Strasbourg Cedex 2 (France); Lamghari, A. [Laboratoire de Radiochimie (LRC), Faculte des Sciences Ben M' sik, Casablanca (Morocco); Hannache, H. [Laboratoire de Materiaux Thermo-Structuraux Faculte des Sciences Ben M' sik, Casablanca (Morocco)

    2007-07-01

    Attention has been focused recently on the use of Moroccan black oil shale as the raw material for production of a new type of adsorbent and its application to U and Th removal from contaminated wastewaters. The purpose of the present work is to provide a better understanding of the composition and structure of this shale and to determine its natural content in uranium and thorium. A black shale collected from Timahdit (Morocco) was analyzed by powder X-ray diffraction and SEM techniques. It was found that calcite, dolomite, quartz and clays constitute the main composition of the inorganic matrix. Pyrite crystals are also present. A selective leaching procedure, followed by radiochemical purification and {alpha}-counting, was performed to assess the distribution of naturally occurring radionuclides. Leaching results indicate that {sup 238}U, {sup 235}U, {sup 234}U, {sup 232}Th, {sup 23}Th and {sup 228}Th have multiple modes of occurrence in the shale. U is interpreted to have been concentrated under anaerobic conditions. An integrated isotopic approach showed the preferential mobilization of uranium carried by humic acids to carbonate and apatite phases. Th is partitioned between silicate minerals and pyrite.

  16. Distribution of naturally occurring radionuclides (U, Th) in Timahdit black shale (Morocco).

    Science.gov (United States)

    Galindo, C; Mougin, L; Fakhi, S; Nourreddine, A; Lamghari, A; Hannache, H

    2007-01-01

    Attention has been focused recently on the use of Moroccan black oil shale as the raw material for production of a new type of adsorbent and its application to U and Th removal from contaminated wastewaters. The purpose of the present work is to provide a better understanding of the composition and structure of this shale and to determine its natural content in uranium and thorium. A black shale collected from Timahdit (Morocco) was analyzed by powder X-ray diffraction and SEM techniques. It was found that calcite, dolomite, quartz and clays constitute the main composition of the inorganic matrix. Pyrite crystals are also present. A selective leaching procedure, followed by radiochemical purification and alpha-counting, was performed to assess the distribution of naturally occurring radionuclides. Leaching results indicate that 238U, 235U, 234U, 232Th, 230Th and 228Th have multiple modes of occurrence in the shale. U is interpreted to have been concentrated under anaerobic conditions. An integrated isotopic approach showed the preferential mobilization of uranium carried by humic acids to carbonate and apatite phases. Th is partitioned between silicate minerals and pyrite.

  17. Aberrant wound healing in the horse: naturally occurring conditions reminiscent of those observed in man.

    Science.gov (United States)

    Theoret, Christine L; Wilmink, Jacintha M

    2013-01-01

    Impaired wound healing represents an enormous clinical and financial problem for companion animals and humans alike. Unfortunately, most models used to study healing rely on rodents, which have significant differences in the healing and scarring process and rarely develop complications. In order to better simulate impaired healing, the model should strive to reproduce the natural processes of healing and delayed healing. Wounds on the limbs of horses display similarities to wounds in humans in their epithelialization/contraction ratio, genetic influence as well as dysregulated cytokine profile and the spontaneous development of fibroproliferative disorders. Veterinarians have access to advanced wound therapies that are often identical to those provided to human patients. Wound research in large animals has resulted in new wound models as well as a better understanding of the physiology, immunology, and local environmental impact on both normal and aberrant wound healing. One such model reproduces the naturally occurring fibroproliferative disorder of horses known as exuberant granulation tissue. Comparisons between the normally healing and impaired wounds provide insight into the repair process and can facilitate product development. A better understanding of the wound healing physiopathology based on clinically accurate animal models should lead to the development of novel therapies thereby improving outcomes in both human and veterinary patients. © 2013 by the Wound Healing Society.

  18. In vitro conversion of vinyl to formyl groups in naturally occurring chlorophylls.

    Science.gov (United States)

    Loughlin, Patrick C; Willows, Robert D; Chen, Min

    2014-08-14

    The chemical structural differences distinguishing chlorophylls in oxygenic photosynthetic organisms are either formyl substitution (chlorophyll b, d, and f) or the degree of unsaturation (8-vinyl chlorophyll a and b) of a side chain of the macrocycle compared with chlorophyll a. We conducted an investigation of the conversion of vinyl to formyl groups among naturally occurring chlorophylls. We demonstrated the in vitro oxidative cleavage of vinyl side groups to yield formyl groups through the aid of a thiol-containing compound in aqueous reaction mixture at room temperature. Heme is required as a catalyst in aqueous solution but is not required in methanolic reaction mixture. The conversion of vinyl- to formyl- groups is independent of their position on the macrocycle, as we observed oxidative cleavages of both 3-vinyl and 8-vinyl side chains to yield formyl groups. Three new chlorophyll derivatives were synthesised using 8-vinyl chlorophyll a as substrate: 8-vinyl chlorophyll d, [8-formyl]-chlorophyll a, and [3,8-diformyl]-chlorophyll a. The structural and spectral properties will provide a signature that may aid in identification of the novel chlorophyll derivatives in natural systems. The ease of conversion of vinyl- to formyl- in chlorophylls demonstrated here has implications regarding the biosynthetic mechanism of chlorophyll d in vivo.

  19. Naturally Occurring Self-Reactive CD4+CD25+ Regulatory T Cells: Universal Immune Code

    Institute of Scientific and Technical Information of China (English)

    Nafiseh Pakravan; Agheel Tabar Molla Hassan; Zuhair Muhammad Hassan

    2007-01-01

    Naturally occurring thymus-arisen CD4+CD25+ regulatory T (Treg) cells are considered to play a central role in self-tolerance. Precise signals that promote the development of Treg cells remain elusive, but considerable evidence suggests that costimulatory molecules, cytokines, the nature of the TCR and the niche or the context in which the T cell encounters antigen in the thymus play important roles. Analysis of TCR from Treg cells has demonstrated that a large proportion of this population has a higher avidity to self-antigen in comparison with TCR from CD4+CD25- cells and that peripheral antigen is required for their development, maintenance, or expansion. Treg cells have been shown to undergo expansion in the periphery, likely regulated by the presence of self-antigen. Many studies have shown that the involvement of Treg cells in the tolerance induction is antigen-specific, even with MHC-mismatched,in transplantation/graft versus host disease (GVHD), autoimmunity, cancer, and pregnancy. Theses studies concluded a vital role for self-reactive Treg cells in maintenance of the body integrity. Based on those studies, we hypothesize that self-reactive Treg cells are shared among all healthy individuals and recognize same self-antigens and their TCR encodes for few dominant antigens of each organ which defines the healthy self. These dominant self antigens can be regarded as "universal immune code".

  20. Acoustic surface perception from naturally occurring step sounds of a dexterous hexapod robot

    Science.gov (United States)

    Cuneyitoglu Ozkul, Mine; Saranli, Afsar; Yazicioglu, Yigit

    2013-10-01

    Legged robots that exhibit dynamic dexterity naturally interact with the surface to generate complex acoustic signals carrying rich information on the surface as well as the robot platform itself. However, the nature of a legged robot, which is a complex, hybrid dynamic system, renders the more common approach of model-based system identification impractical. The present paper focuses on acoustic surface identification and proposes a non-model-based analysis and classification approach adopted from the speech processing literature. A novel feature set composed of spectral band energies augmented by their vector time derivatives and time-domain averaged zero crossing rate is proposed. Using a multi-dimensional vector classifier, these features carry enough information to accurately classify a range of commonly occurring indoor and outdoor surfaces without using of any mechanical system model. A comparative experimental study is carried out and classification performance and computational complexity are characterized. Different feature combinations, classifiers and changes in critical design parameters are investigated. A realistic and representative acoustic data set is collected with the robot moving at different speeds on a number of surfaces. The study demonstrates promising performance of this non-model-based approach, even in an acoustically uncontrolled environment. The approach also has good chance of performing in real-time.

  1. Naturally-Occurring Entomopathogenic Fungi on Three Bark Beetle Species (Coleoptera: Curculionidae in Bulgaria

    Directory of Open Access Journals (Sweden)

    Slavimira A. Draganova

    2010-01-01

    Full Text Available Bark beetles (Coleoptera: Curculionidae: Scolytinae belong to one of the most damaging groups of forest insects and the activity of their natural enemies –pathogens, parasitoids,parasites or predators suppressing their population density,is of great importance. Biodiversity of entomopathogenic fungi on bark beetles in Bulgaria has been investigated sporadically. The aim of this preliminary study was to find, identify and study morphological characteristics of fungal entomopathogens naturally-occurring in populations of three curculionid species – Ips sexdentatus Boern, Ips typographus (L. and Dryocoetes autographus (Ratz.. Dead pest adults were found under the bark of Pinus sylvestris and Picea abies trees collectedfrom forests in the Maleshevska and Vitosha Mountains. Fungal pathogens were isolated into pure cultures on SDAY (Sabouraud dextrose agar with yeast extract and were identified based on morphological characteristics both on the host and in a culture.Morphological characteristics of the isolates were studied by phenotypic methods. The fungal isolates obtained from dead adults of Ips sexdentatus, Ips typographus and D. autographus were found to belong to the species Beauveria bassiana (Bals. – Criv. Vuillemin,Beauveria brongniartii (Saccardo Petch and Isaria farinosa (Holmsk. Fries (anamorph Ascomycota, Sordariomycetes: Hypocreales, Cordycipitaceae. Morphological traits of the isolates are described.

  2. The membrane integration of a naturally occurring alpha-helical hairpin.

    Science.gov (United States)

    Nagy, Akos; Turner, R James

    2007-05-04

    Helical hairpins, two closely spaced helical membrane spanning segments separated by a short surface turn, are thought to be common in integral membrane proteins. Here, we study the membrane integration of a naturally occurring helical hairpin from the secretory Na(+)-K(+)-2Cl(-) cotransporter NKCC1. This sequence is only slightly longer and significantly less hydrophobic than a previously identified minimal poly-leucine model hairpin structure. Using site directed mutagenesis we document the importance of the turn propensity of the amino acids in the intervening surface turn but, somewhat surprisingly, our results indicate that the formation of this natural hairpin apparently does not depend on specific helix-helix interactions. Our results suggest that helical hairpins may be formed quite readily from even minimally hydrophobic sequences separated by a short, sufficiently strong, turn signal, and that current methods for predicting integral membrane protein topology may miss many similar short helical hairpin sequences. Thus the occurrence of these structures may be much more common than presently thought.

  3. 3D pharmacophore-based virtual screening, docking and density functional theory approach towards the discovery of novel human epidermal growth factor receptor-2 (HER2) inhibitors.

    Science.gov (United States)

    Gogoi, Dhrubajyoti; Baruah, Vishwa Jyoti; Chaliha, Amrita Kashyap; Kakoti, Bibhuti Bhushan; Sarma, Diganta; Buragohain, Alak Kumar

    2016-12-21

    Human epidermal growth factor receptor 2 (HER2) is one of the four members of the epidermal growth factor receptor (EGFR) family and is expressed to facilitate cellular proliferation across various tissue types. Therapies targeting HER2, which is a transmembrane glycoprotein with tyrosine kinase activity, offer promising prospects especially in breast and gastric/gastroesophageal cancer patients. Persistence of both primary and acquired resistance to various routine drugs/antibodies is a disappointing outcome in the treatment of many HER2 positive cancer patients and is a challenge that requires formulation of new and improved strategies to overcome the same. Identification of novel HER2 inhibitors with improved therapeutics index was performed with a highly correlating (r=0.975) ligand-based pharmacophore model (Hypo1) in this study. Hypo1 was generated from a training set of 22 compounds with HER2 inhibitory activity and this well-validated hypothesis was subsequently used as a 3D query to screen compounds in a total of four databases of which two were natural product databases. Further, these compounds were analyzed for compliance with Veber's drug-likeness rule and optimum ADMET parameters. The selected compounds were then subjected to molecular docking and Density Functional Theory (DFT) analysis to discern their molecular interactions at the active site of HER2. The findings thus presented would be an important starting point towards the development of novel HER2 inhibitors using well-validated computational techniques.

  4. Potential involvement of Neospora caninum in naturally occurring ovine abortions in New Zealand.

    Science.gov (United States)

    Howe, L; Collett, M G; Pattison, R S; Marshall, J; West, D M; Pomroy, W E

    2012-04-30

    Neospora caninum is an obligate intracellular parasite and is recognised as the leading cause of bovine abortion worldwide. Natural infection with N. caninum has been described in sheep but it has generally not been regarded as a significant cause of abortion. Recently, there have been several New Zealand cases of foetal abortions where N. caninum was detected which strongly suggested the involvement of Neospora in these abortions. However, there is minimal information about the prevalence of N. caninum infection naturally occurring in New Zealand sheep flocks and particularly its impact on reproduction success. Thus, this present study provides preliminary data on the role that Neospora is playing in ovine reproductive failure by establishing the prevalence of N. caninum antibodies and DNA in ewe blood and foetal material present in 21 New Zealand sheep farms with ongoing unexplained abortion problems and 10 farms with consistently high fertility levels. The results of this study demonstrated an overall seroprevalence of 1.4% which varied between Aborting/non-pregnant (1.8%), age-matched pregnant controls (0.6%) and high fertility (2.1%) ewes. However, despite the variation observed, there was no statistical difference between the three groups. In addition, Neospora DNA was detected by PCR in 13% of submitted foetal brains and in ewe blood from aborting/non-pregnant (6.9%), age-matched pregnant controls (3.6%) and high fertility pregnant (2.1%) ewes. When the PCR results were considered with the IFAT and IDEXX ELISA results, there was no correlation between serology positive and PCR positive blood samples. Taken together, these results reveal that reliance on ELISA-based serology or PCR alone may underestimate the involvement of Neospora. Furthermore, determining the involvement of Neospora appears to require a multi-facetted approach where diagnostic methods and serological cut-off values may need to be adjusted as further information about the effect of natural

  5. Levels of naturally occurring gamma radiation measured in British homes and their prediction in particular residences

    Energy Technology Data Exchange (ETDEWEB)

    Kendall, G.M. [University of Oxford, Cancer Epidemiology Unit, Oxford (United Kingdom); Wakeford, R. [University of Manchester, Centre for Occupational and Environmental Health, Institute of Population Health, Manchester (United Kingdom); Athanson, M. [University of Oxford, Bodleian Library, Oxford (United Kingdom); Vincent, T.J. [University of Oxford, Childhood Cancer Research Group, Oxford (United Kingdom); Carter, E.J. [University of Worcester, Earth Heritage Trust, Geological Records Centre, Henwick Grove, Worcester (United Kingdom); McColl, N.P. [Public Health England, Centre for Radiation, Chemical and Environmental Hazards, Chilton, Didcot, Oxon (United Kingdom); Little, M.P. [National Cancer Institute, DHHS, NIH, Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, Bethesda, MD (United States)

    2016-03-15

    Gamma radiation from natural sources (including directly ionising cosmic rays) is an important component of background radiation. In the present paper, indoor measurements of naturally occurring gamma rays that were undertaken as part of the UK Childhood Cancer Study are summarised, and it is shown that these are broadly compatible with an earlier UK National Survey. The distribution of indoor gamma-ray dose rates in Great Britain is approximately normal with mean 96 nGy/h and standard deviation 23 nGy/h. Directly ionising cosmic rays contribute about one-third of the total. The expanded dataset allows a more detailed description than previously of indoor gamma-ray exposures and in particular their geographical variation. Various strategies for predicting indoor natural background gamma-ray dose rates were explored. In the first of these, a geostatistical model was fitted, which assumes an underlying geologically determined spatial variation, superimposed on which is a Gaussian stochastic process with Matern correlation structure that models the observed tendency of dose rates in neighbouring houses to correlate. In the second approach, a number of dose-rate interpolation measures were first derived, based on averages over geologically or administratively defined areas or using distance-weighted averages of measurements at nearest-neighbour points. Linear regression was then used to derive an optimal linear combination of these interpolation measures. The predictive performances of the two models were compared via cross-validation, using a randomly selected 70 % of the data to fit the models and the remaining 30 % to test them. The mean square error (MSE) of the linear-regression model was lower than that of the Gaussian-Matern model (MSE 378 and 411, respectively). The predictive performance of the two candidate models was also evaluated via simulation; the OLS model performs significantly better than the Gaussian-Matern model. (orig.)

  6. Enrichment and particle size dependence of polonium and other naturally occurring radionuclides in coal ash.

    Science.gov (United States)

    Sahu, S K; Tiwari, M; Bhangare, R C; Pandit, G G

    2014-12-01

    Coal fired thermal power contributes 70% of power in India. Coal fired power generation results in huge amounts of fly ash and bottom ash of varying properties. Coal, which contains the naturally occurring radionuclides, on burning results in enrichment of these radionuclides in the ashes. In the present study, coal, bottom ash and fly ash samples collected from six coal-fired power plants in India were measured for (210)Po using alpha spectrometry and for natural U, (226)Ra, (232)Th and (40)K by an HPGe γ-ray spectrometer. (210)Po in fly ash ranged from 25.7 to 70 Bq/kg with a mean value of 40.5 Bq/kg. The range and mean activities of (238)U, (226)Ra, (232)Th, (40)K in fly ash were 38.5-101 (78.1), 60-105.7 (79), 20-125 (61.7) and 43.6-200 (100) Bq/kg respectively. Fly ash and bottom ash contains two to five times more natural radionuclides than feed coal. The results were compared with the available data from earlier studies in other countries. The effect of particle size on enrichment factor of the nuclides in fly ash was studied. (210)Po showed the largest size dependence with its concentration favoring the smaller particle size while (232)Th showed least size dependence. (238)U and (226)Ra showed behavior intermediate to that of (210)Po and (232)Th. Also the correlation between sulfur content of the feed coal and activity of (210)Po was investigated. Increased sulfur content in feed coal enhanced enrichment of (210)Po in ash. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure

    Energy Technology Data Exchange (ETDEWEB)

    Azuma, Koichi [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Tsurutani, Junji, E-mail: tsurutani_j@dotd.med.kindai.ac.jp [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Sakai, Kazuko; Kaneda, Hiroyasu [Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Fujisaka, Yasuhito; Takeda, Masayuki [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Watatani, Masahiro [Department of Surgery, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Arao, Tokuzo [Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Satoh, Taroh; Okamoto, Isamu; Kurata, Takayasu [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Nishio, Kazuto [Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan); Nakagawa, Kazuhiko [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511 (Japan)

    2011-04-01

    Highlights: {yields} A lapatinib-resistant breast cancer cell line, UACC812 (UACC812/LR), was found to harbor amplification of the FGFR2 gene. {yields} Inhibition of the molecule by a specific inhibitor of FGFR dramatically induced growth inhibition accompanied by cell death. {yields} Immunohistochemical analysis of patients with HER2-positive breast cancer demonstrated an association between FGFR2 expression and poor outcome for lapatinib-containing chemotherapy. -- Abstract: Agents that target HER2 have improved the prognosis of patients with HER2-amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cells (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGFR2 and reduced expression of HER2, and a cell proliferation assay showed that the IC{sub 50} of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2-targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that FGFR-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer.

  8. Risk factors for disease progression in HER2-positive breast cancer patients based on the location of metastases

    Directory of Open Access Journals (Sweden)

    Joanna Huszno

    2015-09-01

    Full Text Available Introduction : Trastuzumab therapy significantly improves progression-free and overall survival in HER2-positive [HER2(+] breast cancer (BC patients. However, in most patients with HER2(+ metastatic BC, the disease progress occurred. The aim of this study was to evaluate the clinicopathological risk factors for progression in HER2-positive breast cancer patients during trastuzumab therapy. Material and methods : The analysis included medical records of HER2(+ metastatic BC patients treated with trastuzumab between 2006 and 2013. Results : The most common site of progression during trastuzumab therapy were lungs 25 (39%, central nervous system (CNS 8 (13%, skin 9 (14%, locoregional lymph nodes 19 (30%, liver 18 (28% and bone 17 (27%. Patients with lung metastases significantly more often had a history of cancer in the family than women with other metastasis sites (24% vs. 2.6%, p = 0.048. Metastases to lungs occurred also more often during therapy containing trastuzumab with chemotherapy than trastuzumab alone 17/8 (58% vs. 41%, p = 0.043. Central nervous system metastases were observed insignificantly more frequently in postmenopausal women than premenopausal patients 8/0 (22% vs. 0%, p = 0.093. There was reported a tendency to liver metastases in ER-negative tumors 13/20 (72% vs. 44%, p = 0.053. Bone metastases were associated with the positive steroid receptor status (p = 0.019 and second neoplasm in history (p = 0.06. Conclusions : Risk factors for disease progression were the menopausal status (CNS metastases, steroid receptor status (liver, lymph nodes and bone metastases, history of cancer in the family (lung metastases and history of cigarette smoking (liver metastases.

  9. α-linolenic acid and docosahexaenoic acid, alone and combined with trastuzumab, reduce HER2-overexpressing breast cancer cell growth but differentially regulate HER2 signaling pathways

    OpenAIRE

    2015-01-01

    Background Diets rich in the n-3 fatty acid alpha-linolenic acid (ALA) have been shown to reduce breast tumor growth, enhance the effectiveness of the HER2-targeted drug trastuzumab (TRAS) and reduce HER2 signaling in mouse models. It is unclear whether this is due to direct effects of ALA or due to its long-chain n-3 fatty acids metabolites including docosahexaenoic acid (DHA). Methods The ability of HER2-overexpressing BT-474 human breast cancer cells to convert ALA to long-chain n-3 fatty ...

  10. Biochanin A Modulates Cell Viability, Invasion, and Growth Promoting Signaling Pathways in HER-2-Positive Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Vikas Sehdev

    2009-01-01

    Full Text Available Overexpression of HER-2 receptor is associated with poor prognosis and aggressive forms of breast cancer. Scientific literature indicates a preventive role of isoflavones in cancer. Since activation of HER-2 receptor initiates growth-promoting events in cancer cells, we studied the effect of biochanin A (an isoflavone on associated signaling events like receptor activation, downstream signaling, and invasive pathways. HER-2-positive SK-BR-3 breast cancer cells, MCF-10A normal breast epithelial cells, and NIH-3T3 normal fibroblast cells were treated with biochanin A (2–100 μM for 72 hours. Subsequently cell viability assay, western blotting and zymography were carried out. The data indicate that biochanin A inhibits cell viability, signaling pathways, and invasive enzyme expression and activity in SK-BR-3 cancer cells. Biochanin A did not inhibit MCF-10A and NIH-3T3 cell viability. Therefore, biochanin A could be a unique natural anticancer agent which can selectively target cancer cells and inhibit multiple signaling pathways in HER-2-positive breast cancer cells.

  11. Study on the protein expression and amplification of HER2 gene in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Sunan Wang; Yingying Li; Zhengshun Xu; Wenzhao Zhao; Tian Yun; Wuling Zhu; Yangkun Wang

    2014-01-01

    Objective:The aim of the study was to investigate the human epidermal growth factor receptor 2 (HER2) gene amplification and protein expression and interpretation points in the stomach mixed carcinomas. Methods:Immunohisto-chemistry (IHC) and fluorescence in situ hybridization (FISH) technique were used to detect HER2 gene amplification and ex-pression of HER2 protein in 442 cases of gastric mixed carcinoma. Results:The expression rate of HER2 protein was 41.2%(182/442):the HER2 protein expression IHC 3+extensive type in 18 cases, partial type in 21 cases, focal type in 8 cases, accounting for 10.6%(47/442);the HER2 protein expression IHC 2+extensive type in 23 cases, partial type in 28 cases, focal type in 11 cases, accounting for 14.0%(62/442);the HER2 protein expression IHC 1+extensive type in 27 cases, partial type in 31 cases, focal type in 15 cases, accounting for 16.5%(73/442). HER2 gene amplification rate of 442 cases was 16.1%(71/442). In 182 cases of HER2 protein positive expression, the HER2 gene cluster amplification rate was 14.8%(27/182), large granular amplification rate 11.0%(20/182), punctate amplification rate 6.0%(11/182) and high polysomy 7.1%(13/182). In 71 cases of HER2 gene amplification, there was 42 cases of HER2 protein expression IHC 3+, 22 cases of HER2 protein expression IHC 2+, and 7 cases of IHC 1+. Conclusion:HER2 detection of gastric mixed carcinoma has great heterogeneity, HER2 protein positive expression is divided into extensive type, partial type and focal type, and HER2 gene positive amplifica-tion is divided into cluster amplification, large granular amplification, punctate amplification and high polysomy. These typing of HER2 protein expression and HER2 gene amplification provide reference index to quantify for targeted therapeutic ef ect of anticancer drugs.

  12. Serum HER-2 concentration is associated with insulin resistance and decreases after weight loss

    Directory of Open Access Journals (Sweden)

    Moreno-Navarrete José

    2010-02-01

    Full Text Available Abstract Background HER2/neu is a member of the epidermal growth factor receptor family easily detectable in the serum of cancer patients. We aimed to evaluate circulating HER-2 concentrations in association with insulin resistance in healthy and obese subjects. Methods Insulin sensitivity (minimal model and serum HER-2 concentrations were evaluated in a cross sectional study in men (cohort 1, n = 167 and longitudinally after weight loss in obese subjects (cohort 2, n = 30. Results Serum HER-2 concentrations were positively associated with BMI and waist circumference (both r = 0.18, p = 0.02, post-load glucose (r = 0.28, p = 0.001 and fasting triglycerides (r = 0.26, p = 0.001; and negatively associated with insulin sensitivity (r = -0.29, p = 0.002, n = 109. Subjects with type 2 diabetes showed significantly increased soluble serum HER-2 concentrations. In different multivariate regression models, fasting triglycerides emerged as the factor that independently contributed to 10-11% of serum HER-2 variance. Serum HER-2 concentrations correlated significantly with fasting triglycerides and insulin sensitivity index in subjects from cohort 2. Weight loss led to a significant decrease of serum HER-2 concentrations. The change in serum HER-2 concentrations were significantly associated with the change in percent body fat and fasting triglycerides in young (below the median age of the cohort subjects. Conclusions Serum HER-2 concentrations might be implicated in the pathophysiology of insulin resistance and associated comorbidities.

  13. Selective Disruption of Respiratory Supercomplexes as a New Strategy to Suppress Her2high Breast Cancer

    Science.gov (United States)

    Sachaphibulkij, Karishma; Stursa, Jan; Bezawork-Geleta, Ayenachew; Blecha, Jan; Endaya, Berwini; Werner, Lukas; Cerny, Jiri; Zobalova, Renata; Goodwin, Jacob; Spacek, Tomas; Alizadeh Pesdar, Elham; Yan, Bing; Nguyen, Maria Nga; Vondrusova, Magdalena; Sobol, Margaryta; Jezek, Petr; Hozak, Pavel; Truksa, Jaroslav; Dong, Lan-Feng

    2017-01-01

    Abstract Aims: Expression of the HER2 oncogene in breast cancer is associated with resistance to treatment, and Her2 may regulate bioenergetics. Therefore, we investigated whether disruption of the electron transport chain (ETC) is a viable strategy to eliminate Her2high disease. Results: We demonstrate that Her2high cells and tumors have increased assembly of respiratory supercomplexes (SCs) and increased complex I-driven respiration in vitro and in vivo. They are also highly sensitive to MitoTam, a novel mitochondrial-targeted derivative of tamoxifen. Unlike tamoxifen, MitoTam efficiently suppresses experimental Her2high tumors without systemic toxicity. Mechanistically, MitoTam inhibits complex I-driven respiration and disrupts respiratory SCs in Her2high background in vitro and in vivo, leading to elevated reactive oxygen species production and cell death. Intriguingly, higher sensitivity of Her2high cells to MitoTam is dependent on the mitochondrial fraction of Her2. Innovation: Oncogenes such as HER2 can restructure ETC, creating a previously unrecognized therapeutic vulnerability exploitable by SC-disrupting agents such as MitoTam. Conclusion: We propose that the ETC is a suitable therapeutic target in Her2high disease. Antioxid. Redox Signal. 26, 84–103. PMID:27392540

  14. Significance of HER2 protein examination in ductal carcinoma in situ.

    Science.gov (United States)

    Horimoto, Yoshiya; Tokuda, Emi; Arakawa, Atsushi; Kosaka, Taijiro; Saito, Mitsue; Kasumi, Fujio

    2011-05-15

    HER2 expression is routinely checked in ductal carcinoma in situ, as in invasive ductal carcinoma. However, the effect of HER2 status in ductal carcinoma in situ on the development of malignancy and the significance of overexpression of HER2 are still not clear. We experienced 103 cases that were diagnosed as pure ductal carcinoma in situ from operative specimens in the 2-y period from 2006 to 2007. We examined their HER2 status and other markers. We added 38 cases of ductal carcinoma in situ with small invasive disease 5mm or less in diameter as subjects. We also examined how accurately HER2 status in biopsy specimens predicted the existence of an invasive component. In pure ductal carcinoma in situ, tumors that were comedo type, high grade, or ER negative showed a high frequency of HER2 overexpression. In cases with small invasion, HER2 expression was higher than that in pure ductal carcinoma in situ. Among cases that were diagnosed as ductal carcinoma in situ by biopsy, 28% had invasive disease in operative specimens. In tumors that were palpable, large, or expressed HER2 3+ in biopsy samples, invasive disease was frequently observed in operative specimens. Overexpression of HER2 in ductal carcinoma in situ might not always be necessary for progression to invasive ductal carcinoma. To clarify the significance of HER2 examination in DCIS, further investigations of the potential for invasive ductal carcinoma and the prognosis are still needed. Copyright © 2011 Elsevier Inc. All rights reserved.

  15. Analysis of HER2 gene amplification using Differential PCR in breast cancer patients of Isfahan Province

    Directory of Open Access Journals (Sweden)

    Zohreh Hojati

    2014-10-01

    Full Text Available Background: Amplification of HER2 is seen in 20-30% of breast cancer cases. Measurement of HER2 gene amplification appears to be of vital importance in planning the treatment schedule for patients with breast carcinoma. The aim of our study was to evaluate HER2 amplification status in malignant and benign breast tumors by differential PCR (dPCR. Materials and Methods: The genomic DNA was extracted using the phenol/chloroform extraction procedure from 76 different breast tissues. Differential PCR was performed using the DNA samples isolated from fresh and paraffin- embedded breast cancer tissues. The relative copy number ratio of target gene (HER2 to control gene ( INF-γ was measured. dPCR products were then separated by electrophoresis using 2% agarose gel. The intensity of HER2 and INFγ bands were determined for each sample by ImageJ software. Results: According to the ratio between the band intensity of HER2 to INFγ in tumour and also normal samples, 7% and 26% rates of HER2 amplification were observed in benign and malignant samples respectively. The ratio showed a 2-5 fold increase in HER2 gene copy number for tissues with HER2 amplification whereas, a one-fold increase was found in other samples. Conclusion: Differential PCR provides a relatively rapid and inexpensive technique to assess the HER2 gene amplification, especially alongside immunohistochemistry as a routine assessing method .

  16. HER2 as a promising target for cytotoxicity T cells in human melanoma therapy.

    Directory of Open Access Journals (Sweden)

    Juan Ma

    Full Text Available Anti-HER2/neu antibody therapy has been reported to mediate tumor regression of HER2/ neu(+ tumors. Here we demonstrated the expression of HER2 in a wide range of human melanoma cells including a primary culture and seven cell lines, and we further investigated whether HER2 could be served as a target for T cell mediated immunotherapy of human melanoma. Specific cytolytic activity of activated T cells (ATC armed with anti-CD3 x anti-HER2 bispecific antibody (HER2Bi-Ab against Malme-3M-luc cells was evaluated by bioluminescent signal generated by luciferase reporter which did not alter HER2 expression or proliferation ability of Malme-3M cells. Contrast with unarmed ATC, increased cytotoxic activity of HER2Bi-armed ATC against Malme-3M-luc cells was observed at effector/target (E/T ratios of 1:1, 5:1, and 20:1. Moreover, HER2Bi-armed ATC expressed higher level of activation marker CD69 and secreted significantly higher level of IFN-γ than unarmed ATC counterpart at the E/T ratio of 20:1. In addition, compared with anti-HER2 mAb (Herceptin® or unarmed ATC, HER2Bi-armed ATC showed remarkable suppression effect on Malme-3M-luc tumor cells. Furthermore, in melanoma tumor cell xenograft mice, infusion of HER2Bi-armed ATC successfully inhibited the growth of melanoma tumors. The anti-tumor effect of HER2Bi-armed ATC may provide a promising immunotherapy for melanoma in the future.

  17. PTEN loss is associated with worse outcome in HER2-amplified breast cancer patients but is not associated with trastuzumab resistance

    Science.gov (United States)

    Stern, Howard M.; Gardner, Humphrey; Burzykowski, Tomasz; Elatre, Wafaa; O’Brien, Carol; Lackner, Mark R.; Pestano, Gary A.; Santiago, Angela; Villalobos, Ivonne; Eiermann, Wolfgang; Pienkowski, Tadeusz; Martin, Miguel; Robert, Nicholas; Crown, John; Nuciforo, Paolo; Bee, Valerie; Mackey, John; Slamon, Dennis J.; Press, Michael F.

    2015-01-01

    Purpose To investigate the clinical relevance of PTEN in HER2-amplified and HER2-non-amplified disease. Experimental Design We assessed PTEN status in two large adjuvant breast cancer trials (BCIRG-006 and BCIRG-005) using a PTEN IHC assay that was previously validated in a panel of 33 breast cancer cell lines and prostate cancer tissues with known PTEN gene deletion. Results In the HER2-positive patient population, absence of tumor cell PTEN staining occurred at a rate of 5.4% and was independent of ER/PR status. In contrast, 15.9% of HER2-negative patients exhibited absence of PTEN staining with the highest frequency seen in triple negative breast cancer (TNBC) subgroup versus ER/PR-positive patients (35.1% vs. 10.9%). Complete absence of PTEN staining in tumor cells was associated with poor clinical outcome in HER2-positive disease. Those patients whose cancers demonstrated absent PTEN staining had a significant decrease in disease-free survival (DFS) and overall survival (OS) compared to patients with tumors exhibiting any PTEN staining patterns (low, moderate or high). Trastuzumab appeared to provide clinical benefit even for patients lacking PTEN staining. In the HER2-negative population there were no statistically significant differences in clinical outcome based on PTEN status. Conclusions This study is the largest to date examining PTEN status in breast cancer and the data suggest that the rate and significance of PTEN status differ between HER2-positive and HER2-negative disease. Furthermore, the data clearly suggest that HER2-positive patients with PTEN loss still benefit from trastuzumab. PMID:25649019

  18. Mobilization of arsenic and other naturally occurring contaminants in groundwater of the Main Ethiopian Rift aquifers.

    Science.gov (United States)

    Rango, Tewodros; Vengosh, Avner; Dwyer, Gary; Bianchini, Gianluca

    2013-10-01

    This study investigates the mechanisms of arsenic (As) and other naturally occurring contaminants (F(-), U, V, B, and Mo) mobilization from Quaternary sedimentary aquifers of the Main Ethiopian Rift (MER) and their enrichment in the local groundwater. The study is based on systematic measurements of major and trace elements as well as stable oxygen and hydrogen isotopes in groundwater, coupled with geochemical and mineralogical analyses of the aquifer rocks. The Rift Valley aquifer is composed of rhyolitic volcanics and Quaternary lacustrine sediments. X-ray fluorescence (XRF) results revealed that MER rhyolites (ash, tuff, pumice and ignimbrite) and sediments contain on average 72 wt. % and 65 wt. % SiO2, respectively. Petrographic studies of the rhyolites indicate predominance of volcanic glass, sanidine, pyroxene, Fe-oxides and plagioclase. The As content in the lacustrine sediments (mean = 6.6 mg/kg) was higher than that of the rhyolites (mean: 2.5 mg/kg). The lacustrine aquifers of the Ziway-Shala basin in the northern part of MER were identified as high As risk zones, where mean As concentration in groundwater was 22.4 ± 33.5 (range of 0.60-190 μg/L) and 54% of samples had As above the WHO drinking water guideline value of 10 μg/L. Field As speciation measurements showed that most of the groundwater samples contain predominantly (~80%) arsenate-As(V) over arsenite-As(III) species. The As speciation together with field data of redox potential (mean Eh = +73 ± 65 mV) and dissolved-O2 (6.6 ± 2.2 mg/L) suggest that the aquifer is predominantly oxidative. Water-rock interactions, including the dissolution of volcanic glass produces groundwater with near-neutral to alkaline pH (range 6.9-8.9), predominance of Na-HCO3 ions, and high concentration of SiO2 (mean: 85.8 ± 11.3 mg/L). The groundwater data show high positive correlation of As with Na, HCO3, U, B, V, and Mo (R(2) > 0.5; p ~8, reflecting the pH-dependence of their mobilization. Based on the

  19. Molecular characterization of a naturally occurring intraspecific recombinant begomovirus with close relatives widespread in southern Arabia

    KAUST Repository

    Al-Saleh, Mohammed A

    2014-06-02

    Background: Tomato leaf curl Sudan virus (ToLCSDV) is a single-stranded DNA begomovirus of tomato that causes downward leaf curl, yellowing, and stunting. Leaf curl disease results in significant yield reduction in tomato crops in the Nile Basin. ToLCSDV symptoms resemble those caused by Tomato yellow leaf curl virus, a distinct and widespread begomovirus originating in the Middle East. In this study, tomato samples exhibiting leaf curl symptoms were collected from Gezira, Sudan. The associated viral genome was molecularly characterized, analyzed phylogenetically, and an infectious clone for one isolate was constructed. Findings. The complete genomes for five newly discovered variants of ToLCSDV, ranging in size from 2765 to 2767-bp, were cloned and sequenced, and subjected to pairwise and phylogenetic analyses. Pairwise analysis indicated that the five Gezira isolates shared 97-100% nucleotide identity with each other. Further, these variants of ToLCSDV shared their highest nucleotide identity at 96-98%, 91-95%, 91-92%, and 91-92% with the Shambat, Gezira, Oman and Yemen strains of ToLCSDV, respectively. Based on the high maximum nucleotide identities shared between these ToLCSDV variants from Gezira and other previously recognized members of this taxonomic group, they are considered isolates of the Shambat strain of ToLCSDV. Analysis of the complete genome sequence for these new variants revealed that they were naturally occurring recombinants between two previously reported strains of ToLCSDV. Finally, a dimeric clone constructed from one representative ToLCSV genome from Gezira was shown to be infectious following inoculation to tomato and N. benthamiana plants. Conclusion: Five new, naturally occurring recombinant begomovirus variants (>96% shared nt identity) were identified in tomato plants from Gezira in Sudan, and shown to be isolates of the Shambat strain of ToLCSDV. The cloned viral genome was infectious in N. benthamiana and tomato plants, and symptoms

  20. Characterization of naturally occurring airborne diacetyl concentrations associated with the preparation and consumption of unflavored coffee

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    Jennifer S. Pierce

    2015-01-01

    Full Text Available Diacetyl, a suspected cause of respiratory disorders in some food and flavorings manufacturing workers, is also a natural component of roasted coffee. We characterized diacetyl exposures that would plausibly occur in a small coffee shop during the preparation and consumption of unflavored coffee. Personal (long- and short-term and area (long-term samples were collected while a barista ground whole coffee beans, and brewed and poured coffee into cups. Simultaneously, long-term personal samples were collected as two participants, the customers, drank one cup of coffee each per h. Air sampling and analyses were conducted in accordance with OSHA Method 1012. Diacetyl was detected in all long-term samples. The long-term concentrations for the barista and area samples were similar, and ranged from 0.013–0.016 ppm; long-term concentrations for the customers were slightly lower and ranged from 0.010–0.014 ppm. Short-term concentrations ranged from below the limit of detection (<0.0047 ppm–0.016 ppm. Mean estimated 8 h time-weighted average (8 h TWA exposures for the barista ranged from 0.007–0.013 ppm; these values exceed recommended 8 h TWA occupational exposure limits (OELs for diacetyl and are comparable to long-term personal measurements collected in various food and beverage production facilities. The concentrations measured based on area sampling were comparable to those measured in the breathing zone of the barista, thus exceedances of the recommended OELs may also occur for coffee shop workers who do not personally prepare coffee (e.g., cashier, sanitation/maintenance. These findings suggest that the practicality and scientific basis of the recommended OELs for diacetyl merit further consideration.

  1. Naturally occurring mentoring in Japan and the United States: social roles and correlates.

    Science.gov (United States)

    Darling, Nancy; Hamilton, Stephen; Toyokawa, Teru; Matsuda, Sei

    2002-04-01

    Although the word "mentor"has traditionally been used to describe a relationship between an older adult and a younger person, recent work has extended its usage to relationships with peers and groups rather than with individuals and uncoupled the instrumental and affective qualities of the role. This paper examines (a) the extent to which adolescents' relationships with significant others in different social roles are characterized by mentoring and (b) the extent to which mentoring and other relationship functions covary. Adolescents' naturally occurring social relationships are explored in two very different contexts-Japan and the United States-that differ in the norms and patterning of social interactions. College students (N = 365) used questionnaires to describe the extent to which relations with significant others were characterized by mentoring. Results indicate striking similarity in the patterning of results in the two countries and support the traditional view of mentoring. Mentoring is most likely to occur in relationships with adults (especially parents), rather than with peers, and with same-gender, rather than other-gender associates. Mentoring by parents appears to covary with other aspects of positive relationships, but be more independent in relationships with unrelated adults or peers. Although more of the variability in experienced mentoring is attributed to differences between associates than to differences between adolescents in both the United States and Japan, this is especially true of the United States. Results suggest that although "classic" mentoring is most common in both countries, mentoring is somewhat less constrained by social role differences in Japan than is in the United States.

  2. Bordetella pertussis naturally occurring isolates with altered lipooligosaccharide structure fail to fully mature human dendritic cells.

    Science.gov (United States)

    Brummelman, Jolanda; Veerman, Rosanne E; Hamstra, Hendrik Jan; Deuss, Anna J M; Schuijt, Tim J; Sloots, Arjen; Kuipers, Betsy; van Els, Cécile A C M; van der Ley, Peter; Mooi, Frits R; Han, Wanda G H; Pinelli, Elena

    2015-01-01

    Bordetella pertussis is a Gram-negative bacterium and the causative agent of whooping cough. Despite high vaccination coverage, outbreaks are being increasingly reported worldwide. Possible explanations include adaptation of this pathogen, which may interfere with recognition by the innate immune system. Here, we describe innate immune recognition and responses to different B. pertussis clinical isolates. By using HEK-Blue cells transfected with different pattern recognition receptors, we found that 3 out of 19 clinical isolates failed to activate Toll-like receptor 4 (TLR4). These findings were confirmed by using the monocytic MM6 cell line. Although incubation with high concentrations of these 3 strains resulted in significant activation of the MM6 cells, it was found to occur mainly through interaction with TLR2 and not through TLR4. When using live bacteria, these 3 strains also failed to activate TLR4 on HEK-Blue cells, and activation of MM6 cells or human monocyte-derived dendritic cells was significantly lower than activation induced by the other 16 strains. Mass spectrum analysis of the lipid A moieties from these 3 strains indicated an altered structure of this molecule. Gene sequence analysis revealed mutations in genes involved in lipid A synthesis. Findings from this study indicate that B. pertussis isolates that do not activate TLR4 occur naturally and that this phenotype may give this bacterium an advantage in tempering the innate immune response and establishing infection. Knowledge on the strategies used by this pathogen in evading the host immune response is essential for the improvement of current vaccines or for the development of new ones.

  3. Persistence of naturally occurring antibiotic resistance genes in the bacteria and bacteriophage fractions of wastewater.

    Science.gov (United States)

    Calero-Cáceres, William; Muniesa, Maite

    2016-05-15

    The emergence and prevalence of antibiotic resistance genes (ARGs) in the environment is a serious global health concern. ARGs from bacteria can be mobilized by mobile genetic elements, and recent studies indicate that phages and phage-derived particles, among others, could play a role in the spread of ARGs through the environment. ARGs are abundant in the bacterial and bacteriophage fractions of water bodies and for successful transfer of the ARGs, their persistence in these environments is crucial. In this study, three ARGs (blaTEM, blaCTX-M and sul1) that naturally occur in the bacterial and phage fractions of raw wastewater were used to evaluate the persistence of ARGs at different temperatures (4 °C, 22 °C and 37 °C) and pH values (3, 7 and 9), as well as after various disinfection treatments (thermal treatment, chlorination and UV) and natural inactivation in a mesocosm. Gene copies (GC) were quantified by qPCR; then the logarithmic reduction and significance of the differences between their numbers were evaluated. The ARGs persisted for a long time with minimal reductions after all the treatments. In general, they showed greater persistence in the bacteriophage fraction than in the bacterial fraction. Comparisons showed that the ARGs persisted under conditions that reduced culturable Escherichia coli and infectious coliphages below the limit of detection. The prevalence of ARGs, particularly in the bacteriophage fraction, poses the threat of the spread of ARGs and their incorporation into a new bacterial background that could lead to the emergence of new resistant clones.

  4. Spectral analysis of naturally occurring methylxanthines (theophylline, theobromine and caffeine) binding with DNA.

    Science.gov (United States)

    Johnson, Irudayam Maria; Prakash, Halan; Prathiba, Jeyaguru; Raghunathan, Raghavachary; Malathi, Raghunathan

    2012-01-01

    Nucleic acids exist in a dynamic equilibrium with a number of molecules that constantly interact with them and regulate the cellular activities. The inherent nature of the structure and conformational integrity of these macromolecules can lead to altered biological activity through proper targeting of nucleic acids binding ligands or drug molecules. We studied the interaction of naturally occurring methylxanthines such as theophylline, theobromine and caffeine with DNA, using UV absorption and Fourier transform infrared (FTIR) spectroscopic methods, and especially monitored their binding affinity in the presence of Mg(2+) and during helix-coil transitions of DNA by temperature (T(m)) or pH melting profiles. The study indicates that all these molecules effectively bind to DNA in a dose dependent manner. The overall binding constants of DNA-theophylline = 3.5×10(3) M(-1), DNA-theobromine = 1.1×10(3) M(-1), and DNA-Caffeine = 3.8×10(3) M(-1). On the other hand T(m)/pH melting profiles showed 24-35% of enhanced binding activity of methylxanthines during helix-coil transitions of DNA rather than to its native double helical structure. The FTIR analysis divulged that theophylline, theobromine and caffeine interact with all the base pairs of DNA (A-T; G-C) and phosphate group through hydrogen bond (H-bond) interaction. In the presence of Mg(2+), methylxanthines altered the structure of DNA from B to A-family. However, the B-family structure of DNA remained unaltered in DNA-methylxanthines complexes or in the absence of Mg(2+). The spectral analyses indicated the order of binding affinity as "caffeine≥theophylline>theobromine" to the native double helical DNA, and "theophylline≥theobromine>caffeine to the denatured form of DNA and in the presence of divalent metal ions.

  5. Spectral analysis of naturally occurring methylxanthines (theophylline, theobromine and caffeine binding with DNA.

    Directory of Open Access Journals (Sweden)

    Irudayam Maria Johnson

    Full Text Available Nucleic acids exist in a dynamic equilibrium with a number of molecules that constantly interact with them and regulate the cellular activities. The inherent nature of the structure and conformational integrity of these macromolecules can lead to altered biological activity through proper targeting of nucleic acids binding ligands or drug molecules. We studied the interaction of naturally occurring methylxanthines such as theophylline, theobromine and caffeine with DNA, using UV absorption and Fourier transform infrared (FTIR spectroscopic methods, and especially monitored their binding affinity in the presence of Mg(2+ and during helix-coil transitions of DNA by temperature (T(m or pH melting profiles. The study indicates that all these molecules effectively bind to DNA in a dose dependent manner. The overall binding constants of DNA-theophylline = 3.5×10(3 M(-1, DNA-theobromine = 1.1×10(3 M(-1, and DNA-Caffeine = 3.8×10(3 M(-1. On the other hand T(m/pH melting profiles showed 24-35% of enhanced binding activity of methylxanthines during helix-coil transitions of DNA rather than to its native double helical structure. The FTIR analysis divulged that theophylline, theobromine and caffeine interact with all the base pairs of DNA (A-T; G-C and phosphate group through hydrogen bond (H-bond interaction. In the presence of Mg(2+, methylxanthines altered the structure of DNA from B to A-family. However, the B-family structure of DNA remained unaltered in DNA-methylxanthines complexes or in the absence of Mg(2+. The spectral analyses indicated the order of binding affinity as "caffeine≥theophylline>theobromine" to the native double helical DNA, and "theophylline≥theobromine>caffeine to the denatured form of DNA and in the presence of divalent metal ions.

  6. Corticosterone regulates both naturally occurring and cocaine-induced dopamine signaling by selectively decreasing dopamine uptake.

    Science.gov (United States)

    Wheeler, Daniel S; Ebben, Amanda L; Kurtoglu, Beliz; Lovell, Marissa E; Bohn, Austin T; Jasek, Isabella A; Baker, David A; Mantsch, John R; Gasser, Paul J; Wheeler, Robert A

    2017-10-01

    Stressful and aversive events promote maladaptive reward-seeking behaviors such as drug addiction by acting, in part, on the mesolimbic dopamine system. Using animal models, data from our lab and others show that stress and cocaine can interact to produce a synergistic effect on reward circuitry. This effect is also observed when the stress hormone corticosterone is administered directly into the nucleus accumbens (NAc), indicating that glucocorticoids act locally in dopamine terminal regions to enhance cocaine's effects on dopamine signaling. However, prior studies in behaving animals have not provided mechanistic insight. Using fast-scan cyclic voltammetry, we examined the effect of systemic corticosterone on spontaneous dopamine release events (transients) in the NAc core and shell in behaving rats. A physiologically relevant systemic injection of corticosterone (2 mg/kg i.p.) induced an increase in dopamine transient amplitude and duration (both voltammetric measures sensitive to decreases in dopamine clearance), but had no effect on the frequency of transient release events. This effect was compounded by cocaine (2.5 mg/kg i.p.). However, a second experiment indicated that the same injection of corticosterone had no detectable effect on the dopaminergic encoding of a palatable natural reward (saccharin). Taken together, these results suggest that corticosterone interferes with naturally-occurring dopamine uptake locally, and this effect is a critical determinant of dopamine concentration specifically in situations in which the dopamine transporter is pharmacologically blocked by cocaine. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  7. Clinical and laboratory findings associated with naturally occurring babesiosis in dromedary camels

    Directory of Open Access Journals (Sweden)

    Swelum Ayman A.

    2014-06-01

    Full Text Available Clinical, haematological, and biochemical changes induced by naturally occurring babesiosis in dromedary camels were described. Of 258 dromedary camels studied, 34 camels suffered from fever, appetite loss, weakness, depression, and reluctant movement; abortion and/or infertility were also observed. Parasitological blood examinations were performed using Giemsastained blood smears. The clinically affected animals were diagnosed with babesiosis, with 13.17% overall morbidity. Camels that suffered from babesiosis were subjected to haematological and biochemical analyses and the affected group was compared with a control group containing 34 healthy camels. The affected animals showed a highly significant (P<0.001 reduction of the total red blood cell (RBC count, haemoglobin (HGB concentration, and mean corpuscular volume (MCV as well as a highly significant reduction (P<0.01 of haematocrit (HCT and a significant reduction of (P<0.05 mean corpuscular haemoglobin (MCH. Additional, highly significant increases (P<0.01 in white blood cell (WBC count and plateletcrit (PCT percentage were detected. However, other haematological parameters were not significantly altered. There was a very significant reduction (P<0.001 of the blood iron level and a very significant increase (P<0.001 in blood urea nitrogen (BUN and lactate dehydrogenase (LDH in the affected camels. Additionally, significant increases in total protein, albumin, γ-glutamyltransferase (GGT, aspartate aminotransferase (AST, and total bilirubin were observed in the affected camels. It was concluded that babesiosis highly affects the haematobiochemical parameters of dromedary camels, including the liver, kidney, and muscle functions. These results represent novel findings concerning natural babesiosis in camels.

  8. Immunotherapy with a HER2-Targeting Listeria Induces HER2-Specific Immunity and Demonstrates Potential Therapeutic Effects in a Phase I Trial in Canine Osteosarcoma

    National Research Council Canada - National Science Library

    Mason, Nicola J; Gnanandarajah, Josephine S; Engiles, Julie B; Gray, Falon; Laughlin, Danielle; Gaurnier-Hausser, Anita; Wallecha, Anu; Huebner, Margie; Paterson, Yvonne

    2016-01-01

    .... We used dogs with HER2/neu(+) appendicular osteosarcoma, a well-recognized spontaneous model for pediatric osteosarcoma, to determine whether a highly attenuated, recombinant Listeria monocytogenes expressing a chimeric human...

  9. Protein tyrosine phosphatase SHP-1 sensitizes EGFR/HER-2 positive breast cancer cells to trastuzumab through modulating phosphorylation of EGFR and HER-2

    Directory of Open Access Journals (Sweden)

    Wu YF

    2015-09-01

    Full Text Available Yifen Wu,1,2,* Rong Li,3,* Junyi Zhang,4 Gang Wang,5 Bin Liu,6 Xiaofang Huang,7 Tao Zhang,7 Rongcheng Luo8 1Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, 2Department of Oncology, Dongguan People’s Hospital, Dongguan, 3Department of Oncology, Nanfang Hospital, 4Department of Oncology, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, 5Department of Radiology, Dongguan People’s Hospital, Dongguan, 6Second Affiliated Hospital of Guangzhou Medical College, 7College of Traditional Chinese medicine, Southern Medical University, 8Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China *These authors contributed equally to this work Background: Trastuzumab resistance in HER-2 positive breast cancer cells is closely related to overexpression of both epidermal growth factor receptor (EGFR and human epidermal receptor (HER-2. SHP-1 has been demonstrated to downregulate tyrosine kinase activity including EGFR via its phosphatase function, but its effect on HER-2 activity is still unknown. Here, we examined the hypothesis that SHP-1 enhances the anticancer efficacy of trastuzumab in EGFR/HER-2 positive breast cancer cells through combining dual inhibition of EGFR and HER-2.Methods: Trastuzumab-resistant breast cancer SKBr-3 cells were generated by long-term in vitro culture of SKBr-3cells in the presence of trastuzumab. The SHP-1 was ectopically expressed by stable transfection. The activity and expression of EGFR, HER-2, and downstream signaling pathways were tested by Western blot. Cell viability was examined by the 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay, and apoptosis was examined by flow cytometry. The binding between SHP-1 and EGFR/HER-2 was evaluated by immunoprecipitation assay and bimolecular fluorescence complementation. The effects of SHP-1

  10. Evaluation of occupational exposure to naturally occurring radioactive materials in the Iranian ceramics industry.

    Science.gov (United States)

    Fathabadi, N; Farahani, M V; Amani, S; Moradi, M; Haddadi, B

    2011-06-01

    Zircon contains small amounts of uranium, thorium and radium in its crystalline structure. The ceramic industry is one of the major consumers of zirconium compounds that are used as an ingredient at ∼10-20 % by weight in glaze. In this study, seven different ceramic factories have been investigated regarding the presence of radioactive elements with focus on natural radioactivity. The overall objective of this investigation is to provide information regarding the radiation exposure to workers in the ceramic industry due to naturally occurring radioactive materials. This objective is met by collecting existing radiological data specific to glaze production and generating new data from sampling activities. The sampling effort involves the whole process of glaze production. External exposures are monitored using a portable gamma-ray spectrometer and environmental thermoluminescence dosimeters, by placing them for 6 months in some workplaces. Internal routes of exposure (mainly inhalation) are studied using air sampling, and gross alpha and beta counting. Measurement of radon gas and its progeny is performed by continuous radon gas monitors that use pulse ionisation chambers. Natural radioactivity due to the presence of ²³⁸U, ²³²Th and ⁴⁰K in zirconium compounds, glazes and other samples is measured by a gamma-ray spectrometry system with a high-purity germanium detector. The average concentrations of ²³⁸U and ²³²Th observed in the zirconium compounds are >3300 and >550 Bq kg⁻¹, respectively. The specific activities of other samples are much lower than in zirconium compounds. The annual effective dose from external radiation had a mean value of ∼0.13 mSv y⁻¹. Dust sampling revealed the greatest values in the process at the powdering site and hand weighing places. In these plants, the annual average effective dose from inhalation of long-lived airborne radionuclides was 0.226 mSv. ²²²Rn gas concentrations in the glaze production plant and

  11. Targeting CXCR1/2 Significantly Reduces Breast Cancer Stem Cell Activity and Increases the Efficacy of Inhibiting HER2 via HER2-dependent and -independent Mechanisms

    Science.gov (United States)

    Singh, Jagdeep K.; Farnie, Gillian; Bundred, Nigel J.; Simões, Bruno M; Shergill, Amrita; Landberg, Göran; Howell, Sacha; Clarke, Robert B.

    2012-01-01

    Purpose Breast cancer stem-like cells (CSCs) are an important therapeutic target as they are predicted to be responsible for tumour initiation, maintenance and metastases. Interleukin-8 (IL-8) is upregulated in breast cancer and associated with poor prognosis. Breast cancer cell line studies indicate that IL-8 via its cognate receptors, CXCR1 and CXCR2, is important in regulating breast CSC activity. We investigated the role of IL-8 in the regulation of CSC activity using patient-derived breast cancers and determined the potential benefit of combining CXCR1/2 inhibition with HER2-targeted therapy. Experimental design CSC activity of metastatic and invasive human breast cancers (n=19) was assessed ex vivo using the mammosphere colony forming assay. Results Metastatic fluid IL-8 level correlated directly with mammosphere formation (r=0.652; P<0.05; n=10). Recombinant IL-8 directly increased mammosphere formation/self-renewal in metastatic and invasive breast cancers (n=17). IL-8 induced activation of EGFR/HER2 and downstream signalling pathways and effects were abrogated by inhibition of SRC, EGFR/HER2, PI3K or MEK. Furthermore, lapatinib inhibited the mammosphere-promoting effect of IL-8 in both HER2-positive and negative patient-derived cancers. CXCR1/2 inhibition also blocked the effect of IL-8 on mammosphere formation and added to the efficacy of lapatinib in HER2-positive cancers. Conclusions These studies establish a role for IL-8 in the regulation of patient-derived breast CSC activity and demonstrate that IL-8/CXCR1/2 signalling is partly mediated via a novel SRC and EGFR/HER2-dependent pathway. Combining CXCR1/2 inhibitors with current HER2-targeted therapies has potential as an effective therapeutic strategy to reduce CSC activity in breast cancer and improve the survival of HER2-positive patients. PMID:23149820

  12. HER2 signaling pathway activation and response of breast cancer cells to HER2-targeting agents is dependent strongly on the 3D microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Weigelt, Britta; Lo, Alvin T; Park, Catherine C; Gray, Joe W; Bissell, Mina J

    2009-07-27

    Development of effective and durable breast cancer treatment strategies requires a mechanistic understanding of the influence of the microenvironment on response. Previous work has shown that cellular signaling pathways and cell morphology are dramatically influenced by three-dimensional (3D) cultures as opposed to traditional two-dimensional (2D) monolayers. Here, we compared 2D and 3D culture models to determine the impact of 3D architecture and extracellular matrix (ECM) on HER2 signaling and on the response of HER2-amplified breast cancer cell lines to the HER2-targeting agents Trastuzumab, Pertuzumab and Lapatinib. We show that the response of the HER2-amplified AU565, SKBR3 and HCC1569 cells to these anti-HER2 agents was highly dependent on whether the cells were cultured in 2D monolayer or 3D laminin-rich ECM gels. Inhibition of {beta}1 integrin, a major cell-ECM receptor subunit, significantly increased the sensitivity of the HER2-amplified breast cancer cell lines to the humanized monoclonal antibodies Trastuzumab and Pertuzumab when grown in a 3D environment. Finally, in the absence of inhibitors, 3D cultures had substantial impact on HER2 downstream signaling and induced a switch between PI3K-AKT- and RAS-MAPKpathway activation in all cell lines studied, including cells lacking HER2 amplification and overexpression. Our data provide direct evidence that breast cancer cells are able to rapidly adapt to different environments and signaling cues by activating alternative pathways that regulate proliferation and cell survival, events that may play a significant role in the acquisition of resistance to targeted therapies.

  13. Inhibition of mTOR is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells

    Science.gov (United States)

    Miller, Todd W.; Forbes, James T.; Shah, Chirayu; Wyatt, Shelby K.; Manning, H. Charles; Olivares, Maria G.; Sanchez, Violeta; Dugger, Teresa C.; Granja, Nara de Matos; Narasanna, Archana; Cook, Rebecca S.; Kennedy, J. Phillip; Lindsley, Craig W.; Arteaga, Carlos L.

    2009-01-01

    Purpose A significant fraction of HER2-overexpressing breast cancers exhibit resistance to the HER2 antibody trastuzumab. Hyperactivity of the phosphatidylinositol-3 kinase (PI3K)/AKT pathway confers trastuzumab resistance, and mTOR is a major downstream effector of PI3K/AKT. Therefore, we examined whether mTOR inhibitors synergize with trastuzumab. Experimental Design Immunocompetent mice bearing HER2-positive mammary tumors were treated with trastuzumab, the mTOR inhibitor rapamycin, or the combination. Mice were imaged for tumor cell death using an optical Annexin-V probe and with [18F]FDG-PET. The signaling and growth effects of the mTOR inhibitor RAD001 on HER2+ cells treated with trastuzumab or lapatinib were evaluated. Results Treatment of mice with trastuzumab plus rapamycin was more effective than single-agent treatments, inducing complete regression of 26/26 tumors. The combination induced tumor cell death (Annexin-V binding) and inhibited FDG uptake. Rapamycin inhibited mTOR and tumor cell proliferation as determined by phospho-S6 and Ki67 immunohistochemistry, respectively. In culture, the combination of RAD001 plus trastuzumab inhibited cell growth more effectively than either drug alone. Trastuzumab partially decreased PI3K but not mTOR activity. Knockdown of TSC2 resulted in HER2-independent activation of mTOR and dampened the response to trastuzumab and lapatinib. Treatment with the HER2 inhibitor lapatinib decreased phospho-S6 and growth in TSC2-expressing but not in TSC2-knockdown cells. Conclusions Inhibition of PI3K and mTOR are required for the growth inhibitory effect of HER2 antagonists. These findings collectively support the combined use of trastuzumab and mTOR inhibitors for the treatment of HER2+ breast cancer. PMID:19934303

  14. Characterization of a naturally occurring breast cancer subset enriched in EMT and stem cell characteristics

    Energy Technology Data Exchange (ETDEWEB)

    Hennessy, Bryan T.; Gonzalez-Angulo, Ana-Maria; Stemke-Hale, Katherine; Gilcrease, Michael Z.; Krishnamurthy, Savitri; Lee, Ju-Seog; Fridlyand, Jane; Sahin, Aysegul; Agarwal, Roshan; Joy, Corwin; Liu, Wenbin; Stivers, David; Baggerly, Keith; Carey, Mark; Lluch, Ana; Monteagudo, Carlos; He, Xiaping; Weigman, Victor; Fan, Cheng; Palazzo, Juan; Hortobagyi, Gabriel N.; Nolden, Laura K.; Wang, Nicholas J.; Valero, Vicente; Gray, Joe W.; Perou, Charles M.; Mills, Gordon B.

    2009-05-19

    Metaplastic breast cancers (MBC) are aggressive, chemoresistant tumors characterized by lineage plasticity. To advance understanding of their pathogenesis and relatedness to other breast cancer subtypes, 28 MBCs were compared with common breast cancers using comparative genomic hybridization, transcriptional profiling, and reverse-phase protein arrays and by sequencing for common breast cancer mutations. MBCs showed unique DNA copy number aberrations compared with common breast cancers. PIK3CA mutations were detected in 9 of 19 MBCs (47.4%) versus 80 of 232 hormone receptor-positive cancers (34.5%; P = 0.32), 17 of 75 HER-2-positive samples (22.7%; P = 0.04), 20 of 240 basal-like cancers (8.3%; P < 0.0001), and 0 of 14 claudin-low tumors (P = 0.004). Of 7 phosphatidylinositol 3-kinase/AKT pathway phosphorylation sites, 6 were more highly phosphorylated in MBCs than in other breast tumor subtypes. The majority of MBCs displayed mRNA profiles different from those of the most common, including basal-like cancers. By transcriptional profiling, MBCs and the recently identified claudin-low breast cancer subset constitute related receptor-negative subgroups characterized by low expression of GATA3-regulated genes and of genes responsible for cell-cell adhesion with enrichment for markers linked to stem cell function and epithelial-to-mesenchymal transition (EMT). In contrast to other breast cancers, claudin-low tumors and most MBCs showed a significant similarity to a 'tumorigenic' signature defined using CD44{sup +}/CD24{sup -} breast tumor-initiating stem cell-like cells. MBCs and claudin-low tumors are thus enriched in EMT and stem cell-like features, and may arise from an earlier, more chemoresistant breast epithelial precursor than basal-like or luminal cancers. PIK3CA mutations, EMT, and stem cell-like characteristics likely contribute to the poor outcomes of MBC and suggest novel therapeutic targets.

  15. Theoretical simulations on the antioxidant mechanism of naturally occurring flavonoid: A DFT approach

    Science.gov (United States)

    Praveena, R.; Sadasivam, K.

    2016-05-01

    Synthetic antioxidants such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are found to be toxic, hence non-carcinogenic naturally occurring radical scavengers especially flavonoids have gained considerable importance in the past two decades. In the present investigation, the radical scavenging activity of C-glycosyl flavonoids is evaluated using theoretical approach which could broaden its scope in therapeutic applications. Gas and solvent phase studies of structural and molecular characteristics of C-glycosyl flavonoid, isovitexin is investigated through hydrogen atom transfer mechanism (HAT), Electron transfer-proton transfer (ET-PT) and Sequential proton loss electron transfer (SPLET) by Density functional theory (DFT) using hybrid parameters. The computed values of the adiabatic ionization potential, electron affinity, hardness, softness, electronegativity and electrophilic index indicate that isovitexin possess good radical scavenging activity. The behavior of different -OH groups in polyphenolic compounds is assessed by considering electronic effects of the neighbouring groups and the overall geometry of molecule which in turn helps in analyzing the antioxidant capacity of the polyphenolic molecule. The studies indicate that the H-atom abstraction from 4'-OH site is preferred during the radical scavenging process. From Mulliken spin density analysis and FMOs, B-ring is found to be more delocalized center and capable of electron donation. Comparison of antioxidant activity of vitexin and isovitexin leads to the conclusion that isovitexin acts as a better radical scavenger. This is an evidence for the importance of position of glucose unit in the flavonoid.

  16. Construction of a naturally occurring radioactive material project in the BeAAT hazardous waste facilities.

    Science.gov (United States)

    Abuahmad, H

    2015-06-01

    This paper does not necessarily reflect the views of the International Commission on Radiological Protection. Naturally occurring radioactive material (NORM) is produced during exploration and production operations of subsidiaries of the Abu Dhabi National Oil Company (ADNOC) in the United Arab Emirates, and accumulates in drilling tubulars, plant equipment, and components. These NORM hazardous wastes need to be managed in such a way that they do not damage human health and the environment. The primary radionuclides of concern in the oil and gas industries are radium-226 and radium-228. These radioisotopes are the decay products of uranium and thorium isotopes that are present in subsurface formations from which hydrocarbons are produced. While uranium and thorium are largely immobile, radium is slightly more soluble and may become mobilised in the fluid phases of the formation (International Association of Oil & Gas Producers, 2008). In order to treat and dispose of NORM waste products safely, ADNOC's subsidiary 'TAKREER' is developing a new facility, on behalf of all ADNOC subsidiaries, within the existing Central Environmental Protection Facilities (BeAAT) in Ruwais city. The NORM plant is envisaged to treat, handle, and dispose of NORM waste in the forms of scale, sludge, and contaminated equipment. The NORM treatment facility will cover activities such as decontamination, volume reduction, NORM handling, and concrete immobilisation of NORM waste into packages for designated landfilling. © The International Society for Prosthetics and Orthotics Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  17. Modulation of Banana Polyphenol Oxidase (Ppo Activity by Naturally Occurring Bioactive Compounds From Plant Extracts

    Directory of Open Access Journals (Sweden)

    Alamelumangai. M

    2015-01-01

    Full Text Available Polyphenol Oxidase (PPO (E.C number 1.14.18.1 was extracted from banana (Musa paradisiaca and partially purified by acetone precipitation. The enzyme was found to have high affinity towards its substrate, catechol. In this study, various plant extracts like Glycyrrhiza glabra, Rubia cordifolia, Hesperethusa crenulata and oil from the seeds of Hydnocarpus laurifolia were observed to modulate the activity of banana PPO. Method In this study, various plant extracts were observed to modulate the activity of banana PPO at two different concentrations (0.4 and 40 μg/ml concentrations Result Among these 4 plant extracts, Glycyrrhiza glabra and Rubia cordifolia were found to increase the activity of PPO up to 1.35- 2.7 fold at two different concentrations (4 and 40 μg/ml. Few other two samples like Chaulmogra oil (2 and 4 μl/ml and the Hesperethusa crenulata plant extract (0.4 and 40 μg/ml concentrations, when used at low concentrations decreased the enzyme activity (38 %. Conclusion The novelty of this study is to screen their naturally occurring bioactive compounds from the plant extracts and their inhibitory activity against PPO.

  18. Short communication: Change of naturally occurring benzoic acid during skim milk fermentation by commercial cheese starters.

    Science.gov (United States)

    Han, Noori; Park, Sun-Young; Kim, Sun-Young; Yoo, Mi-Young; Paik, Hyun-Dong; Lim, Sang-Dong

    2016-11-01

    This study sought to investigate the change of naturally occurring benzoic acid (BA) during skim milk fermentation by 4 kinds of commercial cheese starters used in domestic cheese. The culture was incubated at 3-h intervals for 24h at 30, 35, and 40°C. The BA content during fermentation by Streptococcus thermophilus STB-01 was detected after 12h at all temperatures, sharply increasing at 30°C. In Lactobacillus paracasei LC431, BA was detected after 9h at all temperatures, sharply increasing until 18h and decreasing after 18h at 30 and 35°C. In the case of R707 (consisting of Lactococcus lactis ssp. lactis and Lactococcus lactis ssp. cremoris), BA increased from 6h to 15h and decreased after 15h at 40°C. The BA during STB-01 and CHN-11 (1:1; mixture of S. thermophilus, Lc. lactis ssp. lactis, Lc. lactis ssp. cremoris, Lc. lactis ssp. diacetylactis, Leuconostoc mesenteroides ssp. cremoris) fermentation was detected after 3h at 35 and 40°C, sharply increasing up to 12h and decreasing after 15h at 35°C, and after 6h, increasing up to 9h at 30°C. After 3h, it steadily decreased at 40°C. The highest amount of BA was found during the fermentation by R707 at 30°C; 15h with 12.46mg/kg.

  19. A century of oil and gas exploration in Albania: assessment of Naturally Occurring Radioactive Materials (NORMs)

    CERN Document Server

    Xhixha, Gerti; Callegari, Ivan; Colonna, Tommaso; Hasani, Fadil; Mantovani, Fabio; Shala, Ferat; Strati, Virginia; Kaçeli, Merita Xhixha

    2015-01-01

    Because potential Naturally Occurring Radioactive Materials (NORMs) generated from oil and gas extractions in Albania have been disposed without regulatory criteria in many decades, an extensive survey in one of the most productive regions (Vlora-Elbasan) has been performed. Among 52 gamma-ray spectrometry measurements of soil, oil-sand, sludge, produced water and crude oil samples, we discover that relatively low activity concentrations of 226Ra, 228Ra, 228Th and 40K, which are 23 +/- 2 Bq/kg, 23 +/- 2 Bq/kg, 24 +/- 3 Bq/kg and 549 +/- 12 Bq/kg, respectively, come from oil-sand produced by hydrocarbon extraction from molasses formations. The mineralogical characterization together with the 228Ra/40K and 226Ra/40K ratios of these Neogene deposits confirm the geological and geodynamic model that predicts a dismantling of Mesozoic source rocks. The average activity concentrations (+/- standard deviations) of the radium isotopes (226Ra, 228Ra) and of the 228Th and 40K radionuclides in soil samples are determined...

  20. Complications following thiacetarsamide sodium therapy in Louisiana dogs with naturally-occurring heartworm disease.

    Science.gov (United States)

    Hoskins, J D; Hribernik, T N; Kearney, M T

    1985-10-01

    Four hundred and sixteen dogs with naturally-occurring heartworm disease were evaluated for complications following thiacetarsamide sodium therapy. Of these, 109 dogs (26.2%) experienced complications. Increased lung sounds was the most commonly seen complication, followed by fever and coughing. In dogs with complications, 83.5% of them presented without clinical evidence of pulmonary thromboembolism or heart failure. There were no statistically significant differences between the age, sex, breed and body size of dogs that experienced complications following thiacetarsamide therapy and dogs that did not. Complications were most frequently seen 5 to 9 days following thiacetarsamide therapy although some dogs experienced initial complications as late as 28 days. Thirty-three of 109 dogs (33.0%) with complications responded to exercise restriction. The remaining 76 dogs with complications prior to or following thiacetarsamide required adjunct drug therapy. Of these, 35 dogs responded favorably to anti-inflammatory doses of prednisolone or prednisone. Five dogs died or were euthanatized because of the complications experienced. Eighteen of 416 dogs (4.3%) presented with clinical evidence of pulmonary thromboembolism or heart failure prior to the thiacetarsamide therapy. All 18 dogs experienced complications in spite of adjunct drug therapy and exercise restriction prior to, during, and following thiacetarsamide therapy. Survival rate following resolution of the thiacetarsamide-induced complications was greater than 98%.

  1. Polyhydroxyester films obtained by non-catalyzed melt-polycondensation of natural occurring fatty polyhydroxyacids.

    Directory of Open Access Journals (Sweden)

    Jose Jesus Benitez

    2015-08-01

    Full Text Available Free-standing polyesters films from mono and polyhydroxylated fatty acids (C16 and C18 have been obtained by non-catalyzed melt-condensation polymerization in air at 150°C. Chemical characterization by Fourier Transform Infrared Spectroscopy (FTIR and 13C Magic Angle Spinning Nuclear Magnetic Resonance (13C MAS-NMR has confirmed the formation of the corresponding esters and the occurrence of hydroxyl partial oxidation which extent depends on the type of hydroxylation of the monomer (primary or secondary. Generally, polyester films obtained are hydrophobic, insoluble in common solvents, amorphous and infusible as revealed by X-ray Diffraction (XRD and Differential Scanning Calorimetry (DSC. In -polyhydroxy acids, esterification reaction with primary hydroxyls is preferential and, therefore, the structure can be defined as linear with variable branching depending on the amount of esterified secondary hydroxyls. The occurrence side oxidative reactions like the diol cleavage are responsible for chain cross-linking. Films are thermally stable up to 200-250°C though this limit can be extended up to 300°C in the absence of ester bonds involving secondary hydroxyls. By analogy with natural occurring fatty polyesters (i.e. cutin in higher plants these polymers are proposed as biodegradable and non-toxic barrier films or coatings to be used, for instance, in food packing

  2. Polyhydroxyester films obtained by non-catalyzed melt-polycondensation of natural occurring fatty polyhydroxyacids.

    Science.gov (United States)

    Benitez, Jose; Heredia-Guerrero, José; Guzman-Puyol, Susana; Barthel, Markus; Dominguez, Eva; Heredia, Antonio

    2015-08-01

    Free-standing polyesters films from mono and polyhydroxylated fatty acids (C16 and C18) have been obtained by non-catalyzed melt-condensation polymerization in air at 150°C. Chemical characterization by Fourier Transform Infrared Spectroscopy (FTIR) and 13C Magic Angle Spinning Nuclear Magnetic Resonance (13C MAS-NMR) has confirmed the formation of the corresponding esters and the occurrence of hydroxyl partial oxidation which extent depends on the type of hydroxylation of the monomer (primary or secondary). Generally, polyester films obtained are hydrophobic, insoluble in common solvents, amorphous and infusible as revealed by X-ray Diffraction (XRD) and Differential Scanning Calorimetry (DSC). In ?-polyhydroxy acids, esterification reaction with primary hydroxyls is preferential and, therefore, the structure can be defined as linear with variable branching depending on the amount of esterified secondary hydroxyls. The occurrence side oxidative reactions like the diol cleavage are responsible for chain cross-linking. Films are thermally stable up to 200-250°C though this limit can be extended up to 300°C in the absence of ester bonds involving secondary hydroxyls. By analogy with natural occurring fatty polyesters (i.e. cutin in higher plants) these polymers are proposed as biodegradable and non-toxic barrier films or coatings to be used, for instance, in food packing

  3. Investigation of the activity level and radiological impacts of naturally occurring radionuclides in blast furnace slag.

    Science.gov (United States)

    Uğur, F A; Turhan, S; Sahan, H; Sahan, M; Gören, E; Gezer, F; Yeğingil, Z

    2013-01-01

    The activity level and possible radiological impacts of naturally occurring radionuclides on the health of workers and members of the public, as a result of utilisation of blast furnace slag (BFS) samples as a substitute for aggregate in road construction were investigated by using a gamma-ray spectrometer and potential exposure scenarios given in Radiation Protection 122. The mean activity concentrations of the (226)Ra, (232)Th and (40)K in BFS samples were found to be 152.4, 54.9 and 183.1 Bq kg(-1), respectively. These values are compared with typical values measured in BFS samples from the European Union countries, which are 270, 70 and 240 Bq kg(-1) for (226)Ra, (232)Th and (40)K, respectively. The values of radium equivalent activity index calculated for BFS samples were within the recommended safety limits. The highest total annual effective doses evaluated as 0.9 and 0.4 mSv y(-1) for members of the public and workers, respectively, were lower than the annual limit of 1 mSv y(-1).

  4. Regulatory Initiatives for Control and Release of Technologically Enhanced Naturally-Occurring Radioactive Materials

    Energy Technology Data Exchange (ETDEWEB)

    Egidi, P.V.

    1999-03-02

    Current drafts of proposed standards and suggested State regulations for control and release of technologically-enhanced naturally-occurring radioactive material (TENORM), and standards for release of volumetrically-contaminated material in the US are reviewed. These are compared to the recommendations of the International Atomic Energy Association (IAEA) Safety Series and the European Commission (EC) proposals. Past regulatory efforts with respect to TENORM in the US dealt primarily with oil-field related wastes. Currently, nine states (AK, GA, LA, MS, NM, OH, OR SC, TX) have specific regulations pertaining to TENORM, mostly based on uranium mill tailings cleanup criteria. The new US proposals are dose- or risk-based, as are the IAEA and EC recommendations, and are grounded in the linear no threshold hypothesis (LNT). TENORM wastes involve extremely large volumes, particularly scrap metal and mine wastes. Costs to control and dispose of these wastes can be considerable. The current debate over the validity of LNT at low doses and low dose rates is particularly germane to this discussion. Most standards setting organizations and regulatory agencies base their recommendations on the LNT. The US Environmental Protection Agency has released a draft Federal Guidance Report that recommends calculating health risks from low-level exposure to radionuclides based on the LNT. However, some scientific and professional organizations are openly questioning the validity of LNT and its basis for regulations, practices, and costs to society in general. It is not clear at this time how a non-linear regulatory scheme would be implemented.

  5. Single Agent Polysaccharopeptide Delays Metastases and Improves Survival in Naturally Occurring Hemangiosarcoma

    Directory of Open Access Journals (Sweden)

    Dorothy Cimino Brown

    2012-01-01

    Full Text Available The 2008 World Health Organization World Cancer Report describes global cancer incidence soaring with many patients living in countries that lack resources for cancer control. Alternative treatment strategies that can reduce the global disease burden at manageable costs must be developed. Polysaccharopeptide (PSP is the bioactive agent from the mushroom Coriolus versicolor. Studies indicate PSP has in vitro antitumor activities and inhibits the growth of induced tumors in animal models. Clear evidence of clinically relevant benefits of PSP in cancer patients, however, is lacking. The investment of resources required to complete large-scale, randomized controlled trials of PSP in cancer patients is more easily justified if antitumor and survival benefits are documented in a complex animal model of a naturally occurring cancer that parallels human disease. Because of its high metastatic rate and vascular origin, canine hemangiosarcoma is used for investigations in antimetastatic and antiangiogenic therapies. In this double-blind randomized multidose pilot study, high-dose PSP significantly delayed the progression of metastases and afforded the longest survival times reported in canine hemangiosarcoma. These data suggest that, for those cancer patients for whom advanced treatments are not accessible, PSP as a single agent might offer significant improvements in morbidity and mortality.

  6. Perceived risks of produced water management and naturally occurring radioactive material content in North Dakota.

    Science.gov (United States)

    Torres, Luisa; Yadav, Om Prakash; Khan, Eakalak

    2017-07-01

    Unconventional oil and gas development using hydraulic fracturing has caused conflict and controversy across the globe including the U.S. where some States banned the practice. Nevertheless, North Dakota (ND) has supported the practice because the State perceives the risks to be acceptable and because it has brought growth and opportunities to small communities. However, social acceptance of new technology is based on a number of factors and not contingent on economic benefits. To date, no research has been conducted to understand public risk perception of hazards associated with produced water from hydraulic fracturing in ND. This study focuses on understanding the risk perception of select ND stakeholder groups regarding produced water management and naturally occurring radioactive material. The software Qualtrics was used to create an online survey, collect data, and perform statistical analysis. The most important variables that seem to influence risk perception are the images and thoughts associated with produced water, level of knowledge about produced water handling and content, and knowing how to proceed in case of a spill of produced water. Overall, social risk perception could be in alignment with actual technical risk if availability of objective information is improved. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. A naturally occurring diatom frustule as a SERS substrate for the detection and quantification of chemicals

    Science.gov (United States)

    Chamuah, Nabadweep; Chetia, Lakhi; Zahan, Nashrat; Dutta, Sibasish; Ahmed, Gazi A.; Nath, Pabitra

    2017-05-01

    Naturally occurring photonic crystal structures play an important role in different fields of application. Herein, we exploit the periodic pore pattern of a diatom frustule and demonstrate surface-enhanced Raman scattering (SERS) using its structure as a template for the SERS substrate. Gold nanoparticles (AuNPs) were initially allowed to self-assemble on the surface and inside the pores of the diatoms. The enhancement in the localized surface plasmon resonance (LSPR) field magnitude for the assembled AuNPs on the diatom frustule were studied using simulation software. For the proposed SERS substrate, an average field enhancement of the order of 108 magnitude was observed. We demonstrate the operation of the designed substrate for the detection and quantification of Raman signals from two Raman active samples, namely malachite green (MG) and fluoride concentrations in drinking water. Using the proposed SERS substrate, an MG concentration as low as 1 nM with a relative standard deviation (RSD) of 7.57% and a fluoride concentration of 100 nM with an RSD of 17.26% could be measured with the Raman spectrometer. We envision that the proposed technique could emerge as an inexpensive alternative fabrication method of SERS substrates which can produce an enhanced LSPR field magnitude and scatter intense Raman signals from Raman active samples.

  8. Formation of naturally occurring pigments during the production of nitrite-free dry fermented sausages.

    Science.gov (United States)

    De Maere, Hannelore; Fraeye, Ilse; De Mey, Eveline; Dewulf, Lore; Michiels, Chris; Paelinck, Hubert; Chollet, Sylvie

    2016-04-01

    This study investigates the potential of producing red coloured dry fermented sausages without the addition of nitrite and/or nitrate. Therefore, the formation of zinc protoporphyrin IX (Zn(II)PPIX) as naturally occurring pigment, and the interrelated protoporphyrin IX (PPIX) and heme content were evaluated during nitrite-free dry fermented sausage production at different pH conditions. Zn(II)PPIX was only able to form in dry fermented sausages at pH conditions higher than approximately 4.9. Additionally, the presence of Zn(II)PPIX increased drastically at the later phase of the production process (up to day 177), confirming that in addition to pH, time is also a crucial factor for its formation. Similarly, PPIX also accumulated in the meat products at increased pH conditions and production times. In contrast, a breakdown of heme was observed. This breakdown was more gradual and independent of pH and showed no clear relationship with the formed amounts of Zn(II)PPIX and PPIX. A statistically significant relationship between Zn(II)PPIX formation and product redness was established.

  9. Novel class of glutathione transferases from cyanobacteria exhibit high catalytic activities towards naturally occurring isothiocyanates

    Science.gov (United States)

    Wiktelius, Eric; Stenberg, Gun

    2007-01-01

    In the present paper, we report a novel class of GSTs (glutathione transferases), called the Chi class, originating from cyanobacteria and with properties not observed previously in prokaryotic enzymes. GSTs constitute a widespread multifunctional group of proteins, of which mammalian enzymes are the best characterized. Although GSTs have their origin in prokaryotes, few bacterial representatives have been characterized in detail, and the catalytic activities and substrate specificities observed have generally been very modest. The few well-studied bacterial GSTs have largely unknown physiological functions. Genome databases reveal that cyanobacteria have an extensive arsenal of glutathione-associated proteins. We have studied two cyanobacterial GSTs which are the first examples of bacterial enzymes that are as catalytically efficient as the best mammalian enzymes. GSTs from the thermophile Thermosynechococcus elongatus BP-1 and from Synechococcus elongatus PCC 6301 were found to catalyse the conjugation of naturally occurring plant-derived isothiocyanates to glutathione at high rates. The cyanobacterial GSTs studied are smaller than previously described members of this enzyme family, but display many of the typical structural features that are characteristics of GSTs. They are also active towards several classical substrates, but at the same moderate rates that have been observed for other GSTs derived from prokaryotes. The cloning, expression and characterization of two cyanobacterial GSTs are described. The possible significance of the observed catalytic properties is discussed in the context of physiological relevance and GST evolution. PMID:17484723

  10. The Phenotypic Characterization of Naturally Occurring Regulatory CD4+CD25+T Cells

    Institute of Scientific and Technical Information of China (English)

    Huanfa Yi; Yu Zhen; Lingling Jiang; Jialin Zheng; Yong Zhao

    2006-01-01

    The homeostasis of the immune system depends on the balance between the immune response to an invaded pathogen and the immune tolerance to self antigens. Both central and peripheral tolerances are important mechanisms for the induction and maintenance of T cell tolerance. Recently, much attention has been paid to regulatory T cells (Treg), which play a significant role in maintaining peripheral immune tolerance. So far, there has been no satisfactory advance regarding the surface markers of Treg cells, as none is unique for Treg cells. In this review, we summarize some important molecules expressed in naturally occurring CD4+CD25+ Treg cells(nTreg), including forkhead/winged-helix family transcriptional repressor p3 (Foxp3), the tumor necrosis factor receptor (TNFR) family, CD28/CTLA4 molecules, chemokine receptors, Toll-like receptors (TLRs), membranebound TGF-β and other molecules, such as neuropilin-1, lymphocyte activation gene-3 (LAG)-3 and granzyme.This review provides a collective view on current studies of nTreg cell activation and development related to the expression of molecules and cell phenotype markers, which is important for elucidation of nTreg cell origin,development and function.

  11. Molecular characterization of Cryptosporidium and Giardia occurring in natural water bodies in Poland.

    Science.gov (United States)

    Adamska, Małgorzata

    2015-02-01

    Cryptosporidium and Giardia protozoa are zoonotic parasites that cause human gastroenteritis and can be transmitted to human through the fecal-oral route and water or food. Several species belong to these genera and their resistant forms occur in water, but only some of them are infectious to human. Health risk depends on the occurrence of infectious Cryptosporidium and Giardia species and genotypes in water, and only molecular techniques allow detecting them, as well as enable to identify the contamination source. In this work, genotyping and phylogenetic analysis have been performed on the basis of 18S rDNA and ß-giardin genes sequences of Cryptosporidium and Giardia, respectively, in order to provide the molecular characterization of these parasites detected earlier in five natural water bodies in Poland and to track possible sources of their (oo)cysts in water. Genotyping revealed a high similarity (over 99 up to 100 %) of analyzed sequences to cattle genotype of C. parvum isolated from cattle and human and to G. intestinalis assemblage B isolated from human. The sequences obtained by others originated from patients with clinical symptoms of cryptosporidiosis or giardiasis and/or with the infection confirmed by different methods. The contamination of three examined lakes is probably human-originated, while the sources of contamination of two remaining lakes are wild and domestic animals. Obtained phylogenetic trees support suggestions of other authors that the bovine genotype of C. parvum should be a separate species, as well as A and B assemblages of G. intestinalis.

  12. Effect of Naturally Occurring Ozone Air Pollution Episodes on Pulmonary Oxidative Stress and Inflammation

    Directory of Open Access Journals (Sweden)

    Cheryl Pirozzi

    2015-05-01

    Full Text Available This study aimed to determine if naturally occurring episodes of ozone air pollution in the Salt Lake Valley in Utah, USA, during the summer are associated with increased pulmonary inflammation and oxidative stress, increased respiratory symptoms, and decreased lung function in individuals with chronic obstructive pulmonary disease (COPD compared to controls. We measured biomarkers (nitrite/nitrate (NOx, 8-isoprostane in exhaled breath condensate (EBC, spirometry, and respiratory symptoms in 11 former smokers with moderate-to-severe COPD and nine former smokers without airflow obstruction during periods of low and high ozone air pollution. High ozone levels were associated with increased NOx in EBC in both COPD (8.7 (±8.5 vs. 28.6 (±17.6 μmol/L on clean air vs. pollution days, respectively, p < 0.01 and control participants (7.6 (±16.5 vs. 28.5 (±15.6 μmol/L on clean air vs. pollution days, respectively, p = 0.02. There was no difference in pollution effect between COPD and control groups, and no difference in EBC 8-isoprostane, pulmonary function, or respiratory symptoms between clean air and pollution days in either group. Former smokers both with and without airflow obstruction developed airway oxidative stress and inflammation in association with ozone air pollution episodes.

  13. Naturally occurring cancers in dogs: insights for translational genetics and medicine.

    Science.gov (United States)

    Alvarez, Carlos E

    2014-01-01

    Here, we briefly review the state of knowledge of human cancer genetics to elaborate on the need for different types of mammalian models, highlighting the strengths of the dog. Mouse models are unparalleled for their experimental tractability and rapid genetic manipulation but have some key limitations in the area of human relevance. Companion dog models are attractive, because they are genetically more similar to humans, share environmental exposures with their owners, suffer from the same diseases as humans, and receive a high level of health care. They are ideal for the study of chronic diseases, because they age five to eight times faster than humans and generally live to old age. In addition, each dog breed is on the order of 100-fold genetically simpler than the whole human or dog population. These traits make the dog ideal for the study of complex genetics of naturally occurring cancers. Here, we contrast the relative strengths of cancer genetics in humans and dogs. We propose that humans are most ideal for the study of somatic cancer genetics, whereas dogs are most ideal for germline genetics. That proposition is supported by comparison of genome-wide association studies (GWASs) in human and canine cancer. One of the advantages of dog cancer GWASs is the ability to rapidly map complex traits, conduct fine mapping and identification of causative variation, and thus be in a position to move on to functional studies. We mention how these strengths of dog models will lead to rapid advances in translational medicine.

  14. Recombinant Moraxella bovoculi cytotoxin-ISCOM matrix adjuvanted vaccine to prevent naturally occurring infectious bovine keratoconjunctivitis.

    Science.gov (United States)

    Angelos, John A; Lane, V Michael; Ball, Louise M; Hess, John F

    2010-03-01

    A randomized, blinded, controlled field trial was conducted during summer 2006 in a northern California, USA, herd of beef cattle to evaluate the efficacy of a recombinant Moraxella bovoculi cytotoxin subunit vaccine to prevent naturally occurring infectious bovine keratoconjunctivitis (IBK; pinkeye). A convenience sample comprised of 127 steers were administered a subcutaneous dose of either adjuvant alone (ISCOM matrices; control group) or recombinant M. bovoculi cytotoxin carboxy terminus adjuvanted with ISCOM matrices (MbvA group) and were boostered 21 days later. The steers were examined once weekly for 15 weeks for evidence of IBK. No significant difference in the cumulative proportion of corneal ulcerations was detected between groups. Compared to the control calves, the MbvA vaccinates had significantly higher increases in serum neutralizing titers to M. bovoculi hemolysin between week 0 and week 6. The prevalence of M. bovis isolations was higher from ulcerated eyes of calves vaccinated with MbvA as compared to control calves. Vaccination of calves against the carboxy terminus of M. bovoculi RTX toxin resulted in significant increases in serum hemolysin neutralizing titers and may modulate organism type cultured from ulcerated eyes of calves in herds where both M. bovis and M. bovoculi exist. Use of M. bovoculi antigens alone in vaccines to prevent IBK may not be beneficial in herds where IBK is associated with both M. bovoculi and M. bovis.

  15. Genetic basis of hindlimb loss in a naturally occurring vertebrate model

    Directory of Open Access Journals (Sweden)

    Emily K. Don

    2016-03-01

    Full Text Available Here we genetically characterise pelvic finless, a naturally occurring model of hindlimb loss in zebrafish that lacks pelvic fin structures, which are homologous to tetrapod hindlimbs, but displays no other abnormalities. Using a hybrid positional cloning and next generation sequencing approach, we identified mutations in the nuclear localisation signal (NLS of T-box transcription factor 4 (Tbx4 that impair nuclear localisation of the protein, resulting in altered gene expression patterns during pelvic fin development and the failure of pelvic fin development. Using a TALEN-induced tbx4 knockout allele we confirm that mutations within the Tbx4 NLS (A78V; G79A are sufficient to disrupt pelvic fin development. By combining histological, genetic, and cellular approaches we show that the hindlimb initiation gene tbx4 has an evolutionarily conserved, essential role in pelvic fin development. In addition, our novel viable model of hindlimb deficiency is likely to facilitate the elucidation of the detailed molecular mechanisms through which Tbx4 functions during pelvic fin and hindlimb development.

  16. Presence of Naturally Occurring Radioactive Materials in sludge samples from several Spanish water treatment plants

    Energy Technology Data Exchange (ETDEWEB)

    Palomo, M.; Penalver, A.; Aguilar, C. [Unitat de Radioquimica Ambiental i Sanitaria, Universitat Rovira i Virgili, Consorci d' Aigues de Tarragona (CAT), Ctra. Nacional 340 Km. 1094, Ap. correus n.7, 43895 L' Ampolla, Tarragona (Spain); Borrull, F., E-mail: francesc.borrull@urv.cat [Unitat de Radioquimica Ambiental i Sanitaria, Universitat Rovira i Virgili, Consorci d' Aigues de Tarragona (CAT), Ctra. Nacional 340 Km. 1094, Ap. correus n.7, 43895 L' Ampolla, Tarragona (Spain)

    2010-09-15

    Sludge samples from eleven potable water treatment plants (PWTP), three waste water treatment plants (WWTP) and an industrial water treatment plant (IWTP), located in different areas of Spain, mainly in Catalonia, were analyzed for their radiological content in order to determine whether they could be considered as industries affected by naturally occurring radioactive material (NORM). In general, samples from the PWTPs showed higher activity values for the alpha and gamma emitting isotopes than the WWTPs and the IWTP. For example, samples from the area located in the north of Catalonia show values of {sup 234}U, {sup 235}U and {sup 238}U in the range of 84.4-792.1 Bq/kg, 3.3-26.8 Bq/kg and 63.8-585.9 Bq/kg, respectively. In general, for PWTP, the values obtained for the gamma emitter and alpha emitter isotopes showed that both the geology and the industrial activities correlate with the values measured. The magnitude of these results demonstrates the need to measure the radionuclide content of these samples before reaching a decision about their final disposal.

  17. Radiological dose assessment related to management of naturally occurring radioactive materials generated by the petroleum industry

    Energy Technology Data Exchange (ETDEWEB)

    Smith, K.P.; Blunt, D.L.; Williams, G.P. [Argonne National Lab., IL (United States). Environmental Assessment Div.; Tebes, C.L. [Univ. of Illinois, Urbana, IL (United States)

    1996-09-01

    A preliminary radiological dose assessment of equipment decontamination, subsurface disposal, landspreading, equipment smelting, and equipment burial was conducted to address concerns regarding the presence of naturally occurring radioactive materials (NORM) in production waste streams. The assessment estimated maximum individual dose equivalents for workers and the general public. Sensitivity analyses of certain input parameters also were conducted. On the basis of this assessment, it is concluded that (1) regulations requiring workers to wear respiratory protection during equipment cleaning operations are likely to result in lower worker doses, (2) underground injection and downhole encapsulation of NORM wastes present a negligible risk to the general public, and (3) potential doses to workers and the general public related to smelting NORM-contaminated equipment can be controlled by limiting the contamination level of the initial feed. It is recommended that (1) NORM wastes be further characterized to improve studies of potential radiological doses; (2) states be encouraged to permit subsurface disposal of NORM more readily, provided further assessments support this study; results; (3) further assessment of landspreading NORM wastes be conducted; and (4) the political, economic, sociological, and nonradiological issues related to smelting NORM-contaminated equipment be studied to fully examine the feasibility of this disposal option.

  18. Mobilization of Phosphorus by Naturally Occurring Organic Acids in Oxisols and Ultisols

    Institute of Scientific and Technical Information of China (English)

    HANXING-GUO; C.F.JORDAN; 等

    1995-01-01

    Citric and malic acids at concentrations of 0.1,1.0,10,and 100 mmol/L were added to three Ultisols and one Oxisol,The amount of P in solution increased with increasing organic acid concentrations,while the amount of Fe-and Al-bound P decreased.This result suggested that naturally occurring products of organicmatter decomposition could increase the P availability to plants in soils where there is a relatively large pool of Fe-and Al-bound P.The interactions between citric and malic acids at the above concentrations,and p added at rates of 10,20,40,and 80mg/kg were determined.At zero levels of organic acids,all added P became either labile or bound ,and greater proportions remained soluble as the concentration of orgaic acids increased,which suggested that organic acids reduced fixation of dissolved P in Fe-and AL-rich soils .Agricultural practices which increase organic matter input on P-deficient acid soild could decrease P deficiency,This would be important in many tropical and subtropical regions where these soils are common,and where the costs of fertilizers and lime are relatively high.

  19. SUPPLEMENTARY COMPARISON Technically enhanced naturally occurring radionuclides (TENORM) in phosphogypsum: Comparison CCRI(II)-S5

    Science.gov (United States)

    Shakhashiro, A.; Sansone, U.; Wershofen, H.; Bollhöfer, A.; Kim, C. K.; Kim, C. S.; Korun, M.; Moune, M.; Lee, S. H.; Tarjan, S.

    2010-01-01

    Within the frame of mutual cooperation between the IAEA and the BIPM, the Consultative Committee for Ionizing Radiation Section II—Measurement of Radionuclides accepted an IAEA-organized interlaboratory comparison in 2008 on the determination of technically enhanced naturally occurring radionuclides in phosphogypsum. The study was piloted by the Chemistry Unit at the IAEA's Laboratories in Seibersdorf (Austria). This report presents the methodology applied in conducting this comparison and the results. Activity results for Pb-210, Ra-226, Th-230, U-234, U-235 and U-238 were reported by three national metrology institutes (NMI) and five other expert laboratories or designated institutes. Four different approaches were used to calculate the nominal value of the reported results and associated uncertainties, and the results from each individual participant were evaluated and compared with this nominal reference value. The reported evaluation of the measurement results demonstrated agreement amongst the participating laboratories. Main text. To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCRI Section II, according to the provisions of the CIPM Mutual Recognition Arrangement (MRA).

  20. Mitochondrial dysfunction and oxidative stress in Naturally-Occurring Feline Hypertrophic Cardiomyopathy

    DEFF Research Database (Denmark)

    Christiansen, Liselotte Bruun

    Background: Hypertrophic cardiomyopathy (HCM) is a primary myocardial disease, characterized by unexplained hypertrophy of the left ventricle. HCM features similar clinical and pathological characteristics in human beings and cats and is a common cause of sudden death and heart failure. Mitochond......Background: Hypertrophic cardiomyopathy (HCM) is a primary myocardial disease, characterized by unexplained hypertrophy of the left ventricle. HCM features similar clinical and pathological characteristics in human beings and cats and is a common cause of sudden death and heart failure....... Mitochondrial dysfunction and oxidative stress are well known to play a role in the development of various cardiovascular diseases. However, their roles in HCM remain unexplored. Objectives Methods: Cardiac muscle was obtained from eight cats diagnosed with naturally-occuring HCM (5 males; 2-10 years old, 6.......3 ± 2.4 (mean ± SD)) and from nine age-matched control cats (CON) (3 males; 2-11 years, 4.9 ± 3.1). High-resolution respirometry was used to measure mitochondrial function in permeabilized, cardiac muscle fibres. Oxidative stress was assessed by measurements of mitochondrial H2O2 generation...

  1. Theoretical simulations on the antioxidant mechanism of naturally occurring flavonoid: A DFT approach

    Energy Technology Data Exchange (ETDEWEB)

    Praveena, R. [Department of Chemistry, Bannari Amman Institute of Technology, Sathyamangalam, Erode, Tamil Nadu (India); Sadasivam, K. [Department of Physics, Bannari Amman Institute of Technology, Sathyamangalam, Erode, Tamil Nadu (India)

    2016-05-06

    Synthetic antioxidants such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are found to be toxic, hence non-carcinogenic naturally occurring radical scavengers especially flavonoids have gained considerable importance in the past two decades. In the present investigation, the radical scavenging activity of C-glycosyl flavonoids is evaluated using theoretical approach which could broaden its scope in therapeutic applications. Gas and solvent phase studies of structural and molecular characteristics of C-glycosyl flavonoid, isovitexin is investigated through hydrogen atom transfer mechanism (HAT), Electron transfer-proton transfer (ET–PT) and Sequential proton loss electron transfer (SPLET) by Density functional theory (DFT) using hybrid parameters. The computed values of the adiabatic ionization potential, electron affinity, hardness, softness, electronegativity and electrophilic index indicate that isovitexin possess good radical scavenging activity. The behavior of different –OH groups in polyphenolic compounds is assessed by considering electronic effects of the neighbouring groups and the overall geometry of molecule which in turn helps in analyzing the antioxidant capacity of the polyphenolic molecule. The studies indicate that the H–atom abstraction from 4’–OH site is preferred during the radical scavenging process. From Mulliken spin density analysis and FMOs, B–ring is found to be more delocalized center and capable of electron donation. Comparison of antioxidant activity of vitexin and isovitexin leads to the conclusion that isovitexin acts as a better radical scavenger. This is an evidence for the importance of position of glucose unit in the flavonoid.

  2. Use of naturally occurring mercury to determine the importance of cutthroat trout to Yellowstone grizzly bears

    Science.gov (United States)

    Felicetti, L.A.; Schwartz, C.C.; Rye, R.O.; Gunther, K.A.; Crock, J.G.; Haroldson, M.A.; Waits, L.; Robbins, C.T.

    2004-01-01

    Spawning cutthroat trout (Oncorhynchus clarki (Richardson, 1836)) are a potentially important food resource for grizzly bears (Ursus arctos horribilis Ord, 1815) in the Greater Yellowstone Ecosystem. We developed a method to estimate the amount of cutthroat trout ingested by grizzly bears living in the Yellowstone Lake area. The method utilized (i) the relatively high, naturally occurring concentration of mercury in Yellowstone Lake cutthroat trout (508 ± 93 ppb) and its virtual absence in all other bear foods (6 ppb), (ii) hair snares to remotely collect hair from bears visiting spawning cutthroat trout streams between 1997 and 2000, (iii) DNA analyses to identify the individual and sex of grizzly bears leaving a hair sample, (iv) feeding trials with captive bears to develop relationships between fish and mercury intake and hair mercury concentrations, and (v) mercury analyses of hair collected from wild bears to estimate the amount of trout consumed by each bear. Male grizzly bears consumed an average of 5 times more trout/kg bear than did female grizzly bears. Estimated cutthroat trout intake per year by the grizzly bear population was only a small fraction of that estimated by previous investigators, and males consumed 92% of all trout ingested by grizzly bears.

  3. HER-2 positive and p53 negative breast cancers are associated with poor prognosis.

    LENUS (Irish Health Repository)

    2011-06-01

    p53 and HER-2 coexpression in breast cancer has been controversial. These markers were tested using immunohistochemistry and HercepTest. HER-2 expression is related to reduced breast cancer survival (p = .02) . p53 expression relates to HER-2 expression (p = .029). Coexpression between p53 and HER-2 has no relation to prognosis. On univariate and multivariate analysis, combination of HER-2 positive and p53 negative expression was associated with a poor prognosis (p = .018 and p = .027, respectively), while the combination of HER-2 negative and p53 positive expression was associated with a favorable prognosis (p = .022 and p = .010, respectively). Therefore the expression of these markers should be considered collectively.

  4. HER-2 positive and p53 negative breast cancers are associated with poor prognosis.

    LENUS (Irish Health Repository)

    2012-02-01

    p53 and HER-2 coexpression in breast cancer has been controversial. These markers were tested using immunohistochemistry and HercepTest. HER-2 expression is related to reduced breast cancer survival (p = .02) . p53 expression relates to HER-2 expression (p = .029). Coexpression between p53 and HER-2 has no relation to prognosis. On univariate and multivariate analysis, combination of HER-2 positive and p53 negative expression was associated with a poor prognosis (p = .018 and p = .027, respectively), while the combination of HER-2 negative and p53 positive expression was associated with a favorable prognosis (p = .022 and p = .010, respectively). Therefore the expression of these markers should be considered collectively.

  5. Preparation and Characterization of {sup 177}Lu Labeled Antibody against Tyrosine Kinase Receptor Her2

    Energy Technology Data Exchange (ETDEWEB)

    Lee, So-Young; Hong, Young-Don; Choi, Sun-Ju [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2008-05-15

    The tyrosine kinase receptor Her2, also known in humans as erbB2, is a member of the epidermal growth factor receptor (EGFR or erbB1) family. The Her2 is highly expressed in many cancer types and over expressed in approximately 30% of all primary breast cancer. Overexpression of Her2 is associated with a poor prognosis. Her2 is a suitable target because it involves an extracellular domain that can be targeted by antibodies produced by B cells. Based on these advantages, we tried to prepare the {sup 177}Lu labeled Her2 antibody. This radioimmunoconjugate could act by not only blocking the Her2 signalling pathway using antibody but also killing the tumour cell using {beta} energy of {sup 177}Lu.

  6. Highly sensitive proximity mediated immunoassay reveals HER2 status conversion in the circulating tumor cells of metastatic breast cancer patients

    Directory of Open Access Journals (Sweden)

    Kim Phillip

    2011-12-01

    Full Text Available Abstract Background The clinical benefits associated with targeted oncology agents are generally limited to subsets of patients. Even with favorable biomarker profiles, many patients do not respond or acquire resistance. Existing technologies are ineffective for treatment monitoring as they provide only static and limited information and require substantial amounts of tissue. Therefore, there is an urgent need to develop methods that can profile potential therapeutic targets with limited clinical specimens during the course of treatment. Methods We have developed a novel proteomics-based assay, Collaborative Enzyme Enhanced Reactive-immunoassay (CEER that can be used for analyzing clinical samples. CEER utilizes the formation of unique immuno-complex between capture-antibodies and two additional detector-Abs on a microarray surface. One of the detector-Abs is conjugated to glucose oxidase (GO, and the other is conjugated to Horse Radish Peroxidase (HRP. Target detection requires the presence of both detector-Abs because the enzyme channeling event between GO and HRP will not occur unless both Abs are in close proximity. Results CEER was able to detect single-cell level expression and phosphorylation of human epidermal growth factor receptor 2 (HER2 and human epidermal growth factor receptor 1 (HER1 in breast cancer (BCa systems. The shift in phosphorylation profiles of receptor tyrosine kinases (RTKs and other signal transduction proteins upon differential ligand stimulation further demonstrated extreme assay specificity in a multiplexed array format. HER2 analysis by CEER in 227 BCa tissues showed superior accuracy when compared to the outcome from immunohistochemistry (IHC (83% vs. 96%. A significant incidence of HER2 status alteration with recurrent disease was observed via circulating tumor cell (CTC analysis, suggesting an evolving and dynamic disease progression. HER2-positive CTCs were found in 41% (7/17 while CTCs with significant HER2

  7. Why man's best friend, the dog, could also benefit from an anti-HER-2 vaccine

    OpenAIRE

    Fazekas, Judit; Fürdös, Irene; Singer, Josef; Jensen-Jarolim, Erika

    2016-01-01

    Human epidermal growth factor receptor-2 (HER-2) is a well-established target for anticancer anticancerprecision medicine in humans. A HER-2 homologue with 92% amino acid identity has been described in canine mammary tumors, which whichis termed here as ‘dog epidermal growth factor receptor-2 (DER-2)’, with similar biological implications as those in human breast cancer. Both antigens can principally be immunologically targeted by anti-HER-2 antibodies, such as trastuzumab; however, the in vi...

  8. Relationship Between HER2 Status and Prognosis in Women With Brain Metastases From Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Xu Zhiyuan [Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH (United States); Marko, Nicholas F. [Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH (United States); Department of Neurosurgery, Cleveland Clinic, Cleveland, OH (United States); Chao, Sam T. [Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH (United States); Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH (United States); Angelov, Lilyana; Vogelbaum, Michael A. [Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH (United States); Department of Neurosurgery, Cleveland Clinic, Cleveland, OH (United States); Suh, John H. [Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH (United States); Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH (United States); Barnett, Gene H. [Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH (United States); Weil, Robert J., E-mail: weilr@ccf.org [Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH (United States); Department of Neurosurgery, Cleveland Clinic, Cleveland, OH (United States)

    2012-04-01

    Purpose: To analyze factors affecting outcomes in breast cancer patients with brain metastases (BM) and characterize the role of HER2 status. Methods and Materials: We identified 264 breast cancer patients treated between 1999 and 2008 for BM. HER2 status was known definitively for 172 patients and was used to define cohorts in which survival and risk factors were analyzed. Results: Kaplan-Meier survival analysis demonstrated improved mean overall survival (105.7 vs. 74.3 months, p < 0.02), survival after diagnosis of BM (neurologic survival, NS) (32.2 vs. 18.9 months, p < 0.01), and survival after treatment with stereotactic radiosurgery (RS) (31.3 vs. 14.1, p < 0.01) in HER2+ patients relative to those with HER2- breast cancer. HER2+ status was an independent, positive prognostic factor for survival on univariate and multivariate hazard analysis (hazard ratio: overall survival = 0.66, 0.18; NS = 0.50, 0.34). Additionally, subgroup analysis suggests that stereotactic radiosurgery may be of particular benefit in patients with HER2+ tumors. Conclusions: Overall survival, NS, and RS are improved in patients with HER2+ tumors, relative to those with HER2- lesions, and HER2 amplification is independently associated with increased survival in patients with BM from breast cancer. Our findings suggest that the prognosis of HER2+ patients may be better than that of otherwise similar patients who are HER2- and that stereotactic radiosurgery may be beneficial for some patients with HER2+ lesions.

  9. Rapid Translation of a Novel and Potent Vaccine in HER2+ Metastatic Breast Cancer Patients

    Science.gov (United States)

    2013-10-01

    small percentage of the EGR receptors were localized to the cytoplasm basally when co-expressed with HER2 in HEK293 cells (Figure 5A, a, g and 5m... basal -induced and trastuzumab-induced ubi- quitination of HER2 [26]. Our results are consistent with the notion that HER-VIA functions by activating HER2...inhibitors in breast cancer: Gefitinib (Iressa)-induced changes in the expression and nucleo -cytoplasmic trafficking of HER-ligands [review]. Int J Mol

  10. New developments in the treatment of HER2-positive breast cancer

    Directory of Open Access Journals (Sweden)

    Nahta R

    2012-05-01

    Full Text Available Rita NahtaDepartments of Pharmacology and Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USAAbstract: Approximately 20%–30% of metastatic breast cancers show increased expression of the human epidermal growth factor receptor-2 (HER2 tyrosine kinase. Two HER2-specific therapies are currently approved for clinical treatment of patients with HER2-overexpressing metastatic breast cancer. Trastuzumab is a monoclonal antibody against HER2 and is approved for first-line treatment of HER2-positive metastatic breast cancer. Lapatinib is a small molecule dual inhibitor of epidermal growth factor receptor and HER2 tyrosine kinases, and is approved for trastuzumab-refractory disease. Although trastuzumab is a highly effective therapy for patients with HER2-overexpressing metastatic breast cancer, a significant number of patients in the initial clinical trials of trastuzumab monotherapy showed resistance to trastuzumab-based therapy. Further, among those who did respond, the initial trials indicated that the median time to progression was less than 1 year. Similarly, lapatinib is effective in a subset of trastuzumab-refractory cases, but the majority of patients display resistance. This review discusses the multiple molecular mechanisms of resistance that have been proposed in the literature. In addition, novel agents that are being tested for efficacy against HER2-positive breast cancer, including the antibodies pertuzumab and trastuzumab-DM1 and the immunotoxin affitoxin, are reviewed. The introduction of trastuzumab has revolutionized the clinical care of patients with HER2-positive metastatic breast cancer and has resulted in dramatic reductions in recurrences of early-stage HER2-positive breast cancer. The development and implementation of gene- and protein-based assays that measure potential molecular predictors of trastuzumab resistance will allow individualization of HER2-targeted therapeutic approaches

  11. Proto-oncogene HER-2 in normal, dysplastic and tumorous feline mammary glands: an immunohistochemical and chromogenic in situ hybridization study

    Directory of Open Access Journals (Sweden)

    Martín de las Mulas Juana

    2007-09-01

    Full Text Available Abstract Background Feline mammary carcinoma has been proposed as a natural model of highly aggressive, hormone-independent human breast cancer. To further explore the utility of the model by adding new similarities between the two diseases, we have analyzed the oncogene HER-2 status at both the protein and the gene levels. Methods Formalin-fixed, paraffin-embedded tissue samples from 30 invasive carcinomas, 7 benign lesions and two normal mammary glands were analyzed. Tumour features with prognostic value were recorded. The expression of protein HER-2 was analyzed by immunohistochemistry and the number of gene copies by means of DNA chromogenic in situ hybridization. Results Immunohistochemical HER-2 protein overexpression was found in 40% of feline mammary carcinomas, a percentage higher to that observed in human breast carcinoma. As in women, feline tumours with HER-2 protein overexpression had pathological features of high malignancy. However, amplification of HER-2 was detected in 16% of carcinomas with protein overexpression, a percentage much lower than that observed in their human counterpart. Conclusion Feline mammary carcinoma would be a suitable natural model of that subset of human breast carcinomas with HER-2 protein overexpression without gene amplification.

  12. Autocrine motility factor promotes HER2 cleavage and signaling in breast cancer cells

    Science.gov (United States)

    Kho, Dhong Hyo; Nangia-Makker, Pratima; Balan, Vitaly; Hogan, Victor; Tait, Larry; Wang, Yi; Raz, Avraham

    2013-01-01

    Trastuzumab (Herceptin®) is an effective targeted therapy in HER2 overexpressing human breast carcinoma. However, many HER2-positive patients initially or eventually become resistant to this treatment, so elucidating mechanisms of trastuzumab resistance that emerge in breast carcinoma cells is clinically important. Here we show that autocrine motility factor (AMF) binds to HER2 and induces cleavage to the ectodomain-deleted and constitutively active form p95HER2. Mechanistic investigations indicated that interaction of AMF with HER2 triggers HER2 phosphorylation and metalloprotease-mediated ectodomain shedding, activating PI3K and MAPK signaling and ablating the ability of trastuzumab to inhibit breast carcinoma cell growth. Further, we found that HER2 expression and AMF secretion were inversely related in breast carcinoma cells. Based on this evidence that AMF may contribute to HER2-mediated breast cancer progression, our findings suggest that AMF-HER2 interaction might be a novel target for therapeutic management of breast cancer patients whose disease is resistant to trastuzumab. PMID:23248119

  13. Quantum dots-based double-color imaging of HER2 positive breast cancer invasion

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Xiu-Li, E-mail: usually.158@163.com [Department of Oncology, Zhongnan Hospital of Wuhan University, No 169 Donghu Road, Wuchang District, Wuhan 430071 (China); Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, No 169 Donghu Road, Wuchang District, Wuhan 430071 (China); Peng, Chun-Wei, E-mail: pqc278@163.com [Department of Oncology, Zhongnan Hospital of Wuhan University, No 169 Donghu Road, Wuchang District, Wuhan 430071 (China); Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, No 169 Donghu Road, Wuchang District, Wuhan 430071 (China); Chen, Chuang, E-mail: chenc2469@163.com [Department of Oncology, Zhongnan Hospital of Wuhan University, No 169 Donghu Road, Wuchang District, Wuhan 430071 (China); Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, No 169 Donghu Road, Wuchang District, Wuhan 430071 (China); Yang, Xue-Qin, E-mail: yxqjenny@126.com [Department of Oncology, Zhongnan Hospital of Wuhan University, No 169 Donghu Road, Wuchang District, Wuhan 430071 (China); Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, No 169 Donghu Road, Wuchang District, Wuhan 430071 (China); Hu, Ming-Bai, E-mail: humingbai@126.com [Department of Oncology, Zhongnan Hospital of Wuhan University, No 169 Donghu Road, Wuchang District, Wuhan 430071 (China); Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, No 169 Donghu Road, Wuchang District, Wuhan 430071 (China); Xia, He-Shun, E-mail: xiaheshun@yahoo.com.cn [Department of Pathology, Hubei Cancer Hospital, Wuhan, Hubei 430079 (China); Liu, Shao-Ping, E-mail: lsp_77@126.com [Department of Oncology, Zhongnan Hospital of Wuhan University, No 169 Donghu Road, Wuchang District, Wuhan 430071 (China); Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, No 169 Donghu Road, Wuchang District, Wuhan 430071 (China); and others

    2011-06-10

    Highlights: {yields} HER2 level is closely related to the biologic behaviors of breast cancer cells. {yields} A new method to simultaneously image HER2 and type IV collagen was established. {yields} HER2 status and type IV collagen degradation predict breast cancer invasion. {yields} The complex interactions between tumor and its environment were revealed. -- Abstract: It has been well recognized that human epidermal growth factor receptor 2 (HER2) level in breast cancer (BC) is closely related to the malignant biologic behaviors of the tumor, including invasion and metastasis. Yet, there has been a lack of directly observable evidence to support such notion. Here we report a quantum dots (QDs)-based double-color imaging technique to simultaneously show the HER2 level on BC cells and the type IV collagen in the tumor matrix. In benign breast tumor, the type IV collagen was intact. With the increasing of HER2 expression level, there has been a progressive decrease in type IV collagen around the cancer nest. At HER2 (3+) expression level, there has virtually been a total destruction of type IV collagen. Moreover, HER2 (3+) BC cells also show direct invasion into the blood vessels. This novel imaging method provides direct observable evidence to support the theory that the HER2 expression level is directly related to BC invasion.

  14. Novel anti-HER2 monoclonal antibodies: synergy and antagonism with tumor necrosis factor-α

    Directory of Open Access Journals (Sweden)

    Ceran Ceyhan

    2012-10-01

    Full Text Available Abstract Background One-third of breast cancers display amplifications of the ERBB2 gene encoding the HER2 kinase receptor. Trastuzumab, a humanized antibody directed against an epitope on subdomain IV of the extracellular domain of HER2 is used for therapy of HER2-overexpressing mammary tumors. However, many tumors are either natively resistant or acquire resistance against Trastuzumab. Antibodies directed to different epitopes on the extracellular domain of HER2 are promising candidates for replacement or combinatorial therapy. For example, Pertuzumab that binds to subdomain II of HER2 extracellular domain and inhibits receptor dimerization is under clinical trial. Alternative antibodies directed to novel HER2 epitopes may serve as additional tools for breast cancer therapy. Our aim was to generate novel anti-HER2 monoclonal antibodies inhibiting the growth of breast cancer cells, either alone or in combination with tumor necrosis factor-α (TNF-α. Methods Mice were immunized against SK-BR-3 cells and recombinant HER2 extracellular domain protein to produce monoclonal antibodies. Anti-HER2 antibodies were characterized with breast cancer cell lines using immunofluorescence, flow cytometry, immunoprecipitation, western blot techniques. Antibody epitopes were localized using plasmids encoding recombinant HER2 protein variants. Antibodies, either alone or in combination with TNF-α, were tested for their effects on breast cancer cell proliferation. Results We produced five new anti-HER2 monoclonal antibodies, all directed against conformational epitope or epitopes restricted to the native form of the extracellular domain. When tested alone, some antibodies inhibited modestly but significantly the growth of SK-BR-3, BT-474 and MDA-MB-361 cells displaying ERBB2 amplification. They had no detectable effect on MCF-7 and T47D cells lacking ERBB2 amplification. When tested in combination with TNF-α, antibodies acted synergistically on SK-BR-3 cells

  15. Prognostic significance of performing universal HER2 testing in cases of advanced gastric cancer.

    Science.gov (United States)

    Jiménez-Fonseca, Paula; Carmona-Bayonas, Alberto; Sánchez Lorenzo, Maria Luisa; Plazas, Javier Gallego; Custodio, Ana; Hernández, Raquel; Garrido, Marcelo; García, Teresa; Echavarría, Isabel; Cano, Juana María; Rodríguez Palomo, Alberto; Mangas, Monserrat; Macías Declara, Ismael; Ramchandani, Avinash; Visa, Laura; Viudez, Antonio; Buxó, Elvira; Díaz-Serrano, Asunción; López, Carlos; Azkarate, Aitor; Longo, Federico; Castañón, Eduardo; Sánchez Bayona, Rodrigo; Pimentel, Paola; Limón, Maria Luisa; Cerdá, Paula; Álvarez Llosa, Renata; Serrano, Raquel; Lobera, Maria Pilar Felices; Alsina, María; Hurtado Nuño, Alicia; Gómez-Martin, Carlos

    2017-05-01

    Trastuzumab significantly improves overall survival (OS) when added to cisplatin and fluoropyrimidine as a treatment for HER2-positive advanced gastric cancers (AGC). The aim of this study was to evaluate the impact of the gradual implementation of HER2 testing on patient prognosis in a national registry of AGC. This Spanish National Cancer Registry includes cases who were consecutively recruited at 28 centers from January 2008 to January 2016. The effect of missing HER2 status was assessed using stratified Cox proportional hazards (PH) regression. The rate of HER2 testing increased steadily over time, from 58.3 % in 2008 to 92.9 % in 2016. HER2 was positive in 194 tumors (21.3 %). In the stratified Cox PH regression, each 1 % increase in patients who were not tested for HER2 at the institutions was associated with an approximately 0.3 % increase in the risk of death: hazard ratio, 1.0035 (CI 95 %, 1.001-1.005), P = 0.0019. Median OS was significantly lower at institutions with the highest proportions of patients who were not tested for HER2. Patients treated at centers that took longer to implement HER2 testing exhibited worse clinical outcomes. The speed of implementation behaves as a quality-of-care indicator. Reviewed guidelines on HER2 testing should be used to achieve this goal in a timely manner.

  16. Efficacy of HER2-targeted therapy in metastatic breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors

    DEFF Research Database (Denmark)

    Nielsen, Dorte L; Kümler, Iben; Palshof, Jesper Andreas;

    2013-01-01

    Therapies targeting the human epidermal growth factor receptor (HER) 2 are effective in metastatic breast cancer (MBC). We review the efficacy of HER2-directed therapies, focussing on monoclonal antibodies and tyrosine kinase inhibitors targeting HER2 that have been tested in phase II-III studies...... to those obtained for capecitabine plus lapatinib (48%), continuing trastuzumab in combination with capecitabine (48%), pertuzumab plus trastuzumab (24%), and neratinib (24%). Strategies combining multiple HER2-directed therapies might yield additive or synergistic effects and lead to improved outcome...

  17. Significance of TFF3 protein and Her-2/neu status in patients with gastric adenocarcinoma.

    Science.gov (United States)

    Xu, Cong-cong; Yue, Lu; Wei, Hong-jun; Zhao, Wen-wen; Sui, Ai-hua; Wang, Xiu-mei; Qiu, Wen-sheng

    2013-08-01

    Increased knowledge of molecular alterations involved in gastric carcinogenesis has provided useful information for diagnosis and prediction. In this study, we investigated the clinicopathological significance of TFF3 expression and Her-2/neu status in gastric adenocarcinoma and explored the correlation between TFF3 expression and Her-2/neu status. A hundred and twenty-six (126) patients having undergone curative gastrectomy were enrolled. Immunohistochemistry for TFF3 was performed on tumor tissues and non-neoplastic resection margins. Her-2/neu status was assessed by immunohistochemical staining and fluorescence in situ hybridization (FISH) on tumor tissues. As a result, TFF3 expression and Her-2/neu positivity were detected in 46.8% and 11.9% of the cases, respectively. Patients with negative TFF3 exhibited longer survival than the positive group (P=0.0142), while patients with positive Her-2/neu only showed a tendency toward longer overall survival (P>0.05). However, Her-2/neu was significantly associated with improved disease-free survival (P=0.0234). Multivariate analysis demonstrated Her-2/neu and TFF3 to be independent prognostic indicators of recurrence, and a significantly poor prognosis for expression of TFF3 in patients with Her-2/neu negative tumors. TFF3 is an independent indicator for overall survival in gastric cancer, while Her-2/neu, as a marker of long time survival prediction, seems to be limited.

  18. Clinicopathological and prognostic significance of HER-2/neu and VEGF expression in colon carcinomas

    Directory of Open Access Journals (Sweden)

    Li Jing

    2011-06-01

    Full Text Available Abstract Background HER-2/neu and VEGF expression is correlated with disease behaviors in various cancers. However, evidence for their expression in colon cancer is rather contradictory both for the protein expression status and prognostic value. HER-2/neu is found to participate in VEGF regulation, and has known correlation with VEGF expression in some tumors. In this study, we investigated HER-2/neu and VEGF expression in Chinese colon patients and explored whether there was any correlation between their expression patterns. Methods HER-2/neu and VEGF were investigated immunohistochemically using tumor samples obtained from 317 colon cancer patients with all tumor stages. Correlation of the degree of staining with clinicopathological parameters and survival was investigated. Results Positive expression rates of HER-2/neu and VEGF in colon cancer were 15.5% and 55.5% respectively. HER-2/neu expression was significantly correlated with tumor size and distant metastases (P (P > 0.05. Expression of VEGF was significantly correlated with tumor size, tumor stage, lymph node metastases, and distant metastases (P (P = 0.146. No correlation between HER-2/neu and VEGF expression was detected (P = 0.151. Conclusions HER-2/neu and VEGF are not important prognostic markers of colon cancer. The present results do not support any association between HER2/neu and VEGF expression in this setting.

  19. Naturally occurring clay nanoparticles in Latosols of Brazil central region: detection and characterization

    Science.gov (United States)

    Dominika Dybowska, Agnieszka; Luciene Maltoni, Katia; Piella, Jordi; Najorka, Jens; Puntes, Victor; Valsami-Jones, Eugenia

    2015-04-01

    Stability and reactivity of minerals change as a particle size function, which makes mineral nanoparticles (defined here as nanoparticles contribute to many biogeochemical processes, however much remains to be learnt about these materials, their size dependent behavior and environmental significance. Advances in analytical, imaging and spectroscopic techniques made it now possible to study such particles; however we still have limited knowledge of their chemical, structural and morphological identity and reactivity, in particular in soils. The aim of this research was to characterize the naturally occurring nanoparticles in three soils from Brazil central region. The samples were collected in the A horizon, treated with H2O2 to remove organic material, dispersed in ultrasonic bath and wet sieved (53 µm) to remove the sand fraction. The clay fraction was collected by siphoning the supernatant, conditioned in 1000 ml cylinder, according to the Stock's law. This fraction was further processed by re-suspension in water, sonication and repeated centrifugation, to separate the fraction smaller than 100nm. This material, called here the soil "nanofraction", was analyzed using a range of techniques: 1) nanoparticle size/morphology and crystallinity with Transmission Electron Microscopy (TEM operateing in scanning (HAADF-STEM) and High Resolution (HRTEM) mode), 2) size distribution in water with Dynamic Light Scattering (DLS) and surface charge estimated from electrophoretic mobility measurements 3) crystal phase and crystallite size with X-ray Diffraction (XRD) 4) Chemical composition by quantitative analysis of elements (e.g., Si, Fe, Al, Ti) and their spatial distribution with HRTEM/EDS elemental mappings. The nanofraction had an average hydrodynamic particle diameter ranging from 83 to 92nm with a low polydispersity index of 0.13-0.17 and was found highly stable in aqueous suspension (no change in average particle size up to several months of storage). Particle surface

  20. Quantitative Determination of Noa (Naturally Occurring Asbestos) in Rocks : Comparison Between Pcom and SEM Analysis

    Science.gov (United States)

    Baietto, Oliviero; Amodeo, Francesco; Giorgis, Ilaria; Vitaliti, Martina

    2017-04-01

    The quantification of NOA (Naturally Occurring Asbestos) in a rock or soil matrix is complex and subject to numerous errors. The purpose of this study is to compare two fundamental methodologies used for the analysis: the first one uses Phase Contrast Optical Microscope (PCOM) while the second one uses Scanning Electron Microscope (SEM). The two methods, although they provide the same result, which is the asbestos mass to total mass ratio, have completely different characteristics and both present pros and cons. The current legislation in Italy involves the use of SEM, DRX, FTIR, PCOM (DM 6/9/94) for the quantification of asbestos in bulk materials and soils and the threshold beyond which the material is considered as hazardous waste is a concentration of asbestos fiber of 1000 mg/kg.(DM 161/2012). The most used technology is the SEM which is the one among these with the better analytical sensitivity.(120mg/Kg DM 6 /9/94) The fundamental differences among the analyses are mainly: - Amount of analyzed sample portion - Representativeness of the sample - Resolution - Analytical precision - Uncertainty of the methodology - Operator errors Due to the problem of quantification of DRX and FTIR (1% DM 6/9/94) our Asbestos Laboratory (DIATI POLITO) since more than twenty years apply the PCOM methodology and in the last years the SEM methodology for quantification of asbestos content. The aim of our research is to compare the results obtained from a PCOM analysis with the results provided by SEM analysis on the base of more than 100 natural samples both from cores (tunnel-boring or explorative-drilling) and from tunnelling excavation . The results obtained show, in most cases, a good correlation between the two techniques. Of particular relevance is the fact that both techniques are reliable for very low quantities of asbestos, even lower than the analytical sensitivity. This work highlights the comparison between the two techniques emphasizing strengths and weaknesses of

  1. HIV infection of naturally occurring and genetically reprogrammed human regulatory T-cells.

    Science.gov (United States)

    Oswald-Richter, Kyra; Grill, Stacy M; Shariat, Nikki; Leelawong, Mindy; Sundrud, Mark S; Haas, David W; Unutmaz, Derya

    2004-07-01

    A T-cell subset, defined as CD4(+)CD25(hi) (regulatory T-cells [Treg cells]), was recently shown to suppress T-cell activation. We demonstrate that human Treg cells isolated from healthy donors express the HIV-coreceptor CCR5 and are highly susceptible to HIV infection and replication. Because Treg cells are present in very few numbers and are difficult to expand in vitro, we genetically modified conventional human T-cells to generate Treg cells in vitro by ectopic expression of FoxP3, a transcription factor associated with reprogramming T-cells into a Treg subset. Overexpression of FoxP3 in naïve human CD4(+) T-cells recapitulated the hyporesponsiveness and suppressive function of naturally occurring Treg cells. However, FoxP3 was less efficient in reprogramming memory T-cell subset into regulatory cells. In addition, FoxP3-transduced T-cells also became more susceptible to HIV infection. Remarkably, a portion of HIV-positive individuals with a low percentage of CD4(+) and higher levels of activated T-cells have greatly reduced levels of FoxP3(+)CD4(+)CD25(hi) T-cells, suggesting disruption of the Treg cells during HIV infection. Targeting and disruption of the T-cell regulatory system by HIV may contribute to hyperactivation of conventional T-cells, a characteristic of HIV disease progression. Moreover, the ability to reprogram human T-cells into Treg cells in vitro will greatly aid in decoding their mechanism of suppression, their enhanced susceptibility to HIV infection, and the unique markers expressed by this subset.

  2. Identification of myeloid derived suppressor cells in dogs with naturally occurring cancer.

    Science.gov (United States)

    Goulart, Michelle R; Pluhar, G Elizabeth; Ohlfest, John R

    2012-01-01

    Dogs with naturally occurring cancer represent an important large animal model for drug development and testing novel immunotherapies. However, poorly defined immunophenotypes of canine leukocytes have limited the study of tumor immunology in dogs. The accumulation of myeloid derived suppressor cells (MDSCs) is known to be a key mechanism of immune suppression in tumor-bearing mice and in human patients. We sought to identify MDSCs in the blood of dogs with cancer. Peripheral blood mononuclear cells (PBMCs) from dogs with advanced or early stage cancer and from age-matched healthy controls were analyzed by flow cytometry and microscopy. Suppressive function was tested in T cell proliferation and cytokine elaboration assays. Semi-quantitative RT-PCR was used to identify potential mechanisms responsible for immunosuppression. PBMCs from dogs with advanced or metastatic cancer exhibited a significantly higher percentage of CD11b(+)CD14(-)MHCII(-) cells compared to dogs diagnosed with early stage non-metastatic tumors and healthy dogs. These CD11b(+) CD14(-)MHCII(-) cells constitute a subpopulation of activated granulocytes that co-purify with PBMCs, display polymorphonuclear granulocyte morphology, and demonstrate a potent ability to suppress proliferation and IFN-γ production in T cells from normal and tumor-bearing donors. Furthermore, these cells expressed hallmark suppressive factors of human MDSC including ARG1, iNOS2, TGF-β and IL-10. In summary our data demonstrate that MDSCs accumulate in the blood of dogs with advanced cancer and can be measured using this three-marker immunophenotype, thereby enabling prospective studies that can monitor MDSC burden.

  3. Modeling the pulsed light inactivation of microorganisms naturally occurring on vegetable substrates.

    Science.gov (United States)

    Izquier, Adriana; Gómez-López, Vicente M

    2011-09-01

    Pulsed light (PL) is a fast non-thermal method for microbial inactivation. This research studied the kinetics of PL inactivation of microorganisms naturally occurring in some vegetables. Iceberg lettuce, white cabbage and Julienne-style cut carrots were subjected to increasing PL fluences up to 12J/cm(2) in order to study its effect on aerobic mesophilic bacteria determined by plate count. Also, sample temperature increase was determined by infrared thermometry. Survivors' curves were adjusted to several models. No shoulder but tail was observed. The Weibull model showed good fitting performance of data. Results for lettuce were: goodness-of-fit parameter RMSE=0.2289, fluence for the first decimal reduction δ=0.98±0.80J/cm(2) and concavity parameter p=0.33±0.08. Results for cabbage were: RMSE=0.0725, δ=0.81±0.23J/cm(2) and p=0.30±0.02; and for carrot: RMSE=0.1235, δ=0.39±0.24J/cm(2) and p=0.23±0.03. For lettuce, a log-linear and tail model was also suitable. Validation of the Weibull model produced determination coefficients of 0.88-0.96 and slopes of 0.78-0.99. Heating was too low to contribute to inactivation. A single low-energy pulse was enough to achieve one log reduction, with an ultrafast treatment time of 0.5ms. While PL efficacy was found to be limited to high residual counts, the achievable inactivation level may be considered useful for shelf-life extension.

  4. Naturally occurring variation in trophoblast invasion as a source of novel (epigenetic biomarkers

    Directory of Open Access Journals (Sweden)

    Marie eVan DIjk

    2012-02-01

    Full Text Available During the first trimester of pregnancy fetal trophoblasts invade the maternal decidua, thereby remodelling the maternal spiral arteries. This process of trophoblast invasion is very similar to cancer cell invasion, with multiple signaling pathways shared between the two. Pregnancy-related diseases, e.g. pre-eclampsia, and cancer metastasis start with a decrease or increase in cellular invasion, respectively. Here, we investigate if first trimester placental explants can be used to identify epigenetic factors associated with changes in cellular invasion and their potential use as biomarkers. We show that the outgrowth potential of first trimester explants significantly correlates with promoter methylation of PRKCDBP and MMP2, two genes known to be differentially methylated in both placenta and cancer. The increase in methylation percentage coincides with an increase in invasion potential. Subsequently, as a non-invasive marker must be detectable in blood, plasma samples of pregnant and non-pregnant women were analyzed. The MMP2 promoter showed high methylation levels in non-pregnant plasma samples, which decreased in pregnant plasma. The decrease in methylated plasma DNA during pregnancy is most likely due to the fractional increase in unmethylated placental DNA. This suggests that the level of unmethylated DNA has the potential to be used as an invasion marker, where higher levels of unmethylated DNA indicate a lower invasion potential of trophoblasts.These proof of principle data provide evidence that human first trimester placental explants are an excellent ex vivo model system to identify (epigenetic factors and thus potential biomarkers associated with changes in cellular invasion, e.g. to detect pregnancy-related diseases or cancer metastasis. To identify novel biomarkers the next step is to correlate naturally occurring variation in invasion potential to changes in (epigenetic factors by genome-wide approaches such as massively parallel

  5. Antioxidant effect of naturally occurring xanthines on the oxidative damage of DNA bases

    Science.gov (United States)

    Vieira, A. J. S. C.; Telo, J. P.; Pereira, H. F.; Patrocínio, P. F.; Dias, R. M. B.

    1999-01-01

    The repair of the oxidised radicals of adenine and guanosine by several naturally occurring xanthines was studied. Each pair of DNA purine/xanthine was made to react with the sulphate radical and the decrease of the concentration of both compounds was measured by HPLC as a function of irradiation time. The results show that xanthine efficiently prevents the oxidation of the two DNA purines. Theophyline and paraxanthine repair the oxidised radical of adenine but not the one from guanosine. Theobromine and caffeine do not show any protecting effect. An order of the oxidation potentials of all the purines studied is proposed. La réparation des radicaux oxydés de l'adénine et de la guanosine par des xanthines naturelles a été étudiée en soumettant chaque paire base de l'ADN/xanthine à l'oxydation par le radical sulfate et en mesurant par HPLC la disparition des deux composés en fonction du temps d'irradiation. Les résultats montrent que la xanthine joue un rôle protecteur efficace contre l'oxydation des deux purines de l'ADN. La théophyline et la paraxanthine réparent le radical oxydé de l'adénine mais pas celui de la guanosine. La théobromine et la cafeíne n'ont pas d'effet protecteur. Un ordre de potentiels d'oxydation des purines étudiées est proposé.

  6. Wetland defense: naturally occurring pesticide resistance in zooplankton populations protects the stability of aquatic communities.

    Science.gov (United States)

    Bendis, Randall J; Relyea, Rick A

    2016-06-01

    Anthropogenic stressors are ubiquitous and have been implicated in worldwide declines of terrestrial and aquatic species. Pesticides are one such stressor that can have profound effects on aquatic communities by directly affecting sensitive species and indirectly affecting other species via trophic cascades, which can alter ecosystem function. However, there is growing evidence that non-target species can evolve increased resistance. When such species are important drivers of the food web, then evolved resistance should help buffer communities from the effects of pesticides. To examine this possibility, we cultured four populations of the common zooplankton Daphnia pulex that we previously demonstrated were either sensitive or resistant to a common insecticide (i.e., chlorpyrifos) due to their proximity to agriculture. Using outdoor mesocosms that contained identical aquatic communities of phytoplankton, periphyton, and leopard frog tadpoles (Lithobates pipiens), we manipulated four D. pulex populations and four insecticide concentrations. As we monitored the communities for nearly 3 months, we found that the insecticide caused direct mortality of D. pulex in communities containing sensitive populations, and this led to a bloom of phytoplankton. In contrast, the insecticide caused much less direct mortality in communities containing resistant D. pulex populations, and the trophic cascade was prevented under low to moderate insecticide concentrations. Across all insecticide treatments, survivorship of leopard frogs was approximately 72 % in communities with resistant D. pulex but only 35 % in communities with sensitive D. pulex. To our knowledge, this is one of the first studies to use naturally occurring population variation in insecticide resistance to show that the evolution of pesticide resistance in zooplankton can mitigate the effects of insecticide-induced trophic cascades, and that this outcome can have far-reaching community effects.

  7. Removal of arsenite and arsenate using hydrous ferric oxide incorporated into naturally occurring porous diatomite.

    Science.gov (United States)

    Jang, Min; Min, Soo-Hong; Kim, Tak-Hyun; Park, Jae Kwang

    2006-03-01

    In this study, a simplified and effective method was tried to immobilize iron oxide onto a naturally occurring porous diatomite. Experimental resultsfor several physicochemical properties and arsenic edges revealed that iron oxide incorporated into diatomite was amorphous hydrous ferric oxide (HFO). Sorption trends of Fe (25%)-diatomite for both arsenite and arsenate were similar to those of HFO, reported by Dixit and Hering (Environ. Sci. Technol. 2003, 37, 4182-4189). The pH at which arsenite and arsenate are equally sorbed was 7.5, which corresponds to the value reported for HFO. Judging from the number of moles of iron incorporated into diatomite, the arsenic sorption capacities of Fe (25%)-diatomite were comparable to or higher than those of the reference HFO. Furthermore, the surface complexation modeling showed that the constants of [triple bond]SHAsO4- or [triple bond]SAsO4(2-) species for Fe (25%)-diatomite were larger than those reference values for HFO or goethite. Larger differences in constants of arsenate surface species might be attributed to aluminum hydroxyl ([triple bond]Al-OH) groups that can work better for arsenate removal. The pH-controlled differential column batch reactor (DCBR) and small-scale column tests demonstrated that Fe (25%)-diatomite had high sorption speeds and high sorption capacities compared to those of a conventional sorbent (AAFS-50) that is known to be the first preference for arsenic removal performance in Bangladesh. These results could be explained by the fact that Fe (25%)-diatomite contained well-dispersed HFO having a great affinity for arsenic species and well-developed macropores as shown by scanning electron microscopy (SEM) and pore size distribution (PSD) analyses.

  8. Polyporus tenuiculus: a new naturally occurring mushroom that can be industrially cultivated on agricultural waste.

    Science.gov (United States)

    Omarini, Alejandra; Lechner, Bernardo E; Albertó, Edgardo

    2009-05-01

    Polyporus tenuiculus is a naturally occurring species from Central and South America that is consumed by different ethnic groups in the region. To determine the optimal conditions for fruiting body production, two strains were assayed on wheat straw and sawdust with or without supplements. Sixty days of incubation at 25 degrees C were needed to produce a solid block. The highest yield was obtained with strain ICFC 383/00 grown on supplemented willow sawdust. In a second experiment the strain ICFC 383/00 and different supplements were used to improve the biological efficiency (BE) and to determine the quality traits and its biodegradation capacity. The highest yields were obtained on sawdust with 25% of supplements reaching 82.7% of BE. Supplements raised the number of flushes, generally from four to five, contributing to increased yields. The type of substrate had a significant effect on fruiting body diameters of P. tenuiculus, and the largest mushrooms were harvested on supplemented substrate with the highest BE coinciding with the highest dry matter loss in substrates. P. tenuiculus showed a capacity to degrade sawdust, causing a decrease of 67.2-74.5% in cellulose, 80.4-85.7% in hemicellulose, and 60.6-66.2% in lignin content at the end of the cultivation cycle. The decrease in hemicellulose was relatively greater than that of cellulose and lignin on supplemented substrates. This is the first report of the cultivation of P. tenuiculus on lignocellulosic waste, and it is a promising species both for commercial production and for its potential use in the degradation of other biowastes.

  9. HIV infection of naturally occurring and genetically reprogrammed human regulatory T-cells.

    Directory of Open Access Journals (Sweden)

    Kyra Oswald-Richter

    2004-07-01

    Full Text Available A T-cell subset, defined as CD4(+CD25(hi (regulatory T-cells [Treg cells], was recently shown to suppress T-cell activation. We demonstrate that human Treg cells isolated from healthy donors express the HIV-coreceptor CCR5 and are highly susceptible to HIV infection and replication. Because Treg cells are present in very few numbers and are difficult to expand in vitro, we genetically modified conventional human T-cells to generate Treg cells in vitro by ectopic expression of FoxP3, a transcription factor associated with reprogramming T-cells into a Treg subset. Overexpression of FoxP3 in naïve human CD4(+ T-cells recapitulated the hyporesponsiveness and suppressive function of naturally occurring Treg cells. However, FoxP3 was less efficient in reprogramming memory T-cell subset into regulatory cells. In addition, FoxP3-transduced T-cells also became more susceptible to HIV infection. Remarkably, a portion of HIV-positive individuals with a low percentage of CD4(+ and higher levels of activated T-cells have greatly reduced levels of FoxP3(+CD4(+CD25(hi T-cells, suggesting disruption of the Treg cells during HIV infection. Targeting and disruption of the T-cell regulatory system by HIV may contribute to hyperactivation of conventional T-cells, a characteristic of HIV disease progression. Moreover, the ability to reprogram human T-cells into Treg cells in vitro will greatly aid in decoding their mechanism of suppression, their enhanced susceptibility to HIV infection, and the unique markers expressed by this subset.

  10. Studying human respiratory disease in animals--role of induced and naturally occurring models.

    Science.gov (United States)

    Williams, Kurt; Roman, Jesse

    2016-01-01

    Respiratory disorders like asthma, emphysema, and pulmonary fibrosis affect millions of Americans and many more worldwide. Despite advancements in medical research that have led to improved understanding of the pathophysiology of these conditions and sometimes to new therapeutic interventions, these disorders are for the most part chronic and progressive; current interventions are not curative and do not halt disease progression. A major obstacle to further advancements relates to the absence of animal models that exactly resemble the human condition, which delays the elucidation of relevant mechanisms of action, the unveiling of biomarkers of disease progression, and identification of new targets for intervention in patients. There are currently many induced animal models of human respiratory disease available for study, and even though they mimic features of human disease, discoveries in these models have not always translated into safe and effective treatments in humans. A major obstacle relates to the genetic, anatomical, and functional variations amongst species, which represents the major challenge to overcome when searching for appropriate models of respiratory disease. Nevertheless, rodents, in particular mice, have become the most common species used for experimentation, due to their relatively low cost, size, and adequate understanding of murine genetics, among other advantages. Less well known is the fact that domestic animals also suffer from respiratory illnesses similar to those found in humans. Asthma, bronchitis, pneumonia, and pulmonary fibrosis are among the many disorders occurring naturally in dogs, cats, and horses, among other species. These models might better resemble the human condition and are emphasized here, but further investigations are needed to determine their relevance.

  11. Molecular analysis of Porcine Circovirus Type 2 strains from Uruguay: evidence for natural occurring recombination.

    Science.gov (United States)

    Ramos, Natalia; Mirazo, Santiago; Castro, Gustavo; Arbiza, Juan

    2013-10-01

    Porcine Circovirus Type 2 (PCV2) is a worldwide distributed virus and is considered an important emerging pathogen related to several distinct disease syndromes in pigs. Genomic structure consists of three major open reading frames (ORFs). ORF1 (rep gene) encodes replication-related proteins, ORF2 (cap gene) encodes the capsid protein and ORF3 encodes a protein putatively involved in virus-induced apoptosis. Based on cap gene sequences, PCV2 strains are classified into two main genotypes, PCV2a with five clusters (2A-2E) and PCV2b with three clusters (1A-1C). According to previous theoretical studies, PCV2 strains can eventually undergo intra and inter-genotype recombination, mainly within the rep gene. Ever since, several evidences of recombination in the field have been reported and confirmed this hypothesis. In South America, data regarding molecular characterization of PCV2 strains is still scant. Genotyping studies in the region have concluded that PCV2b is the predominant circulating genotype in the region and till now, no recombinant strains have ever been reported. In this work we thoroughly characterized at the molecular level Uruguayan PCV2 strains by extensive sequence data analysis. Moreover, recombination software tools were applied to explore and characterize eventual occurrence of natural recombination events. Two recombinant PCV2 strains were detected in this study, as a consequence of an inter-genotype recombination event between PCV2b-1A and PCV2a-2D, as the major and minor parent, respectively. According to recombination software analysis, in both cases the event occurred within the ORF1. Herein, extensive viral sequence dataset is provided, including the characterization of the first PCV2 recombinant strains ever reported in South America. Additionally, our results suggested a multi-centered source of PCV2 infection in Uruguay, which probably involved Brazilian and European origins.

  12. The naturally occurring steroid solasodine induces neurogenesis in vitro and in vivo.

    Science.gov (United States)

    Lecanu, L; Hashim, A I; McCourty, A; Giscos-Douriez, I; Dinca, I; Yao, W; Vicini, S; Szabo, G; Erdélyi, F; Greeson, J; Papadopoulos, V

    2011-06-02

    In this study, we explored the capacity of the naturally occurring compound solasodine to promote neurogenesis in vitro and in vivo. Mouse embryonic teratocarcinoma P19 cells exposed to solasodine for 2 days followed by a 5-day washout differentiated into cholinergic neurons that expressed specific neuronal markers and displayed important axonal formation that continued growing even 30 days after treatment. In vivo, a 2-week infusion of solasodine into the left ventricle of the rat brain followed by a 3-week washout resulted in a significant increase in bromodeoxyuridine uptake by cells of the ependymal layer, subventricular zone, and cortex that co-localized with doublecortin immunostaining, demonstrating the proliferative and differentiating properties of solasodine on neuronal progenitors. In addition, these data demonstrate that under our experimental conditions adult ependymal cells retrieved their proliferative and differentiating abilities. The GAP-43/HuD pathway was activated both in vitro and in vivo, suggesting a role in the differentiating process triggered by solasodine. Solasodine treatment in rats resulted in a dramatic increase in expression of the cholesterol- and drug-binding translocator protein in ependymal cells, suggesting a possible role played by neurosteroid production in solasodine-induced neurogenesis. In GAD65-GFP mice that express the green fluorescent protein under the control of the glutamic acid decarboxylase 65-kDa promoter, solasodine treatment increased the number of GABAergic progenitors and neuroblasts generated in the subventricular zone and present in the olfactory migratory tract. Taken together, these results suggest that solasodine offers an interesting approach to stimulate in situ neurogenesis from resident neuronal progenitors as part of neuron replacement therapy.

  13. A century of oil and gas exploration in Albania: assessment of Naturally Occurring Radioactive Materials (NORMs).

    Science.gov (United States)

    Xhixha, G; Baldoncini, M; Callegari, I; Colonna, T; Hasani, F; Mantovani, F; Shala, F; Strati, V; Xhixha Kaçeli, M

    2015-11-01

    The Naturally Occurring Radioactive Materials (NORMs) that are potentially generated from oil and gas extractions in Albania have been disposed of without regulations for many decades, and therefore, an extensive survey in one of the most productive regions (Vlora-Elbasan) was performed. A total of 52 gamma ray spectrometry measurements of soil, oil-sand, sludge, produced water and crude oil samples were performed. We discovered that relatively low activity concentrations of (226)Ra, (228)Ra, (228)Th and (40)K, with concentrations of 23±2Bq/kg, 23±2Bq/kg, 24±3Bq/kg and 549±12Bq/kg, respectively, came from the oil-sands produced by the hydrocarbon extraction of the molasses formations. The mineralogical characterizations and the (228)Ra/(40)K and (226)Ra/(40)K ratios of these Neogene deposits confirmed the predictions of the geological and geodynamic models of a dismantling of the Mesozoic source rocks. The average activity concentrations (±standard deviations) of the radium isotopes ((226)Ra and (228)Ra) and of the (228)Th and (40)K radionuclides in soil samples were 20±5Bq/kg, 25±10Bq/kg, 25±9Bq/kg and 326±83Bq/kg, respectively. Based on the measurements in this study, the future radiological assessments of other fields in the region should be strategically planned to focus on the oil-sands from the molasses sediments. Disequilibrium in the (228)Ra decay segment was not observed in the soil, sludge or oil-sand samples within the standard uncertainties. After a detailed radiological characterization of the four primary oil fields, we concluded that the outdoor absorbed dose rate never exceeded the worldwide population weighted average absorbed dose rate in outdoor air from terrestrial gamma radiation.

  14. Naturally Occurring Radioactive Materials in Coals and Coal Combustion Residuals in the United States.

    Science.gov (United States)

    Lauer, Nancy E; Hower, James C; Hsu-Kim, Heileen; Taggart, Ross K; Vengosh, Avner

    2015-09-15

    The distribution and enrichment of naturally occurring radioactive materials (NORM) in coal combustion residuals (CCRs) from different coal source basins have not been fully characterized in the United States. Here we provide a systematic analysis of the occurrence of NORM ((232)Th, (228)Ra, (238)U, (226)Ra, and (210)Pb) in coals and associated CCRs from the Illinois, Appalachian, and Powder River Basins. Illinois CCRs had the highest total Ra ((228)Ra + (226)Ra = 297 ± 46 Bq/kg) and the lowest (228)Ra/(226)Ra activity ratio (0.31 ± 0.09), followed by Appalachian CCRs (283 ± 34 Bq/kg; 0.67 ± 0.09), and Powder River CCRs (213 ± 21 Bq/kg; 0.79 ± 0.10). Total Ra and (228)Ra/(226)Ra variations in CCRs correspond to the U and Th concentrations and ash contents of their feed coals, and we show that these relationships can be used to predict total NORM concentrations in CCRs. We observed differential NORM volatility during combustion that results in (210)Pb enrichment and (210)Pb/(226)Ra ratios greater than 1 in most fly-ash samples. Overall, total NORM activities in CCRs are 7-10- and 3-5-fold higher than NORM activities in parent coals and average U.S. soil, respectively. This study lays the groundwork for future research related to the environmental and human health implications of CCR disposal and accidental release to the environment in the context of this elevated radioactivity.

  15. Reciprocal regulation of annexin A2 and EGFR with Her-2 in Her-2 negative and herceptin-resistant breast cancer.

    Directory of Open Access Journals (Sweden)

    Praveenkumar K Shetty

    Full Text Available Alternative survival pathways are commonly seen to be upregulated upon inhibition of receptor tyrosine kinases (RTK, including Her-2. It is established that treatment with Herceptin leads to selective overexpression and activation of epidermal growth factor receptor (EGFR and Src which further contributes to oncogenesis in Herceptin resistant and triple negative breast cancer (TNBC patients. Here, we show a co-regulated upregulation in the expression of Annexin A2 (AnxA2, a known substrate of Src and one of the regulators of EGFR receptor endocytosis, in Herceptin resistant and Her-2 negative breast cancer. Immunohistochemical expression analysis revealed a reciprocal regulation between Her-2 and AnxA2 in breast cancer clinical samples as well as in cell lines as confirmed by protein and RNA analysis. The siRNA and Herceptin mediated downregulation/inhibition of Her-2 in Her-2 amplified cells induced AnxA2 expression and membrane translocation. In this study we report a possible involvement of AnxA2 in maintaining constitutively activated EGFR downstream signaling intermediates and hence in cell proliferation, migration and viability. This effect was consistent in Herceptin resistant JIMT-1 cells as well as in Her-2 negative breast cancer. The siRNA mediated AnxA2 downregulation leads to increased apoptosis, decreased cell viability and migration. Our studies further indicate the role of AnxA2 in EGFR-Src membrane bound signaling complex and ligand induced activation of downstream signaling pathways. Targeting this AnxA2 dependent positive regulation of EGFR signaling cascade may be of therapeutic value in Her-2 negative breast cancer.

  16. Amplification of HER2 is a marker for global genomic instability.

    Science.gov (United States)

    Ellsworth, Rachel E; Ellsworth, Darrell L; Patney, Heather L; Deyarmin, Brenda; Love, Brad; Hooke, Jeffrey A; Shriver, Craig D

    2008-10-14

    Genomic alterations of the proto-oncogene c-erbB-2 (HER-2/neu) are associated with aggressive behavior and poor prognosis in patients with breast cancer. The variable clinical outcomes seen in patients with similar HER2 status, given similar treatments, suggests that the effects of amplification of HER2 can be influenced by other genetic changes. To assess the broader genomic implications of structural changes at the HER2 locus, we investigated relationships between genomic instability and HER2 status in patients with invasive breast cancer. HER2 status was determined using the PathVysion assay. DNA was extracted after laser microdissection from the 181 paraffin-embedded HER2 amplified (n=39) or HER2 negative (n=142) tumor specimens with sufficient tumor available to perform molecular analysis. Allelic imbalance (AI) was assessed using a panel of microsatellite markers representing 26 chromosomal regions commonly altered in breast cancer. Student t-tests and partial correlations were used to investigate relationships between genomic instability and HER2 status. The frequency of AI was significantly higher (P.005) in HER2 amplified (27%) compared to HER2 negative tumors (19%). Samples with HER2 amplification showed significantly higher levels of AI (P.05) at chromosomes 11q23, 16q22-q24 and 18q21. Partial correlations including ER status and tumor grade supported associations between HER2 status and alterations at 11q13.1, 16q22-q24 and 18q21. The poor prognosis associated with HER2 amplification may be attributed to global genomic instability as cells with high frequencies of chromosomal alterations have been associated with increased cellular proliferation and aggressive behavior. In addition, high levels of DNA damage may render tumor cells refractory to treatment. In addition, specific alterations at chromosomes 11q13, 16q22-q24, and 18q21, all of which have been associated with aggressive tumor behavior, may serve as genetic modifiers to HER2 amplification

  17. Amplification of HER2 is a marker for global genomic instability

    Directory of Open Access Journals (Sweden)

    Love Brad

    2008-10-01

    Full Text Available Abstract Background Genomic alterations of the proto-oncogene c-erbB-2 (HER-2/neu are associated with aggressive behavior and poor prognosis in patients with breast cancer. The variable clinical outcomes seen in patients with similar HER2 status, given similar treatments, suggests that the effects of amplification of HER2 can be influenced by other genetic changes. To assess the broader genomic implications of structural changes at the HER2 locus, we investigated relationships between genomic instability and HER2 status in patients with invasive breast cancer. Methods HER2 status was determined using the PathVysion® assay. DNA was extracted after laser microdissection from the 181 paraffin-embedded HER2 amplified (n = 39 or HER2 negative (n = 142 tumor specimens with sufficient tumor available to perform molecular analysis. Allelic imbalance (AI was assessed using a panel of microsatellite markers representing 26 chromosomal regions commonly altered in breast cancer. Student t-tests and partial correlations were used to investigate relationships between genomic instability and HER2 status. Results The frequency of AI was significantly higher (P P Conclusion The poor prognosis associated with HER2 amplification may be attributed to global genomic instability as cells with high frequencies of chromosomal alterations have been associated with increased cellular proliferation and aggressive behavior. In addition, high levels of DNA damage may render tumor cells refractory to treatment. In addition, specific alterations at chromosomes 11q13, 16q22-q24, and 18q21, all of which have been associated with aggressive tumor behavior, may serve as genetic modifiers to HER2 amplification. These data not only improve our understanding of HER in breast pathogenesis but may allow more accurate risk profiles and better treatment options to be developed.

  18. Control of Her-2 tumor immunity and thyroid autoimmunity by MHC and regulatory T cells.

    Science.gov (United States)

    Jacob, Jennifer B; Kong, Yi-chi M; Meroueh, Chady; Snower, Daniel P; David, Chella S; Ho, Ye-Shih; Wei, Wei-Zen

    2007-07-15

    Immune reactivity to self-antigens in both cancer and autoimmune diseases can be enhanced by systemic immune modulation, posing a challenge in cancer immunotherapy. To distinguish the genetic and immune regulation of tumor immunity versus autoimmunity, immune responses to human ErbB-2 (Her-2) and mouse thyroglobulin (mTg) were tested in transgenic mice expressing Her-2 that is overexpressed in several cancers, and HLA-DRB1*0301 (DR3) that is associated with susceptibility to several human autoimmune diseases, as well as experimental autoimmune thyroiditis (EAT). To induce Her-2 response, mice were electrovaccinated with pE2TM and pGM-CSF encoding the extracellular and transmembrane domains of Her-2 and the murine granulocyte macrophage colony-stimulating factor, respectively. To induce EAT, mice received mTg i.v. with or without lipopolysaccharide. Depletion of regulatory T cells (Treg) with anti-CD25 monoclonal antibody enhanced immune reactivity to Her-2 as well as mTg, showing control of both Her-2 and mTg responses by Treg. When immunized with, Her-2xDR3 and B6xDR3 mice expressing H2(b)xDR3 haplotype developed more profound mTg response and thyroid pathology than Her-2 or B6 mice that expressed the EAT-resistant H2(b) haplotype. In Her-2xDR3 mice, the response to mTg was further amplified when mice were also immunized with pE2TM and pGM-CSF. On the contrary, Her-2 reactivity was comparable whether mice expressed DR3 or not. Therefore, induction of Her-2 immunity was independent of DR3 but development of EAT was dictated by this allele, whereas Tregs control the responses to both self-antigens. These results warrant close monitoring of autoimmunity during cancer immunotherapy, particularly in patients with susceptible MHC class II alleles.

  19. Effects of Herceptin on circulating tumor cells in HER2 positive early breast cancer.

    Science.gov (United States)

    Zhang, J-L; Yao, Q; Chen Y Wang, J-H; Wang, H; Fan, Q; Ling, R; Yi, J; Wang, L

    2015-03-20

    The objective of this study was to determine the changes in peripheral blood circulating tumor cells in HER2-positive early breast cancer before and after Herceptin therapy, and to explore the effects of the HER2 gene and Herceptin on circulating tumor cells. CK19 mRNA expression in peripheral blood was evaluated by qRT-PCR as an index of circulating tumor cells in 15 cases of HER-2-positive breast cancer and 18 cases of HER2-negative breast cancer before, and after chemotherapy as well. Ten cases of HER2-positive breast cancer continued on Herceptin therapy for 3 months after chemotherapy, and their peripheral blood was again drawn and assayed for CK-19 mRNA expression. Preoperatively, all cases of HER2-positive cancer were positive for CK19 mRNA in peripheral blood, but 6 cases of HER2-negative breast cancer were positive (33.3%), where there was a substantial difference between the two groups. After 6 cycles of adjuvant chemotherapy, CK19 positive rates in cases of HER2-positive and -negative breast cancer reduced by 93.3 and 11.1%, respectively, with a significant difference still existing. After 3 months of Herceptin therapy, expression of CK19 mRNA declined considerably in 10 cases of HER2 positive breast cancer (113.66 ± 88.65 vs 63.35 ± 49.27, P = 0.025). HER-2 gene expression closely correlated with circulating tumor cells in peripheral blood of early breast cancer patients. Moreover, Herceptin, a monoclonal antibody for HER2, can reduce the number of circulating tumor cells, which can be an early predictive factor for Herceptin therapy effectiveness against breast cancer.

  20. Stratigraphic and geochemical controls on naturally occurring arsenic in groundwater, eastern Wisconsin, USA

    Science.gov (United States)

    Schreiber, M. E.; Simo, J. A.; Freiberg, P. G.

    High arsenic concentrations (up to 12,000μg/L) have been measured in groundwater from a confined sandstone aquifer in eastern Wisconsin. The main arsenic source is a sulfide-bearing secondary cement horizon (SCH) that has variable thickness, morphology, and arsenic concentrations. Arsenic occurs in pyrite and marcasite as well as in iron oxyhydroxides but not as a separate arsenopyrite phase. Nearly identical sulfur isotopic signatures in pyrite and dissolved sulfate and the correlation between dissolved sulfate, iron, and arsenic concentrations suggest that sulfide oxidation is the dominant process controlling arsenic release to groundwater. However, arsenic-bearing oxyhydroxides can potentially provide another arsenic source if reducing conditions develop or if they are transported as colloids in the aquifer. Analysis of well data indicates that the intersection of the SCH with static water levels measured in residential wells is strongly correlated with high concentrations of arsenic in groundwater. Field and laboratory data suggest that the most severe arsenic contamination is caused by localized borehole interactions of air, water, and sulfides. Although arsenic contamination is caused by oxidation of naturally occurring sulfides, it is influenced by water-level fluctuations caused by municipal well pumping or climate changes, which can shift geographic areas in which contamination occurs. Résumé De fortes concentrations en arsenic, jusqu'à 12000μg/L, ont été mesurées dans l'eau souterraine d'un aquifère gréseux captif, dans l'est du Wisconsin. La principale source d'arsenic est un horizon à cimentation secondaire (SCH) comportant des sulfures, dont l'épaisseur, la morphologie et les concentrations en arsenic sont variables. L'arsenic est présent dans la pyrite et dans la marcassite, de même que dans des oxy-hydroxydes de fer, mais non pas dans une phase séparée d'arsénopyrite. Les signatures isotopiques du soufre presque identiques dans la

  1. Current situation and development of HER-2 testing in breast cancer%乳腺癌HER-2检测的概况与进展

    Institute of Scientific and Technical Information of China (English)

    耿强; 钱晓龙; 付丽

    2014-01-01

    人类表皮生长因子受体-2(HER-2/neu)是乳腺癌重要的预后和HER-2靶向药物治疗的预测指标,准确检测乳腺癌患者的HER-2状态对临床诊疗具有重要意义。目前美国临床肿瘤学会(ASCO)和美国病理医师学会(CAP)推荐免疫组织化学(IHC)、荧光原位杂交(FISH)和亮视野原位杂交(BISH)3种HER-2检测方法。虽存在各自的优势和不足,但在少数情况下仍无法检测部分患者HER-2的状态。银增强原位杂交(SISH)、多重连接探针扩增技术(MLPA)、定量逆转录聚合酶链反应(Q-RT-PCR)和RNA原位杂交(RNA-ISH)等新的检测方法也不断应用到HER-2检测中,因其自身的独特优势,满足了部分患者的HER-2检测需求,因而有很好的临床应用前景。本文将对这些技术的特点及其优势和存在的不足进行综述。%Human epidermal growth factor receptor 2 (HER-2/neu) is an important prognostic predictor and the key predictor of anti-HER-2 therapy of breast cancer. Accurate testing of HER-2 status for breast cancer patients is important in clinical practice. As of this writing, the American Society of Clinical Oncology and the College of American Pathologists recommend three methods for HER-2 detection, namely, immunohistochemistry, fluorescence in situ hybridization, and bright-field in situ hybridization. The abovementioned methods have their own advantages and disadvantages. New methods, such as multiplex ligation-dependent probe amplification, quantitative reverse transcription polymerase chain reaction, and RNA in situ hybridization, are currently applied to detect HER-2 status. New technologies not only make up for the shortcomings of routine methods but also have unique benefits that can meet the demands for HER-2 testing of some breast cancer patients. Thus, these methods are promising for clinical applications and can improve clinical diagnosis and treatment. The characteristics

  2. The stretch-shortening cycle : a model to study naturally occurring neuromuscular fatigue.

    Science.gov (United States)

    Nicol, Caroline; Avela, Janne; Komi, Paavo V

    2006-01-01

    Neuromuscular fatigue has traditionally been examined using isolated forms of either isometric, concentric or eccentric actions. However, none of these actions are naturally occurring in human (or animal) ground locomotion. The basic muscle function is defined as the stretch-shortening cycle (SSC), where the preactivated muscle is first stretched (eccentric action) and then followed by the shortening (concentric) action. As the SSC taxes the skeletal muscles very strongly mechanically, its influence on the reflex activation becomes apparent and very different from the isolated forms of muscle actions mentioned above. The ground contact phases of running, jumping and hopping etc. are examples of the SSC for leg extensor muscles; similar phases can also be found for the upper-body activities. Consequently, it is normal and expected that the fatigue phenomena should be explored during SSC activities. The fatigue responses of repeated SSC actions are very versatile and complex because the fatigue does not depend only on the metabolic loading, which is reportedly different among muscle actions. The complexity of SSC fatigue is well reflected by the recovery patterns of many neuromechanical parameters. The basic pattern of SSC fatigue response (e.g. when using the complete exhaustion model of hopping or jumping) is the bimodality showing an immediate reduction in performance during exercise, quick recovery within 1-2 hours, followed by a secondary reduction, which may often show the lowest values on the second day post-exercise when the symptoms of muscle soreness/damage are also greatest. The full recovery may take 4-8 days depending on the parameter and on the severity of exercise. Each subject may have their own time-dependent bimodality curve. Based on the reviewed literature, it is recommended that the fatigue protocol is 'completely' exhaustive to reduce the important influence of inter-subject variability in the fatigue responses. The bimodality concept is

  3. Naturally occurring heavy radioactive elements in the geothermal microcosm of the Los Azufres (Mexico) volcanic complex.

    Science.gov (United States)

    Abuhani, W A; Dasgupta-Schubert, N; Villaseñor, L M; García Avila, D; Suárez, L; Johnston, C; Borjas, S E; Alexander, S A; Landsberger, S; Suárez, M C

    2015-01-01

    The Los Azufres geothermal complex of central Mexico is characterized by fumaroles and boiling hot-springs. The fumaroles form habitats for extremophilic mosses and ferns. Physico-chemical measurements of two relatively pristine fumarolic microcosms point to their resemblance with the paleo-environment of earth during the Ordovician and Devonian periods. These geothermal habitats were analysed for the distribution of elemental mass fractions in the rhizospheric soil (RS), the native volcanic substrate (VS) and the sediments (S), using the new high-sensitivity technique of polarized x-ray energy dispersive fluorescence spectrometry (PEDXRF) as well as instrumental neutron activation analysis (INAA) for selected elements. This work presents the results for the naturally occurring heavy radioactive elements (NOHRE) Bi, Th and U but principally the latter two. For the RS, the density was found to be the least and the total organic matter content the most. Bi was found to be negligibly present in all substrate types. The average Th and U mass fractions in the RS were higher than in the VS and about equal to their average mass fractions in the S. The VS mass fraction of Th was higher, and of U lower, than the mass fractions in the earth's crust. In fact for the fumaroles of one site, the average RS mass fractions of these elements were higher than the averaged values for S (without considering the statistical dispersion). The immobilization of the NOHRE in the RS is brought about by the bio-geochemical processes specific to these extremophiles. Its effectiveness is such that despite the small masses of these plants, it compares with, or may sometimes exceed, the immobilization of the NOHRE in the S by the abiotic and aggressive chemical action of the hot-springs. These results indicate that the fumarolic plants are able to transform the volcanic substrate to soil and to affect the NOHRE mass fractions even though these elements are not plant nutrients. Mirrored back to

  4. Distribution of naturally occurring radionuclides activity concentration in East Malaysian marine sediment

    Energy Technology Data Exchange (ETDEWEB)

    Yii, M.W. [Malaysian Nuclear Agency (Nuclear Malaysia), Bangi, 43000 Kajang (Malaysia)], E-mail: yii@nuclearmalaysia.gov.my; Zaharudin, A.; Abdul-Kadir, I. [Malaysian Nuclear Agency (Nuclear Malaysia), Bangi, 43000 Kajang (Malaysia)

    2009-04-15

    Studies of naturally occurring radioactive materials (NORM) distribution of {sup 226}Ra, {sup 228}Ra and {sup 40}K in East Malaysia were carried out as part of a marine coastal environment project. The results of measurements will serve as baseline data and background reference level for Malaysia coastlines. Sediments from 21 coastal locations and 10 near shore locations were collected for analyses. The samples were dried, finely ground, sealed in a container and stored for a minimum of 30 days to establish secular equilibrium between {sup 226}Ra and {sup 228}Ra and their respective radioactive progenies. They were counted using a high-purity germanium (HPGe) spectrometer covering the respective progeny energy peak. For {sup 40}K, the presence of this was measured directly via its 1460 keV energy peak. The concentration of {sup 226}Ra, {sup 228}Ra and {sup 40}K in samples obtained from coastal Sarawak ranged between 23 and 41 (mean 30{+-}2) Bq/kg, 27 and 45 (mean 39{+-}4) Bq/kg and 142 and 680 (mean 462{+-}59) Bq/kg, respectively. Meanwhile, the concentration of {sup 226}Ra, {sup 228}Ra and {sup 40}K for samples obtained from coastal Sabah ranged between 16 and 30 (mean 23{+-}2) Bq/kg, 23 and 45 (mean 35{+-}4) Bq/kg and 402 and 842 (mean 577{+-}75) Bq/kg, respectively. For the Sarawak near shore stations, the concentration of {sup 226}Ra, {sup 228}Ra and {sup 40}K ranged between 11 and 36 (mean 22{+-}2) Bq/kg, 21 and 65 (mean 39{+-}5) Bq/kg and 149 and 517 (mean 309{+-}41) Bq/kg, respectively. Meanwhile, the concentration of {sup 226}Ra, {sup 228}Ra and {sup 40}K for samples obtained from Sabah ranged between 9 and 31 (mean 14{+-}2) Bq/kg, 10 and 48 (mean 21{+-}3) Bq/kg and 140 and 580 (mean 269{+-}36) Bq/kg, respectively. The calculated external hazard values of between 0.17 and 0.33 (less than unity) showed that there is little risk of external hazard to the workers handling the sediments.

  5. A naturally occurring omega current in a Kv3 family potassium channel from a platyhelminth

    Directory of Open Access Journals (Sweden)

    Spencer Andrew N

    2008-06-01

    Full Text Available Abstract Background Voltage-gated ion channels are membrane proteins containing a selective pore that allows permeable ions to transit the membrane in response to a change in the transmembrane voltage. The typical selectivity filter in potassium channels is formed by a tetrameric arrangement of the carbonyl groups of the conserved amino-acid sequence Gly-Tyr-Gly. This canonical pore is opened or closed by conformational changes that originate in the voltage sensor (S4, a transmembrane helix with a series of positively charged amino acids. This sensor moves through a gating pore formed by elements of the S1, S2 and S3 helices, across the plane of the membrane, without allowing ions to pass through the membrane at that site. Recently, synthetic mutagenesis studies in the Drosophila melanogaster Shaker channel and analysis of human disease-causing mutations in sodium channels have identified amino acid residues that are integral parts of the gating-pore; when these residues are mutated the proteins allow a non-specific cation current, known as the omega current, to pass through the gating-pore with relatively low selectivity. Results The N.at-Kv3.2 potassium channel has an unusual weak inward rectifier phenotype. Several mutations of two amino acids in the voltage sensing (S4 transmembrane helix change the phenotype to a typical delayed rectifier. The inward rectifier channels (wild-type and mutant are sensitive to 4-aminopyridine (4-AP but not tetra-ethyl ammonium (TEA, whereas the delayed rectifier mutants are sensitive to TEA but not 4-AP. The inward rectifier channels also manifest low cation selectivity. The relative selectivity for different cations is sensitive to specific mutations in the S4 helix, Conclusion N.at-Kv3.2, a naturally occurring potassium channel of the Kv3 sequence family, mediates ion permeation through a modified gating pore, not the canonical, highly selective pore typical of potassium channels. This channel has evolved to

  6. Assessment of inhalation dose sensitivity by physicochemical properties of airborne particulates containing naturally occurring radioactive materials

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Si Young; Choi, Cheol Kyu; Kim, Yong Geon; Choi, Won Chul; Kim, Kwang Pyo [Kyung Hee University, Seoul (Korea, Republic of)

    2015-12-15

    Facilities processing raw materials containing naturally occurring radioactive materials (NORM) may give rise to enhanced radiation dose to workers due to chronic inhalation of airborne particulates. Internal radiation dose due to particulate inhalation varies depending on particulate properties, including size, shape, density, and absorption type. The objective of the present study was to assess inhalation dose sensitivity to physicochemical properties of airborne particulates. Committed effective doses to workers resulting from inhalation of airborne particulates were calculated based on International Commission on Radiological Protection 66 human respiratory tract model. Inhalation dose generally increased with decreasing particulate size. Committed effective doses due to inhalation of 0.01μm sized particulates were higher than doses due to 100μm sized particulates by factors of about 100 and 50 for {sup 238}U and {sup 230}Th, respectively. Inhalation dose increased with decreasing shape factor. Shape factors of 1 and 2 resulted in dose difference by about 18 %. Inhalation dose increased with particulate mass density. Particulate mass densities of 11 g·cm{sup -3} and 0.7 g·cm{sup -3} resulted in dose difference by about 60 %. For {sup 238}U, inhalation doses were higher for absorption type of S, M, and F in that sequence. Committed effective dose for absorption type S of {sup 238}U was about 9 times higher than dose for absorption F. For {sup 230}Th, inhalation doses were higher for absorption type of F, M, and S in that sequence. Committed effective dose for absorption type F of {sup 230}Th was about 16 times higher than dose for absorption S. Consequently, use of default values for particulate properties without consideration of site specific physiochemical properties may potentially skew radiation dose estimates to unrealistic values up to 1-2 orders of magnitude. For this reason, it is highly recommended to consider site specific working materials and

  7. Assessment of radiological hazards of naturally occurring radioactive materials in cement industry.

    Science.gov (United States)

    Aslam, Muhammad; Gul, Rahmat; Ara, Tauseef; Hussain, Manzur

    2012-09-01

    A study on the radiological hazard in Portland cement due to the presence of naturally occurring radioactive materials is being carried out. The Portland cement manufactured in the Islamabad/Rawalpindi region of Pakistan, intermediate products (clinker) and the various raw materials which compose the product have been analysed for (226)Ra, (232)Th and (40)K using a gamma spectrometry system with a N-type high-purity germanium detector of 80 % relative efficiency. From the measured gamma ray spectra, specific activities were determined. The mean values of the total specific activity of (226)Ra, (232)Th and (40)K are 34.2±11.9, 29.1±3.6 and 295.1±66.9 Bq kg(-1), respectively in Portland cement, 28.4±8.7, 11.3±1.7 and 63.1±17.3 Bq kg(-1), respectively in lime stone, 8.2±1.9, 16.2±3.9 and 187.7±53.2 Bq kg(-1), respectively in gypsum, 34.7±13.1, 41.2±6.7 and 187.6±17.2 Bq kg(-1), respectively in clay, 41.1±11.8, 39.3±6.9 and 195.1±29.2 Bq kg(-1), respectively in latrite and 51.1±18.2, 23.2±1.2 and 258.4±15.3 Bq kg(-1), respectively in clinker. The radium equivalent activities (Ra(eq)), external hazard index (H(ex)), internal hazard index (H(in)), absorbed dose rate in air (D) and annual effective dose rate (E(eff)) were also determined. The measured activity concentrations for these radio nuclides and radiological indices were compared with the reported national and international data. All these measured values are comparable with the worldwide data reported in UNSCEAR publications.

  8. Manufactured Home Testing in Simulated and Naturally Occurring High Winds for WCTE Conference

    Energy Technology Data Exchange (ETDEWEB)

    William D. Richins; Thomas K. Larson; Jeffrey M. Lacy; Ryan G. Kobbe

    2006-08-01

    A typical double-wide manufactured home was tested in simulated and naturally occurring high winds to understand structural behavior and improve performance during severe windstorms. Seven (7) lateral load tests were conducted on a double-wide manufactured home at a remote field test site in Wyoming. An extensive instrumentation package monitored the overall behavior of the home and collected data vital to validating computational software for the manufactured housing industry. The tests were designed to approach the design load of the home without causing structural damage, thus allowing the behavior of the home to be accessed when the home was later exposed to high winds (to 80-mph). The data generally show near-linear initial system response with significant non-linear behavior as the applied loads increase. Load transfer across the marriage line is primarily compression. Racking, while present, is very small. Interface slip and shear displacement along the marriage line are nearly insignificant. Horizontal global displacements reached 0.6 inch. These tests were designed primarily to collect data necessary to calibrate a desktop analysis and design software tool, MHTool, under development at the Idaho National Laboratory specifically for manufactured housing. Currently available analysis tools are, for the most part, based on methods developed for "stick built" structures and are inappropriate for manufactured homes. The special materials utilized in manufactured homes, such as rigid adhesives used in the connection of the sheathing materials to the studs, significantly alter the behavior of manufactured homes under lateral loads. Previous full scale tests of laterally loaded manufactured homes confirm the contention that conventional analysis methods are not applicable. System behavior dominates the structural action of manufactured homes and its prediction requires a three dimensional analysis of the complete unit, including tie-downs. This project was

  9. Application of fusion protein 4D5 scFv-dibarnase:barstar-gold complex for studying P185HER2 receptor distribution in human cancer cells.

    Science.gov (United States)

    Ivanova, Julia L; Edelweiss, Evelina F; Leonova, Olga G; Balandin, Taras G; Popenko, Vladimir I; Deyev, Sergey M

    2012-08-01

    Overexpression of the P185(HER2) protein determines the malignancy and unfavorable prognosis of ovarian and breast tumors. In this work, the distribution of P185(HER2) in human cancer cells was studied by electron microscopy, using a novel approach. It is based on the interaction between barnase (a ribonuclease from Bacillus amyloliquefaciens) and its specific inhibitor barstar. The monoclonal antibody 4D5 scFv to extracellular P185(HER2) domain fused with two molecules of barnase was used as a recognizing agent, and the conjugate of colloidal gold with barstar, as an electron dense label for electron microscopic visualization. For labeling, we used supramolecular complexes 4D5 scFv-dibarnase:barstar-Au. The distribution of P185(HER2) in human ovarian carcinoma cells SKOV-3 and breast carcinoma cells BT-474 was studied at 4 °C and 37 °C. It was shown that at 4 °C the protein P185(HER2) occurs exclusively on the cell surface, mainly on protrusions or close to their bases. At 37 °C, the internalization of P185(HER2) caused by its interaction with 4D5 scFv-dibarnase was observed. Inside the cells, P185(HER2) was located in the coated pits and vesicles, endosomes and multivesicular bodies. The data obtained indicate that the supramolecular 4D5 scFv-dibarnase:barstar-gold complex can be used as a new immunodetection system for exploring the P185(HER2) distribution.

  10. Degradation of HER2/neu by apigenin induces apoptosis through cytochrome c release and caspase-3 activation in HER2/neu-overexpressing breast cancer cells.

    Science.gov (United States)

    Way, Tzong-Der; Kao, Ming-Ching; Lin, Jen-Kun

    2005-01-03

    We have shown that exposure of the HER2/neu-overexpressing breast cancer cells to apigenin resulted in induction of apoptosis by depleting HER2/neu protein and, in turn, suppressing the signaling of the HER2/HER3-PI3K/Akt pathway. Here, we examined whether inhibition of this pathway played a role in the anti-tumor effect. The results revealed that treatment with apigenin induced apoptosis through cytochrome c release and caused a rapid induction of caspase-3 activity and stimulated proteolytic cleavage of DFF-45. Furthermore, apigenin downregulated cyclin D1, D3 and Cdk4 and increased p27 protein levels. Colony formation in the soft agar assay, a hallmark of the transformation phenotype, was preferentially suppressed in HER2/neu-overexpressing breast cancer cells in the presence of apigenin. In addition, a structure-activity relationship study indicated that (1) the position of B ring; and (2) the existence of the 3', 4'-hydroxyl group on the 2-phenyl group were important for the depletion of HER2/neu protein by flavonoids. These results provided new insights into the structure-activity relationship of flavonoids.

  11. Demographics, nature and treatment of orthopaedic trauma injuries occurring in an agricultural context in the West of Ireland.

    LENUS (Irish Health Repository)

    Byrne, F J

    2011-03-01

    Farming is a major industry in the West of Ireland. This prospective study examined the age profile, nature and treatment of orthopaedic injuries occurring in agricultural surroundings presenting at the Orthopaedic Unit of Merlin Park Hospital, Galway.

  12. Aromatase, cyclooxygenase 2, HER-2/neu, and p53 as prognostic factors in endometrioid endometrial cancer

    NARCIS (Netherlands)

    Jongen, Vincent H. W. M.; Briet, Justine M.; de Jong, Renske A.; Joppe, Erna; ten Hoor, Klaske A.; Boezen, H. M.; Evans, Dean B.; Hollema, Harry; van der Zee, Ate G. J.; Nijman, Hans W.

    2009-01-01

    The prognostic value of aromatase, cyclooxygenase 2 (COX-2), HER-2/neu, and p53 expression was determined in endometrioid endometrial cancer. Tissue microarrays were constructed comprising samples from 315 endometrioid endometrial cancer patients. Expression of aromatase, COX-2, HER-2/neu, and p53 w

  13. Modeling ductal carcinoma in situ: a HER2-Notch3 collaboration enables luminal filling.

    LENUS (Irish Health Repository)

    Pradeep, C-R

    2012-02-16

    A large fraction of ductal carcinoma in situ (DCIS), a non-invasive precursor lesion of invasive breast cancer, overexpresses the HER2\\/neu oncogene. The ducts of DCIS are abnormally filled with cells that evade apoptosis, but the underlying mechanisms remain incompletely understood. We overexpressed HER2 in mammary epithelial cells and observed growth factor-independent proliferation. When grown in extracellular matrix as three-dimensional spheroids, control cells developed a hollow lumen, but HER2-overexpressing cells populated the lumen by evading apoptosis. We demonstrate that HER2 overexpression in this cellular model of DCIS drives transcriptional upregulation of multiple components of the Notch survival pathway. Importantly, luminal filling required upregulation of a signaling pathway comprising Notch3, its cleaved intracellular domain and the transcriptional regulator HES1, resulting in elevated levels of c-MYC and cyclin D1. In line with HER2-Notch3 collaboration, drugs intercepting either arm reverted the DCIS-like phenotype. In addition, we report upregulation of Notch3 in hyperplastic lesions of HER2 transgenic animals, as well as an association between HER2 levels and expression levels of components of the Notch pathway in tumor specimens of breast cancer patients. Therefore, it is conceivable that the integration of the Notch and HER2 signaling pathways contributes to the pathophysiology of DCIS.

  14. HER2 Analysis in Sporadic Thyroid Cancer of Follicular Cell Origin

    Directory of Open Access Journals (Sweden)

    Rosaria M. Ruggeri

    2016-12-01

    Full Text Available The Epidermal Growth Factor Receoptor (EGFR family member human epidermal growth factor receptor 2 (HER2 is overexpressed in many human epithelial malignancies, representing a molecular target for specific anti-neoplastic drugs. Few data are available on HER2 status in differentiated thyroid cancer (DTC. The present study was aimed to investigate HER2 status in sporadic cancers of follicular cell origin to better clarify the role of this receptor in the stratification of thyroid cancer. By immunohistochemistry and fluorescence in-situ hybridization, HER2 expression was investigated in formalin-fixed paraffin-embedded surgical specimens from 90 DTC patients, 45 follicular (FTC and 45 papillary (PTC histotypes. No HER2 immunostaining was recorded in background thyroid tissue. By contrast, overall HER2 overexpression was found in 20/45 (44% FTC and 8/45 (18% PTC, with a significant difference between the two histotypes (p = 0.046. Five of the six patients who developed metastatic disease during a median nine-year follow-up had a HER2-positive tumor. Therefore, we suggest that HER2 expression may represent an additional aid to identify a subset of patients who are characterized by a worse prognosis and are potentially eligible for targeted therapy.

  15. Her2 expression and gene amplification is rarely detectable in patients with oral squamous cell carcinomas.

    Science.gov (United States)

    Hanken, Henning; Gaudin, Robert; Gröbe, Alexander; Fraederich, Meike; Eichhorn, Wolfgang; Smeets, Ralf; Simon, Ronald; Sauter, Guido; Grupp, Katharina; Izbicki, Jacob R; Sehner, Susanne; Heiland, Max; Blessmann, Marco

    2014-04-01

    Her2 (ErbB2) transforms cells when overexpressed and is an important therapeutic target in breast cancer. Contrary to breast cancer, studies on Her2 overexpression and gene amplification in squamous cell carcinomas of the head and neck region described largely different results. This study was undertaken to learn more on the prevalence and clinical significance of HER2 amplification and overexpression in squamous cell carcinomas of the head and neck. Her2 expression and gene amplification was analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) on two tissue microarrays composed of 427 squamous cell carcinomas of the head and neck region and 222 oral squamous cell carcinomas. Results were compared with clinicopathological features. Her2 expression and gene amplification was rarely detectable in squamous cell carcinomas of the head and neck region and unrelated to tumor phenotype or survival of the patients with oral squamous carcinoma. Our results demonstrate that Her2 protein and gene amplification was only detectable in a small subset of squamous cell carcinomas of the head and neck region as well as oral squamous cell carcinomas. However, it can be speculated that those few patients with Her2 overexpressing and gene amplificated tumors may possibly benefit from an anti-Her2 therapy. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. HER2 expression in Brazilian patients with estrogen and progesterone receptor-negative breast carcinoma.

    Science.gov (United States)

    Ramalho, Susana; Serra, Katia Piton; Vassallo, Jose; Soares, Fernando Augusto; Pinto, Glauce Aparecida; Teixeira, Luiz Carlos; da Cunha, Isabela Werneck; Derchain, Sophie F M; de Souza, Gustavo

    2013-03-01

    The aim of the study was to evaluate the relationship between clinical and pathological factors and survival in patients with double negative HER2-overexpressing carcinoma and triple negative carcinoma. One hundred and sixty-one (161) patients diagnosed with breast cancer negative for estrogen receptor (ER) and progesterone receptor (PR) were included. Of the total, 58 patients had double negative HER2-overexpressing (ER/PR-negative and HER2-positive) and 103 had triple negative (ER-negative, PR-negative and HER2-negative). ER and PR expression was assessed through immunohistochemistry (IHC) and HER2 expression was measured by immunohistochemistry and Fluorescent in situ Hybridization (FISH) analysis in tissue microarray. More than 80% had stages II and III disease and histologic grade III and nuclear grade 3. Patients with triple negative breast carcinoma had undifferentiated histologic types in 11% of cases and vascular invasion in 14.5%. Both groups had more than 50% visceral metastases. HER2 expression (p=0.42) and vascular invasion (p=0.05) did not interfere with survival. Survival of patients with Stages I-II disease was significantly longer than in those with Stage III disease both for double negative HER2-overexpressing carcinomas (p<0.0001) and triple negative carcinomas (p=0.03). The study shows that hormone receptor-negative breast carcinomas were undifferentiated and diagnosed at advanced stages and that HER2 expression was not associated with overall survival.

  17. Plasma HER2 amplification in cell-free DNA during neoadjuvant chemotherapy in breast cancer

    DEFF Research Database (Denmark)

    Bechmann, Troels; Andersen, Rikke Fredslund; Pallisgaard, Niels

    2013-01-01

    Measurement of human epidermal growth factor receptor 2 (HER2) gene amplification in cell-free DNA (cfDNA) is an evolving technique in breast cancer, enabling liquid biopsies and treatment monitoring. The present study investigated the dynamics of plasma HER2 gene copy number and amplification in...... in cfDNA during neoadjuvant chemotherapy....

  18. Modeling invasive breast cancer: growth factors propel progression of HER2-positive premalignant lesions.

    Science.gov (United States)

    Pradeep, C-R; Zeisel, A; Köstler, W J; Lauriola, M; Jacob-Hirsch, J; Haibe-Kains, B; Amariglio, N; Ben-Chetrit, N; Emde, A; Solomonov, I; Neufeld, G; Piccart, M; Sagi, I; Sotiriou, C; Rechavi, G; Domany, E; Desmedt, C; Yarden, Y

    2012-08-01

    The HER2/neu oncogene encodes a receptor-like tyrosine kinase whose overexpression in breast cancer predicts poor prognosis and resistance to conventional therapies. However, the mechanisms underlying aggressiveness of HER2 (human epidermal growth factor receptor 2)-overexpressing tumors remain incompletely understood. Because it assists epidermal growth factor (EGF) and neuregulin receptors, we overexpressed HER2 in MCF10A mammary cells and applied growth factors. HER2-overexpressing cells grown in extracellular matrix formed filled spheroids, which protruded outgrowths upon growth factor stimulation. Our transcriptome analyses imply a two-hit model for invasive growth: HER2-induced proliferation and evasion from anoikis generate filled structures, which are morphologically and transcriptionally analogous to preinvasive patients' lesions. In the second hit, EGF escalates signaling and transcriptional responses leading to invasive growth. Consistent with clinical relevance, a gene expression signature based on the HER2/EGF-activated transcriptional program can predict poorer prognosis of a subgroup of HER2-overexpressing patients. In conclusion, the integration of a three-dimensional cellular model and clinical data attributes progression of HER2-overexpressing lesions to EGF-like growth factors acting in the context of the tumor's microenvironment.

  19. Quantification and imaging of HER2 protein using nanocrystals conjugated with single-domain antibodies

    Science.gov (United States)

    Glukhov, S.; Berestovoy, M.; Chames, P.; Baty, D.; Nabiev, I.; Sukhanova, A.

    2017-01-01

    This study dealt with quantification and imaging of human epidermal growth factor receptor 2 (HER2), an important prognostic marker for cancer diagnosis and treatment, using specific quantum-dot-based conjugates. Fluorescent inorganic nanocrystals or quantum dots (QDs) are extremely highly resistant to photobleaching and have a high emission quantum yield and a continuous range of emission spectra, from the ultraviolet to the infrared regions. Ultrasmall nanoprobes consisting of highly affine anti-HER2 single-domain antibodies (sdAbs or "nanobodies") conjugated with QDs in a strictly oriented manner have been designed. QDs with a fluorescence peak maxima at wavelengths of 562 nm, 569 nm, 570 nm or in the near-infrared region were used. Here, we present our results of ISA quantification of HER2 protein, in situ imaging of HER2 protein on the surface of HER2-positive SK-BR-3 cells in immunohistochemical experiments, and counting of stained with anti-HER2 conjugates HER2-positive SK-BR-3 cells in their mixture with unstained cells of the same culture in flow cytometry experiments. The data demonstrate that the anti-HER2 QD-sdAb conjugates obtained are highly specific and sensitive and could be used in numerous applications for advanced integrated diagnosis.

  20. Inhibitor of Apoptosis (IAP) survivin is indispensable for survival of HER2 gene-amplified breast cancer cells with primary resistance to HER1/2-targeted therapies

    Energy Technology Data Exchange (ETDEWEB)

    Oliveras-Ferraros, Cristina; Vazquez-Martin, Alejandro; Cufi, Silvia; Torres-Garcia, Violeta Zenobia [Unit of Translational Research, Catalan Institute of Oncology-Girona, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Girona Biomedical Research Institute, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Sauri-Nadal, Tamara; Barco, Sonia Del [Girona Biomedical Research Institute, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Medical Oncology, Catalan Institute of Oncology-Girona, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Lopez-Bonet, Eugeni [Girona Biomedical Research Institute, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Department of Anatomical Pathology, Dr. Josep Trueta University Hospital, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Brunet, Joan [Girona Biomedical Research Institute, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Medical Oncology, Catalan Institute of Oncology-Girona, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Martin-Castillo, Begona [Girona Biomedical Research Institute, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Unit of Clinical Research, Catalan Institute of Oncology-Girona, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Menendez, Javier A., E-mail: jmenendez@idibgi.org [Unit of Translational Research, Catalan Institute of Oncology-Girona, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain); Girona Biomedical Research Institute, Avenida de Francia S/N, E-17007 Girona, Catalonia (Spain)

    2011-04-08

    Highlights: {yields} Intrinsic trastuzumab resistance occurs in {approx}70% of metastatic HER2 + breast carcinomas (BC). {yields} Approximately 15% of early HER2 + BC relapse in spite of treatment with trastuzumab-based therapies. {yields} HER2-independent downstream pro-survival pathways might underlie trastuzumab refractoriness. {yields} Survivin is indispensable for proliferation and survival of HER2 + BC unresponsive to HER2-targeted therapies ab initio. {yields} Survivin antagonists may clinically circumvent the occurrence of de novo resistance to HER2-directed drugs. -- Abstract: Primary resistance of HER2 gene-amplified breast carcinomas (BC) to HER-targeted therapies can be explained in terms of overactive HER2-independent downstream pro-survival pathways. We here confirm that constitutive overexpression of Inhibitor of Apoptosis (IAP) survivin is indispensable for survival of HER2-positive BC cells with intrinsic cross-resistance to multiple HER1/2 inhibitors. The IC{sub 50} values for the HER1/2 Tyrosine Kinase Inhibitors (TKIs) gefitinib, erlotinib and lapatinib were up to 40-fold higher in trastuzumab-unresponsive JIMT-1 cells than in trastuzumab-naive SKBR3 cells. ELISA-based and immunoblotting assays demonstrated that trastuzumab-refractory JIMT-1 cells constitutively expressed {approx}4 times more survivin protein than trastuzumab-responsive SKBR3 cells. In response to trastuzumab, JIMT-1 cells accumulated {approx}10 times more survivin than SKBR3 cells. HER1/2 TKIs failed to down-regulate survivin expression in JIMT-1 cells whereas equimolar doses of HER1/HER2 TKIs drastically depleted survivin protein in SKBR3 cells. ELISA-based detection of histone-associated DNA fragments confirmed that trastuzumab-refractory JIMT-1 cells were intrinsically protected against the apoptotic effects of HER1/2 TKIs. Of note, when we knocked-down survivin expression using siRNA and then added trastuzumab, cell proliferation and colony formation were completely

  1. The expression of HER-2/neu gene in colon cancer tissues and its clinical significance

    Institute of Scientific and Technical Information of China (English)

    Jing Jin; Yuxuan Che; Qimin Wang; Fang Liu; Man Li; Lifen Wang; Xiuhua Sun; Yang Zhang

    2013-01-01

    Objective:The article aims to detect the expression of HER-2/neu gene in colon cancer tissues and adjacent tissues, to analyze the relationship between dif erent pathologic types and clinical features, also to invest the distribution of patients with positive expression of HER-2 gene. Methods:The expression of HER-2 gene in the 223 samples with colon can-cer was detected by immunochemical approach. The expression of HER-2 gene in colon cancer tissues and adjacent tissues and dif erent pathologic types was analyzed byχ2 test. The correlation between the expression of HER-2 gene and clinical features was analyzed by Spearman. Results:The number of positive expression of HER-2 gene in colon cancer tissues and adjacent tissues were 74 and 0 respectively, the dif erence has statistical significance. The number of papil ary or tubular adenocarcinoma was 182, among them, 60 cases were positive expression. The number of mucinous adenocarcinoma was 41, among them, 14 cases were positive expression. The expression of HER-2/neu gene has no correlation with sex, age, the maximum diameter, general classification, degree of dif erentiation and depth of invasion, which has no statistical significance. However, the expression of HER-2/neu gene has correlation with metastasis of lymph node and Dukes stage, which has statistical significance. The expression of HER-2/neu gene was positive correlation with metastasis of lymph node and Dukes stage. The correlated coef icient index was 0.320 and 0.320 respectively. In the 74 patients with positive expression of HER-2 gene, 59.4%of them were 60-74 years old. And there was 97.3%of the patients without family history of adenocarcinoma. Conclusion:The expression of HER-2/neu gene in colon cancer tissues was higher than in adjacent tissues. The expression of HER-2/neu gene has no correlation with sex, age, the maximum diameter, general classification, degree of dif erentiation and depth of invasion, but has correlation with metastasis of

  2. HER2 induces expression of leptin in human breast epithelial cells

    Directory of Open Access Journals (Sweden)

    Aree Moon

    2012-12-01

    Full Text Available A close association between the obesity hormone leptin andbreast cancer progression has been suggested. The presentstudy investigated the molecular mechanism for enhancedleptin expression in breast cancer cells and its functionalsignificance in breast cancer aggressiveness. We examinedwhether leptin expression level is affected by the oncoproteinhuman epidermal growth factor receptor2 (HER2, which isoverexpressed in ∼30% of breast tumors. Here, we report, forthe first time, that HER2 induces transcriptional activation ofleptin in MCF10A human breast epithelial cells. We alsoshowed that p38 mitogen-activated protein kinase signalingwas involved in leptin expression induced by HER2. Weshowed a crucial role of leptin in the invasiveness ofHER2-MCF10A cells using an siRNA molecule targeting leptin.Taken together, the results indicate a molecular link betweenHER2 and leptin, providing supporting evidence that leptinrepresents a target for breast cancer therapy.

  3. Intrathecal trastuzumab: immunotherapy improves the prognosis of leptomeningeal metastases in HER-2+ breast cancer patient.

    Science.gov (United States)

    Lu, Nu T; Raizer, Jeffrey; Gabor, Erwin P; Liu, Natalie M; Vu, James Q; Slamon, Dennis J; Barstis, John L

    2015-01-01

    We describe the clinical and therapeutic course of a 51-year-old woman with HER-2+ breast cancer who developed leptomeningeal (LM) and spinal cord metastases after 8 years of stable disease on combination therapy with intravenous (IV) trastuzumab. Due to progressive CNS disease, intrathecal (IT) trastuzumab was introduced to enhance HER-2+ therapy into the CSF space. A combination HER-2+ targeted approach achieved clinical remission with stable disease in our patient 46 months after she was diagnosed with LM metastases. However, spinal cord C-1 metastasis was not fully controlled with IT trastuzumab, ultimately leading to the patient's respiratory compromise. In our patient, IT trastuzumab immunotherapy improved prognosis and was an effective strategy to manage HER-2+ LM disease. Given alone or alongside other anti-HER-2+ therapeutics with sufficient CNS penetration, IT trastuzumab could extend the lifespan of patients with leptomeningeal and CNS metastases.

  4. Improved Aptamers for the Diagnosis and Potential Treatment of HER2-Positive Cancer

    Directory of Open Access Journals (Sweden)

    Marlies Gijs

    2016-05-01

    Full Text Available Aptamers provide a potential source of alternative targeting molecules for existing antibody diagnostics and therapeutics. In this work, we selected novel DNA aptamers targeting the HER2 receptor by an adherent whole-cell SELEX approach. Individual aptamers were identified by next generation sequencing and bioinformatics analysis. Two aptamers, HeA2_1 and HeA2_3, were shown to bind the HER2 protein with affinities in the nanomolar range. In addition, both aptamers were able to bind with high specificity to HER2-overexpressing cells and HER2-positive tumor tissue samples. Furthermore, we demonstrated that aptamer HeA2_3 is being internalized into cancer cells and has an inhibitory effect on cancer cell growth and viability. In the end, we selected novel DNA aptamers with great potential for the diagnosis and possible treatment of HER2-positive cancer.

  5. Heat Shock Protein 90 (HSP90 and Her2 in Adenocarcinomas of the Esophagus

    Directory of Open Access Journals (Sweden)

    Julia Slotta-Huspenina

    2014-06-01

    Full Text Available Her2 overexpression and amplification can be found in a significant subset of esophageal adenocarcinomas. The activity of Her2 has been shown to be modulated by molecular chaperones such as HSP90. We analyzed expression/amplification data for HSP90 and Her2 on 127 primary resected esophageal adenocarcinomas in order to evaluate a possible relationship between these two molecules. HSP90 expression determined by immunohistochemistry was observed in various levels. Thirty nine (39 tumors (30.7% were classified as Her2-positive according to their immunoreactivity and amplification status. There was a significant correlation between HSP90 expression and Her2-status (p = 0.008. This could also be demonstrated by quantitative protein expression analysis with reverse phase protein arrays (r = 0.9; p < 0.001. Her2-status was associated withpT-category (p = 0.041, lymph node metastases (p = 0.049 and tumor differentiation (p = 0.036 with a higher percentage of cases with negative Her2 status in lower tumor stagesA negative Her2-status was also associated with better survival in univariate and multivariate analysis (p = 0.001 and p = 0.014. For HSP90, no associations between clinical and pathological parameters were found. The observed association between HSP90 expression and Her2 suggests a co-regulation of these molecules in at least a subset of esophageal adenocarcinomas. Anti-HSP90 drugs, which recently have been introduced in cancer treatment, may also be an option for these tumors by targeting HSP90 alone or in combination with Her2.

  6. Ideal number of biopsy tumor fragments for predicting HER2 status in gastric carcinoma resection specimens.

    Science.gov (United States)

    Ahn, Sangjeong; Ahn, Soomin; Van Vrancken, Michael; Lee, Minju; Ha, Sang Yun; Lee, Hyuk; Min, Byung-Hoon; Lee, Jun Haeng; Kim, Jae J; Choi, Sunkyu; Jung, Sin-Ho; Choi, Min Gew; Lee, Jun-Ho; Sohn, Tae Sung; Bae, Jae Moon; Kim, Sung; Kim, Kyoung-Mee

    2015-11-10

    Intratumoral heterogeneity of HER2 expression is common in gastric cancers and pose a challenge for identifying patients who would benefit from anti-HER2 therapy. The aim of this study is to compare HER2 expression in biopsy and resection specimens of gastric carcinoma by immunohistochemistry (IHC) and to find the ideal number of biopsy tumor fragments that can accurately predict HER2 overexpression in the corresponding surgically resected specimen. The HER2 IHC results of 702 paired biopsy and resection specimens of gastric cancer were compared.The mean number of biopsy fragments among all cases was 4.3 (range 1-11). HER2 was positive in 130 (18.5%) endoscopic biopsies and in 102 (14.5%) gastrectomy specimens. Intratumoral heterogeneity of HER2 was found in 80 (61.5%) biopsies and 70 (68.6%) resection specimens. Out of the 70 surgical specimens with intratumoral heterogeneity, 24 (34.3%) of the corresponding biopsies were categorized as negative (positive conversion). In the 86 (12.3%) discrepant cases, negative conversion was observed in 57 (66.3%) cases and positive conversion in 29 (33.7%). The fragment numbers were significantly correlated with the discrepancy of results and positive predictability (P = 0.0315 and P = 0.0052). ROC curve analysis and positive predictability showed that 4 fragments should be obtained to minimize the differences in HER2 scores between biopsy and resection specimen.In gastric carcinomas with discrepant HER2 results between biopsy and surgical resection specimens, intratumoral heterogeneity is common with most of them showing positive conversion. To predict HER2 status precisely, at least 4 biopsy fragments containing tumor cells are required.

  7. Hypothesized role of pregnancy hormones on HER2+ breast tumor development.

    Science.gov (United States)

    Cruz, Giovanna I; Martínez, María Elena; Natarajan, Loki; Wertheim, Betsy C; Gago-Dominguez, Manuela; Bondy, Melissa; Daneri-Navarro, Adrian; Meza-Montenegro, María Mercedes; Gutierrez-Millan, Luis Enrique; Brewster, Abenaa; Schedin, Pepper; Komenaka, Ian K; Castelao, J Esteban; Carracedo, Angel; Redondo, Carmen M; Thompson, Patricia A

    2013-01-01

    Breast cancer incidence rates have declined among older but not younger women; the latter are more likely to be diagnosed with breast cancers carrying a poor prognosis. Epidemiological evidence supports an increase in breast cancer incidence following pregnancy with risk elevated as much as 10 years post-partum. We investigated the association between years since last full-term pregnancy at the time of diagnosis (≤10 or >10 years) and breast tumor subtype in a case series of premenopausal Hispanic women (n = 627). Participants were recruited in the United States, Mexico, and Spain. Cases with known estrogen receptor (ER), progesterone receptor (PR), and HER2 status, with one or more full-term pregnancies ≥1 year prior to diagnosis were eligible for this analysis. Cases were classified into three tumor subtypes according to hormone receptor (HR+ = ER+ and/or PR+; HR- = ER- and PR-) expression and HER2 status: HR+/HER2-, HER2+ (regardless of HR), and triple negative breast cancer. Case-only odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated for HER2+ tumors in reference to HR+/HER2- tumors. Participants were pooled in a mixed-effects logistic regression model with years since pregnancy as a fixed effect and study site as a random effect. When compared to HR+/HER2- cases, women with HER2+ tumors were more likely be diagnosed in the post-partum period of ≤10 years (OR = 1.68; 95 % CI, 1.12-2.52). The effect was present across all source populations and independent of the HR status of the HER2+ tumor. Adjusting for age at diagnosis (≤45 or >45 years) did not materially alter our results (OR = 1.78; 95 % CI, 1.08-2.93). These findings support the novel hypothesis that factors associated with the post-partum breast, possibly hormonal, are involved in the development of HER2+ tumors.

  8. Heat Shock Protein 90 (HSP90) and Her2 in Adenocarcinomas of the Esophagus

    Energy Technology Data Exchange (ETDEWEB)

    Slotta-Huspenina, Julia; Becker, Karl-Friedrich [Institute of Pathology, Technische Universität München, München 81765 (Germany); Feith, Marcus [Department of Surgery, Klinikum Rechts der Isar der Technischen Universität München, München 81622 (Germany); Walch, Axel [Institute of Pathology, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg 85764 (Germany); Langer, Rupert, E-mail: rupert.langer@pathology.unibe.ch [Institute of Pathology, University of Bern, Bern 3010 (Switzerland)

    2014-06-27

    Her2 overexpression and amplification can be found in a significant subset of esophageal adenocarcinomas. The activity of Her2 has been shown to be modulated by molecular chaperones such as HSP90. We analyzed expression/amplification data for HSP90 and Her2 on 127 primary resected esophageal adenocarcinomas in order to evaluate a possible relationship between these two molecules. HSP90 expression determined by immunohistochemistry was observed in various levels. Thirty nine (39) tumors (30.7%) were classified as Her2-positive according to their immunoreactivity and amplification status. There was a significant correlation between HSP90 expression and Her2-status (p = 0.008). This could also be demonstrated by quantitative protein expression analysis with reverse phase protein arrays (r = 0.9; p < 0.001). Her2-status was associated withpT-category (p = 0.041), lymph node metastases (p = 0.049) and tumor differentiation (p = 0.036) with a higher percentage of cases with negative Her2 status in lower tumor stagesA negative Her2-status was also associated with better survival in univariate and multivariate analysis (p = 0.001 and p = 0.014). For HSP90, no associations between clinical and pathological parameters were found. The observed association between HSP90 expression and Her2 suggests a co-regulation of these molecules in at least a subset of esophageal adenocarcinomas. Anti-HSP90 drugs, which recently have been introduced in cancer treatment, may also be an option for these tumors by targeting HSP90 alone or in combination with Her2.

  9. TFF3 and HER2 expression and their correlation with survival in gastric cancer.

    Science.gov (United States)

    Gu, Jianchun; Zheng, Leizhen; Zhang, Li; Chen, Siyu; Zhu, Meiling; Li, Xiaoping; Wang, Yajie

    2015-04-01

    The molecular biomarkers human epidermal growth factor receptor-2 (HER2) and trefoil factor 3 (TFF3) are reported to play important roles in the pathogenesis of gastric cancer (GC). In this study, we investigated the clinicopathological and prognostic significance of TFF3 and HER2 expression in GC and explored the correlation between these two biomarkers. Ninety-two patients who were diagnosed with GC were enrolled. TFF3 and HER2 expression was determined on tumor tissues. The results showed that TFF3 and HER2 were positively expressed in 42.7 and 10.9% of the cases, respectively. There were significantly higher rates of TFF3 positivity in patients with deep invasive tumors and advanced stage ones. Patients with negative TFF3 staining survived longer than those with the presence of TFF3, with 5-year overall survival (OS) rates of 57.1 ± 7.1 and 39.5 ± 7.5%, respectively (P = 0.033). However, HER2 positivity was not significantly associated with OS (P = 0.262). Multivariate analysis demonstrated TFF3 expression to be an independent indicator for short-term survival, with a hazard ratio of 2.327 (95% confidence interval (CI), 1.202-4.507, P = 0.012). There was a trend that the expression of TFF3 was more frequent in HER2 negative tumors than in HER2 positive ones (positive rates: 16.3 vs. 4.7%, P = 0.098). Patients with HER2-negative/TFF3-negative GC presented higher OS than those with other phenotypes (P = 0.009). This study suggests that TFF3 is an independent indicator for survival in GC, while HER2 is not associated with the outcome. Patients with HER2-negative/TFF3-negative GC have the best outcome.

  10. Football Injuries Occurring on Natural Grass and Tartan Turf. A Comparison Study Covering 17 Years at the University of Wisconsin.

    Science.gov (United States)

    Keene, J. S.; And Others

    A longitudinal study of university football players who played on Tartan Turf and/or natural grass was conducted to determine the types and severity of injuries occuring on the different field surfaces. Overall injury rates on Tartan Turf were found to be significantly lower than those sustained on natural grass. (JD)

  11. Development and Characterization of Clinical-Grade Zr-89-Trastuzumab for HER2/neu ImmunoPET Imaging

    NARCIS (Netherlands)

    Dijkers, Eli C. F.; Kosterink, Jos G. W.; Rademaker, Anna P.; Perk, Lars R.; van Dongen, Guus A. M. S.; Bart, Joost; de Jong, Johan R.; de Vries, Elisabeth G. E.; Lub-de Hooge, Marjolijn N.

    2009-01-01

    The anti-human epidermal growth factor receptor 2 (HER2/neu) antibody trastuzumab is administered to patients with HER2/neu-overexpressing breast cancer. Whole-body noninvasive HER2/neu scintigraphy could help to assess and quantify the HER2/neu expression of all lesions, including nonaccessible met

  12. The naturally occurring furanones: formation and function from pheromone to food.

    Science.gov (United States)

    Colin Slaughter, J

    1999-08-01

    Three closely related 4-hydroxy-3(2H)-furanones have been found in a range of highly cooked foodstuffs where they are important flavour compounds with aroma threshold values as low as 20 micrograms kg-1 water (approximately 0.14 mumol l-1). The compounds are formed mainly as a result of the operation of the Maillard reactions between sugars and amino acids during heating but one compound, 5-(or 2)-ethyl-2-(or 5)-methyl-4-hydroxy-3(2H)-furanone, appears in practice to be produced by yeast, probably from a Maillard intermediate, during the fermentation stages in the production of soy sauce and beer. The compounds are also important in the flavour of strawberry, raspberry, pineapple and tomato but the route of biosynthesis is unknown. Two 3-hydroxy-2(5H)-furanones, emoxyfuranone and sotolon, which are produced spontaneously from amino acids such as threonine and 4-hydroxy-L-leucine are major contributors to meaty and spicy/nutty flavours in foods. The biosynthesis of 5-(1,2-dihydroxyethyl)-3,4-dihydroxy-2(5H)-furanone (ascorbic acid, vitamin C) and 5-hydroxymethyl-3,4-dihydroxy-2(5H)-furanone (erythroascorbic acid) from sugars in plants and yeast, respectively, has been characterized to the enzymic level. After treatment with chlorine, humic waters contain a range of chloro-furanones, some of which, particularly 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), are powerful mutagens. The furanones which occur in foods are also mutagenic to bacteria and cause DNA damage in laboratory tests. However, these compounds are, in practice, very effective anti-carcinogenic agents in the diets of animals which are being treated with known cancer-inducing compounds such as benzo[alpha]pyrene or azoxymethane. Two of the food-derived furanones have antioxidant activity comparable to that of ascorbic acid. A biological function has been discovered for some of the furanones besides vitamin C. 5-Methyl-4-hydroxy-3(2H)-furanone is a male pheromone in the cockroach Eurycolis

  13. Molecular imaging of HER2-positive breast cancer: a step toward an individualized 'image and treat' strategy

    DEFF Research Database (Denmark)

    Capala, Jacek; Bouchelouche, Kirsten

    2010-01-01

    HER2 overexpression is correlated with aggressive tumor behavior and poor clinical outcome. Therefore, HER2 has become an important prognostic and predictive factor, as well as a target for molecular therapies. The article reviews recent advances in molecular imaging of HER2 that could facilitate...... individual approaches to targeted therapy of HER2-positive breast cancers.......HER2 overexpression is correlated with aggressive tumor behavior and poor clinical outcome. Therefore, HER2 has become an important prognostic and predictive factor, as well as a target for molecular therapies. The article reviews recent advances in molecular imaging of HER2 that could facilitate...

  14. Notch-EGFR/HER2 Bidirectional Crosstalk in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Andrew T Baker

    2014-12-01

    Full Text Available The Notch pathway is a well-established mediator of cell-cell communication that plays a critical role in stem cell survival, self-renewal, cell fate decisions, tumorigenesis, invasion, metastasis, and drug resistance in a variety of cancers. An interesting form of crosstalk exists between the Notch receptor and the Epidermal Growth Factor Receptor Tyrosine Kinase family which consists of HER-1, -2, -3, and -4. Overexpression of HER and/or Notch occurs in several human cancers including brain, lung, breast, ovary, and skin making them potent oncogenes capable of advancing malignant disease. Continued assessment of interplay between these two critical signaling networks uncovers new insight into mechanisms used by HER-driven cancer cells to exploit Notch as a compensatory pathway. The compensatory Notch pathway maintains HER-induced downstream signals transmitted to pathways such as Mitogen Activated Protein Kinase (MAPK and Phosphatidylinositol 3-Kinase (PI3K, thereby allowing cancer cells to survive molecular targeted therapies, undergo EMT, and increase cellular invasion. Uncovering the critical crosstalk between the HER and Notch pathways can lead to improved screening for the expression of these oncogenes enabling patients to optimize their personal treatment options and predict potential treatment resistance. This review will focus on the current state of crosstalk between the HER and Notch receptors and the effectiveness of current therapies targeting HER-driven cancers.

  15. Adjusting breast cancer patient prognosis with non-HER2-gene patterns on chromosome 17.

    Directory of Open Access Journals (Sweden)

    Vassiliki Kotoula

    Full Text Available BACKGROUND: HER2 and TOP2A gene status are assessed for diagnostic and research purposes in breast cancer with fluorescence in situ hybridization (FISH. However, FISH probes do not target only the annotated gene, while chromosome 17 (chr17 is among the most unstable chromosomes in breast cancer. Here we asked whether the status of specifically targeted genes on chr17 might help in refining prognosis of early high-risk breast cancer patients. METHODS: Copy numbers (CN for 14 genes on chr17, 4 of which were within and 10 outside the core HER2 amplicon (HER2- and non-HER2-genes, respectively were assessed with qPCR in 485 paraffin-embedded tumor tissue samples from breast cancer patients treated with adjuvant chemotherapy in the frame of two randomized phase III trials. PRINCIPAL FINDINGS: HER2-genes CN strongly correlated to each other (Spearman's rho >0.6 and were concordant with FISH HER2 status (Kappa 0.6697 for ERBB2 CN. TOP2A CN were not concordant with TOP2A FISH status (Kappa 0.1154. CN hierarchical clustering revealed distinct patterns of gains, losses and complex alterations in HER2- and non-HER2-genes associated with IHC4 breast cancer subtypes. Upon multivariate analysis, non-HER2-gene gains independently predicted for shorter disease-free survival (DFS and overall survival (OS in patients with triple-negative cancer, as compared to luminal and HER2-positive tumors (interaction p = 0.007 for DFS and p = 0.011 for OS. Similarly, non-HER2-gene gains were associated with worse prognosis in patients who had undergone breast-conserving surgery as compared to modified radical mastectomy (p = 0.004 for both DFS and OS. Non-HER2-gene losses were unfavorable prognosticators in patients with 1-3 metastatic nodes, as compared to those with 4 or more nodes (p = 0.017 for DFS and p = 0.001 for OS. CONCLUSIONS: TOP2A FISH and qPCR may not identify the same pathology on chr17q. Non-HER2 chr17 CN patterns may further predict outcome in breast cancer

  16. Determination of HER2 amplification status in breast cancer cells using Raman spectroscopy

    Science.gov (United States)

    Bi, Xiaohong; Rexer, Brent; Arteaga, Carlos L.; Guo, Mingsheng; Li, Ming; Mahadevan-Jansen, Anita

    2010-02-01

    The overexpression of HER2 (human epidermal growth factor receptor 2) in breast cancer is associated with increased disease recurrence and worse prognosis. Current diagnosis of HER2 positive breast cancer is time consuming with an estimated 20% inaccuracy. Raman spectroscopy is a proven method for pathological diagnosis based on the molecular composition of tissues. This study aimed to determine the feasibility of Raman spectroscopy to differentially identify the amplification of HER2 in cells. Three cell lines including BT474 (HER2 overexpressing breast cancer cell), MCF-10A (human breast epithelial cell), and MCF-10A with overexpressing HER2, were investigated using a bench top confocal Raman system. A diagnostic algorithm based on generalized linear model (GLM) with elastic-net penalties was established to discriminate 318 spectra collected from the cells, and to identify the spectra regions that differentiate the cell lines. The algorithm was able to differentially identify BT474 breast cancer cells with an overall sensitivity of 100% and specificity of 99%. The results demonstrate the capability of Raman spectroscopy to determine HER2 status in cells. Raman spectroscopy shows promise for application in the diagnosis of HER2 positive breast cancer in clinical practice.

  17. Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling.

    Directory of Open Access Journals (Sweden)

    Qing-Bai She

    Full Text Available BACKGROUND: Dysregulated PI3K/Akt signaling occurs commonly in breast cancers and is due to HER2 amplification, PI3K mutation or PTEN inactivation. The objective of this study was to determine the role of Akt activation in breast cancer as a function of mechanism of activation and whether inhibition of Akt signaling is a feasible approach to therapy. METHODOLOGY/PRINCIPAL FINDINGS: A selective allosteric inhibitor of Akt kinase was used to interrogate a panel of breast cancer cell lines characterized for genetic lesions that activate PI3K/Akt signaling: HER2 amplification or PI3K or PTEN mutations in order to determine the biochemical and biologic consequences of inhibition of this pathway. A variety of molecular techniques and tissue culture and in vivo xenograft models revealed that tumors with mutational activation of Akt signaling were selectively dependent on the pathway. In sensitive cells, pathway inhibition resulted in D-cyclin loss, G1 arrest and induction of apoptosis, whereas cells without pathway activation were unaffected. Most importantly, the drug effectively inhibited Akt kinase and its downstream effectors in vivo and caused complete suppression of the growth of breast cancer xenografts with PI3K mutation or HER2 amplification, including models of the latter selected for resistance to Herceptin. Furthermore, chronic administration of the drug was well-tolerated, causing only transient hyperglycemia without gross toxicity to the host despite the pleiotropic normal functions of Akt. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that breast cancers with PI3K mutation or HER2 amplification are selectively dependent on Akt signaling, and that effective inhibition of Akt in tumors is feasible and effective in vivo. These findings suggest that direct inhibition of Akt may represent a therapeutic strategy for breast and other cancers that are addicted to the pathway including tumors with resistant to Herceptin.

  18. Natural transformation of Campylobacter jejuni occurs beyond limits of growth

    DEFF Research Database (Denmark)

    Vegge, Christina Skovgaard; Brøndsted, Lone; Ligowska, Małgorzata;

    2012-01-01

    Campylobacter jejuni is a human bacterial pathogen. While poultry is considered to be a major source of food borne campylobacteriosis, C. jejuni is frequently found in the external environment, and water is another well-known source of human infections. Natural transformation is considered...

  19. Characterizing resilient behavior of naturally occurring bituminous sands for road construction

    CSIR Research Space (South Africa)

    Anochie-Boateng, Joseph

    2010-11-01

    Full Text Available Oil sand is a generic name given to natural deposits of bituminous sand materials that are mined for crude oil production. These materials are currently used as subgrade materials of temporary and permanent roads in oil sand fields for operating...

  20. Incorporation monitoring, above all for naturally occuring radionuclides; Inkorporationsueberwachung, vor allem bei natuerlichen radioaktiven Stoffen

    Energy Technology Data Exchange (ETDEWEB)

    Breustedt, Bastian [Karlsruher Institut fuer Technologie (KIT), Eggenstein-Leopoldshafen (Germany). Inst. fuer Strahlenforschung; Buchholz, Werner [Bundesamt fuer Strahlenschutz, Oberschleissheim (Germany). FB Strahlenschutz und Gesundheit; Burow, Mechthild [Forschungszentrum Juelich GmbH (Germany). Geschaeftsbereich ' ' Sicherheit und Strahlenschutz' ' ; and others

    2017-08-01

    The contribution of the main topic deals with further development of ICRP-models and standardization of regulations in the field of incorporation monitoring. Natural radionuclides, medically used radionuclides and quality assurance, will be discussed. The planning and realization of a shielding chamber for a whole body counter is presented.

  1. HER2 over-expression and response to different chemotherapy regimens in breast cancer

    Institute of Scientific and Technical Information of China (English)

    Jin ZHANG; Yan LIU

    2008-01-01

    Purpose: To exam the relationship between HER2 over-expression and different adjuvant chemotherapies in breast cancer. Patients and Methods: A total of 1625 primary breast cancer patients who received post-surgery adjuvant chemotherapy in Tianjin Cancer Hospital, China, from July 2002 to November 2005 were included in the study. Among them, 600 patients were given CMF (CTX+MTX+5-Fu) regimen, 600 given CEF (CTX+E-ADM+5-Fu) regimen, and 425 given anthracyclines plus taxanes regimen, with mean follow-up time of 42 months. Results: In CMF treatment group, the 3-year disease free survival (DFS)in HER2 over-expressed patients was lower than that of the HER2-negative ones (89.80% vs 91.24%, P=0.0348); in node-positive subgroup, the 3-year DFS was 84.72% in HER2 over-expressed patients, and 90.18% in the HER-2-negative ones (P=0.0271).Compared to CMF regimen, anthracyclines and anthracyclines plus taxanes regimens are more effective (P<0.05) in node-positive HER2 over-expression than those in the node-negative. Conclusion: HER2 over-expression is an independent index for predicting poor prognosis and short DFS for breast cancer patients. HER2 over-expressed patients are resistant to CMF regimen chemotherapy, but sensitive to anthracyclines-based or anthracyclines plus taxanes regimen. HER2 expression can be taken as a marker for therapies in breast cancer.

  2. Correlations of β-catenin, Ki67 and Her-2/neu with gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Hong-Wen Wu; Cheng-Yong Qin; Ji-Lai Huang; Xian-Yi Kong; Wen-Ji Wang; Wen-Kun Bai

    2014-01-01

    Objective: To study the clinical pathologic characteristics of β-catenin, Ki67 and Her-2/neu in gastric cancer and the correlation of β-catenin and Ki67 to the protein expression and gene conditions of Her-2/Neu. Methods: The protein expression of β-catenin, Ki67 and Her-2/Neu was detected by immunohistochemistry in 101 cases of gastric cancer and the gene conditions of Her-2/Neu by fluorescence in situ hybridization (FISH). Results: The protein expression ofβ-catenin, Ki67 and Her-2/Neu had close relationship with the clinical pathologic characteristics of gastric cancer. The β-catenin and Ki67 had obvious correlation to the differentiation, infiltration and lymphatic metastasis of the gastric cancer (P<0.05). The Ki67 had close relationship with the tumor-node-metastasis staging staging of gastric cancer (P<0.05). Her-2/Neu had close relationship with the differentiation and tumor-node-metastasis staging of gastric cancer (P<0.05) but had no relationship with the infiltration and lymphatic metastasis of the gastric cancer (P<0.05). The protein expression of Ki67 had significantly positive correlation to the protein expression and gene amplification conditions of Her-2/Neu (r=0.567, P<0.05 for protein; r=0.304, P<0.05 for gene). Conclusions: Combined detection of β-catenin, Ki67 and Her-2/Neu can be used as a reliable method to help the observation of biological behavior, diagnosis and prognosis of gastric cancer, and Ki67 can be used to serve the preliminary screening of Her-2/Neu gene state.

  3. 靶向沉默人HER2/neu基因的RNA干扰%RNA Interference to Silence Human HER2/neu Gene

    Institute of Scientific and Technical Information of China (English)

    雷莉妍; 孙晓莉; 朱利民; 修志明; 王丽萍

    2013-01-01

    针对人HER2/neu基因的mRNA序列,设计并构建shRNA干扰载体,经聚合酶链式反应(PCR)及测序鉴定后转染SK-BR-3细胞,并检测HER2/neu mRNA和蛋白抑制情况及SK-BR-3细胞迁移能力的变化.实验结果表明:构建了3个HER2/neu-shRNA真核表达质粒;3个重组质粒均可不同程度下调HER2/neu mRNA和蛋白表达水平,并抑制SK-BR-3细胞的迁移;其中1号重组质粒效应最强,对mRNA和蛋白的抑制率分别为84.65%00和74.98%.

  4. TIMP-1 overexpression does not affect sensitivity to HER2-targeting drugs in the HER2-gene-amplified SK-BR-3 human breast cancer cell line.

    Science.gov (United States)

    Deng, Xiaohong; Fogh, Louise; Lademann, Ulrik; Jensen, Vibeke; Stenvang, Jan; Yang, Huanming; Brünner, Nils; Schrohl, Anne-Sofie

    2013-04-01

    Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been suggested as a marker of prognosis and response to treatment in breast cancer. In vitro, TIMP-1 can regulate shedding of the extracellular domain of HER2 and signalling via the Akt pathway, and we hypothesize that TIMP-1 therefore can affect sensitivity to the HER2-targeting drugs trastuzumab and lapatinib. SK-BR-3 human breast cancer cells were stably transfected with TIMP-1, characterized with regard to TIMP-1 protein expression, proliferation, and functionality of the secreted TIMP-1, and the sensitivity to trastuzumab and lapatinib was studied in five selected single-cell subclones expressing TIMP-1 protein at various levels plus the parental SK-BR-3 cell line. Both trastuzumab and lapatinib reduced cell viability, as determined by MTT assay, but the sensitivity to the drugs was not associated with the expression level of TIMP-1 protein. Western blotting showed that the activation of Akt, PTEN, and HER2 as well as ADAM10 was similar in all clones. In conclusion, in this model, TIMP-1 overexpression does not affect HER2 cleavage by ADAM10 or signalling via the Akt pathway, and TIMP-1 does not influence sensitivity to trastuzumab and lapatinib.

  5. HER2 testing in the UK: recommendations for breast and gastric in-situ hybridisation methods

    LENUS (Irish Health Repository)

    Bartlett, J. M. S.

    2011-01-01

    These guidelines supplement existing guidelines on HER2 testing by immunohistochemistry and in-situ hybridisation(ISH) methods in the UK. They provide a specific focus on aspects of guidance relevant to HER2 ISH testing methods, both fluorescent and chromogenic. They are formulated to give advice on methodology, interpretation and quality control for ISH-based testing of HER2 status in common tumour types, including both breast and gastric tumours. The aim is to ensure that all ISH-based testing is accurate, reliable and timely.

  6. Effects of a naturally occurring compatible osmolyte on the internal dynamics of ribonuclease A.

    Science.gov (United States)

    Wang, A; Robertson, A D; Bolen, D W

    1995-11-21

    Osmolytes are small organic solutes accumulated intracellularly by many organisms as they adapt to environmental stresses. Compatible osmolytes, a functional class of osmolytes, increase protein stability while having little or no effect on protein function. To investigate the interrelationships between protein stability, function, and internal dynamics, a hydrogen exchange (HX) quench method was established and used to study the effects of sucrose (a typical compatible osmolyte) on the structural fluctuations of ribonuclease A. It was found that the HX rates of the amide protons with intermediate rates are not affected by 1 M sucrose, but the slow-exchanging amide protons exchange even slower in 1 M sucrose. The protection factors of the slow-exchanging protons fall into a comparatively narrow range while those of the intermediate-exchanging protons vary widely. In agreement with the two-process model [Woodward, C.K., & Hilton, B. D. (1980) Biophys. J. 32, 561-575], we conclude that for those slow-exchanging amide protons, the exchange occurs mainly from the compact unfolded state ensemble of the protein. The internal dynamics leading to slow exchange involve exposure of large protein surface areas, similar to that which occurs upon the unfolding of protein. Because sucrose opposes such an increase in protein surface area exposure, both the slow HX rates and the protein stability are affected by sucrose. For those amide protons with fast and intermediate HX rates, the exchange occurs mainly from the native state ensemble of the protein. The internal dynamics involved in the exchange are localized without much surface area change, and functionally important structural fluctuations are likely to occur within this dynamic range.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. SPARC and Her-2's expression in breast cancer tissue%乳腺癌组织中SPARC和Her-2的表达

    Institute of Scientific and Technical Information of China (English)

    孙孝媛; 于国华; 张居民

    2014-01-01

    Objective To investigate SPARC and Her-2 in breast cancer tissue and its relationship with clinicopathological parameters. Methods Immunohistochemistry was used to detect the expression of 70 cases of breast cancer and 20 cases of breast fibroadenoma SPARC and Her-2's. Results SPARC overexpression in breast cancer rates between stromal cells 68.6% (48/70) was significantly higher than the rate of tumor cells expressing 37.1%(26/70) (P<0.05);mammary stromal cells SPARC expression rate of cancer in 68.6%(48/70) was significantly higher than the expression of breast fibroadenoma 40.0%(8/20) (P < 0.05); in lymph node metastasis,TNM stage ⅢSPARC expression in breast cancer rates rise(P < 0.05).Her-2 was mainly expressed on the membrane of breast cancer cells,high expression rate in breast cancer cells in 45.7%(32/70) was significantly higher than the expression of breast fibroadenoma 10.0% (2/20) (P<0.05). Her-2 expression rate of lymph node metastasis than those without lymph node metastasis high(P<0.05). Conclusion Breast Cancer SPARC,high expression of Her-2 breast cancer i ncidence,progression,metastasis and prognosis.%目的:探讨富含半胱氨酸的酸性分泌蛋白(SPARC)和人表皮生长因子受体(Her-2)在乳腺癌组织中的表达及与临床病理参数的关系。方法应用免疫组织化学方法检测70例乳腺癌和20例乳腺纤维腺瘤中SPARC和Her-2的表达。结果SPARC在乳腺癌间质细胞的高表达率为68.6%(48/70)明显高于肿瘤细胞表达率为37.1%(26/70)(P<0.05);间质细胞中乳腺癌的SPARC表达率为68.6%(48/70)明显高于乳腺纤维腺瘤的表达率为40.0%(8/20)(P<0.05);在有淋巴结转移、TNM分期为Ⅲ期的乳腺癌中SPARC的表达率升高(P<0.05)。乳腺癌中SPARC的高表达率与腋窝淋巴结转移相关。Her-2在乳腺癌肿瘤细胞中的高表达率为45.7%(32/70)明显高于乳腺纤维腺瘤表达率的10.0%(2/20)(P<0.05)。Her

  8. Naturally occurring radioactive materials (NORMs) generated from lignite-fired power plants in Kosovo.

    Science.gov (United States)

    Hasani, F; Shala, F; Xhixha, G; Xhixha, M K; Hodolli, G; Kadiri, S; Bylyku, E; Cfarku, F

    2014-12-01

    The energy production in Kosovo depends primarily on lignite-fired power plants. During coal combustion, huge amounts of fly ash and bottom ash are generated, which may result in enriched natural radionuclides; therefore, these radionuclides need to be investigated to identify the possible processes that may lead to the radiological exposure of workers and the local population. Lignite samples and NORMs of fly ash and bottom ash generated in lignite-fired power plants in Kosovo are analyzed using a gamma-ray spectrometry method for the activity concentration of natural radionuclides. The average activity concentrations of (40)K, (226)Ra and (232)Th in lignite are found to be 36 ± 8 Bq kg(-1), 9 ± 1 Bq kg(-1) and 9 ± 3 Bq kg(-1), respectively. Indications on the occurrence and geochemical behavior of uranium in the lignite matrix are suggested. The activity concentrations of natural radionuclides in fly ash and bottom ash samples are found to be concentrated from 3 to 5 times that of the feeding lignite. The external gamma-ray absorbed dose rate and the activity concentration index are calculated to assess the radiological hazard arising from ash disposal and recycling in the cement industry. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Nanostructural Organization of Naturally Occurring Composites—Part I: Silica-Collagen-Based Biocomposites

    Directory of Open Access Journals (Sweden)

    Hermann Ehrlich

    2008-01-01

    Full Text Available Glass sponges, as examples of natural biocomposites, inspire investigations aiming at both a better understanding of biomineralization mechanisms and novel developments in the synthesis of nanostructured biomimetic materials. Different representatives of marine glass sponges of the class Hexactinellida (Porifera are remarkable because of their highly flexible basal anchoring spicules. Therefore, investigations of the biochemical compositions and the micro- and nanostructure of the spicules as examples of naturally structured biomaterials are of fundamental scientific relevance. Here we present a detailed study of the structural and biochemical properties of the basal spicules of the marine glass sponge Monorhaphis chuni. The results show unambiguously that in this glass sponge a fibrillar protein of collagenous nature is the template for the silica mineralization in all silica-containing structural layers of the spicule. The structural similarity and homology of collagens derived from M. chuni spicules to other sponge and vertebrate collagens have been confirmed by us using FTIR, amino acid analysis and mass spectrometric sequencing techniques. We suggest that nanomorphology of silica formed on proteinous structures could be determined as an example of biodirected epitaxial nanodistribution of amorphous silica phase on oriented fibrillar collagen templates. Finally, the present work includes a discussion relating to silica-collagen-based hybrid materials for practical applications as biomaterials.

  10. Relationship between serum HER2 extracellular domain levels,tissue HER2 expression,and clinico-pathological parameters in early stage breast cancer

    Institute of Scientific and Technical Information of China (English)

    MA Li; YANG Hong-ying; HAN Xiao-hong; LI Jia; WANG Fang; ZHANG Chun-ling; YAO Jia-rui; SHI Yuan-kai

    2012-01-01

    Background Measurement of human epidermal growth factor receptor 2(HER2)protein in the serum of metastatic breast cancer patients has previously been reported,but there are no consistent data to support the clinical utility of serum HER2 extracellufar domain for patients with early stage breast cancer.We aimed to evaluate the correlation between serum extracellular domain levels and tissue HER2 expression,and analyzed their relationship with clinico-pathological parameters in patients with early stage disease.Methods A prospective study was conducted on 232 breast cancer patients with stage Ⅰ-Ⅲ?prior to treatment.Preoperative serum samples were measured by enzyme-linked immunosorbent assay.Tissue HER2 status was analyzed by immunohistochemistry and fluorescence in situ hybridization assays.Results The median serum extracellular domain concentration was 6.8 ng/ml.The best diagnostic cut-off value was 7.4 ng/ml,with 62.9% sensitivity and 85.3% specificity.High serum extracellular domain levels were reported in 89 patients(38.3%),and HER2-positive expression was observed in 77 patients(33.2%).Multivariate analysis showed that elevated serum extracellular domain correlated with postmenopausal status(P<0.001),high histological grade(P<0.001),negativity of both estrogen(P=0.012)and progesterone receptors(P<0.001),and high levels of carcinoembryonic antigen 153(P=0.048).Conclusions We recommend that 7.4 ng/ml should be used as the cut-off value when evaluating serum extracellular domain levels in early stage of breast cancer.Patients with high serum extracellular domain levels have a certain clinicopathological characteristics,may provide a basis for clinical practice.

  11. A naturally-occurring ‘cold earth’ spot in Northern China

    OpenAIRE

    Fujun Niu; Guodong Cheng; Yonghong Niu; Mingyi Zhang; Jing Luo; Zhanju Lin

    2016-01-01

    Permafrost is determined to a large extent by the Earth’s surface temperature, therefore it distributes mainly in high altitude and latitude regions. However, stable, warm (about −1 °C) permafrost occurs within a scree slope in northern China that is more than 600 km south of the southernmost limit of latitudinal permafrost on the Eurasian Continent. It is at an elevation of only 900 m above sea level (ASL). The area has a mean annual air temperature (MAAT) of 6 to 8 °C. Thermal processes of ...

  12. Distribution of naturally occurring radionuclides (U, Th) in Timahdit black shale (Morocco)

    OpenAIRE

    Galindo, C.; Mougin, L.; Fakhi, S.; Nourreddine, A.; Lamghari, A.; Hannache, H.

    2007-01-01

    Attention has been focused recently on the use of Moroccan black oil shale as the raw material for production of a new type of adsorbent and its application to U and Th removal from contaminated wastewaters. The purpose of the present work is to provide a better understanding of the composition and structure of this shale and to determine its natural content in uranium and thorium. A black shale collected from Timahdit (Morocco) was analyzed by powder X-ray diffraction and SEM techniques. It ...

  13. A Phase I Study of LJM716 in Squamous Cell Carcinoma of Head and Neck, or HER2+ Breast Cancer or Gastric Cancer

    Science.gov (United States)

    2014-04-21

    HER2 + Breast Cancer, HER2 + Gastric Cancer, Squamous Cell Carcinoma of Head and Neck, Esophageal Squamous Cell Carcinoma; HER2 + Breast Cancer; HER2 + Gastric Cancer; Squamous Cell Carcinoma of Head and Neck; Esophageal Squamous Cell Carcinoma

  14. A naturally-occurring ‘cold earth’ spot in Northern China

    Science.gov (United States)

    Niu, Fujun; Cheng, Guodong; Niu, Yonghong; Zhang, Mingyi; Luo, Jing; Lin, Zhanju

    2016-09-01

    Permafrost is determined to a large extent by the Earth’s surface temperature, therefore it distributes mainly in high altitude and latitude regions. However, stable, warm (about ‑1 °C) permafrost occurs within a scree slope in northern China that is more than 600 km south of the southernmost limit of latitudinal permafrost on the Eurasian Continent. It is at an elevation of only 900 m above sea level (ASL). The area has a mean annual air temperature (MAAT) of 6 to 8 °C. Thermal processes of the scree slope, investigated through field monitoring and numerical simulation, showed that the permafrost is caused by winter air convection within the porous rock deposits and is stable as air convection does not occur in summer time. The deposit is covered by a 30-cm-thick peaty soil layer dated (carbon C-14) to between 1,000 to 1,600 years ago. The layer also contributes to the permafrost’s existence due to the peat’s thermal conductivity offset when frozen and thawed. The existence of permafrost under such warm climatic conditions confirms the effectiveness of using crushed rock layer as basement or slope cover to protect the warm permafrost subgrade of the recently-constructed Qinghai-Tibet Railway (QTR), even under the predicted climate warming conditions.

  15. Naturally occurring and melengestrol acetate-associated reproductive tract lesions in zoo canids.

    Science.gov (United States)

    Moresco, A; Munson, L; Gardner, I A

    2009-11-01

    As husbandry practices have improved, safe and effective contraception for captive wildlife management has become a necessity. Melengestrol acetate (MGA), a synthetic progestin, is highly effective and has been used in many zoo species. Long-term use of MGA has been associated with uterine lesions in zoo felids, but effects in zoo canids have not been evaluated. This retrospective study documented spontaneously occurring lesions and investigated the impact of MGA on the reproductive health of zoo canids. Reproductive tracts from adult females were submitted by US zoos to the Association of Zoos & Aquariums' Wildlife Contraception Center Health Surveillance Program. Reproductive tracts were sampled and processed for histopathologic examination following standard protocols. Microscopic evaluations were performed without prior knowledge of MGA treatment status. Prevalence of uterine lesions was evaluated and compared between MGA-treated animals (n = 20) and control (untreated) animals (n = 61). Common lesions within the study population as a whole included endometrial hyperplasia (predominantly cystic) (53%), hydrometra (33%), and adenomyosis (25%). Treatment with MGA was a risk factor for endometrial hyperplasia, hydrometra, fibrosis, and adenomyosis. Uterine mineralization occurred exclusively in MGA-treated animals. Results indicate that MGA contraception can lead to lesions that may permanently impair the fertility of females. Therefore, if long-term contraception of zoo canids is necessary, the use of alternate methods of reproductive control such as gonadotropin-releasing hormone (GnRH) analogs or GnRH vaccines that reduce gonadal hormone exposure should be pursued.

  16. A naturally-occurring ‘cold earth’ spot in Northern China

    Science.gov (United States)

    Niu, Fujun; Cheng, Guodong; Niu, Yonghong; Zhang, Mingyi; Luo, Jing; Lin, Zhanju

    2016-01-01

    Permafrost is determined to a large extent by the Earth’s surface temperature, therefore it distributes mainly in high altitude and latitude regions. However, stable, warm (about −1 °C) permafrost occurs within a scree slope in northern China that is more than 600 km south of the southernmost limit of latitudinal permafrost on the Eurasian Continent. It is at an elevation of only 900 m above sea level (ASL). The area has a mean annual air temperature (MAAT) of 6 to 8 °C. Thermal processes of the scree slope, investigated through field monitoring and numerical simulation, showed that the permafrost is caused by winter air convection within the porous rock deposits and is stable as air convection does not occur in summer time. The deposit is covered by a 30-cm-thick peaty soil layer dated (carbon C-14) to between 1,000 to 1,600 years ago. The layer also contributes to the permafrost’s existence due to the peat’s thermal conductivity offset when frozen and thawed. The existence of permafrost under such warm climatic conditions confirms the effectiveness of using crushed rock layer as basement or slope cover to protect the warm permafrost subgrade of the recently-constructed Qinghai-Tibet Railway (QTR), even under the predicted climate warming conditions. PMID:27685441

  17. The source of naturally occurring arsenic in a coastal sand aquifer of eastern Australia.

    Science.gov (United States)

    O'Shea, Bethany; Jankowski, Jerzy; Sammut, Jesmond

    2007-07-01

    The discovery of dissolved arsenic in a coastal aquifer used extensively for human consumption has led to widespread concern for its potential occurrence in other sandy coastal environments in eastern Australia. The development of an aquifer specific geomorphic model (herein) suggests that arsenic is regionally derived from erosion of arsenic-rich stibnite (Sb(2)S(3)) mineralisation present in the hinterland. Fluvial processes have transported the eroded material over time to deposit an aquifer lithology elevated in arsenic. Minor arsenic contribution to groundwater is derived from mineralised bedrock below the unconsolidated aquifer. An association with arsenic and pyrite has been observed in the aquifer in small discrete arsenian pyrite clusters rather than actual acid sulfate soil horizons. This association is likely to influence arsenic distribution in the aquifer, but is not the dominant control on arsenic occurrence. Arsenic association with marine clays is considered a function of their increased adsorptive capacity for arsenic and not solely on the influence of sea level inundation of the aquifer sediments during the Quaternary Period. These findings have implications for, but are not limited to, coastal aquifers. Rather, any aquifer containing sediments derived from mineralised provenances may be at risk of natural arsenic contamination. Groundwater resource surveys should thus incorporate a review of the aquifer source provenance when assessing the likely risk of natural arsenic occurrence in an aquifer.

  18. Climate change enhances the mobilisation of naturally occurring metals in high altitude environments.

    Science.gov (United States)

    Zaharescu, Dragos G; Hooda, Peter S; Burghelea, Carmen I; Polyakov, Viktor; Palanca-Soler, Antonio

    2016-08-01

    Manmade climate change has expressed a plethora of complex effects on Earth's biogeochemical compartments. Climate change may also affect the mobilisation of natural metal sources, with potential ecological consequences beyond mountains' geographical limits; however, this question has remained largely unexplored. We investigated this by analysing a number of key climatic factors in relationship with trace metal accumulation in the sediment core of a Pyrenean lake. The sediment metal contents showed increasing accumulation trend over time, and their levels varied in step with recent climate change. The findings further revealed that a rise in the elevation of freezing level, a general increase in the frequency of drier periods, changes in the frequency of winter freezing days and a reducing snow cover since the early 1980s, together are responsible for the observed variability and augmented accumulation of trace metals. Our results provide clear evidence of increased mobilisation of natural metal sources - an overlooked effect of climate change on the environment. With further alterations in climate equilibrium predicted over the ensuing decades, it is likely that mountain catchments in metamorphic areas may become significant sources of trace metals, with potentially harmful consequences for the wider environment.

  19. Prognostic Impact of VEGFA Germline Polymorphisms in Patients with HER2-positive Primary Breast Cancer

    DEFF Research Database (Denmark)

    Maae, Else; Andersen, Rikke Fredslund; Dahl Steffensen, Karina;

    2012-01-01

    Background: Vascular endothelial growth factor A (VEGFA) is essential in tumour angiogenesis, and polymorphisms in the VEGFA gene have been associated with breast cancer prognosis. The human epidermal growth factor receptor 2 (HER2) is overexpressed in breast tumours and is also associated...... multivariate analysis, only the -634CC genotype remained an independent prognostic factor (p=0.008). Conclusion: The VEGFA -634CC genotype was found to be associated with an inferior prognosis for patients with HER2-positive breast cancer....... with angiogenesis. We investigated the possible prognostic impact of VEGFA single nucleotide polymorphisms (SNPs) in patients with HER2-positive primary breast cancer. Patients and Methods: DNA was isolated from venous blood samples from 116 HER2-positive patients and genotyped for VEGFA -2578C>A, -1498T>C, -1154G...

  20. RON confers lapatinib resistance in HER2-positive breast cancer cells.

    Science.gov (United States)

    Wang, Quanren; Quan, Haitian; Zhao, Jie; Xie, Chengying; Wang, Lei; Lou, Liguang

    2013-10-28

    Lapatinib-resistance is a major problem for HER2-positive breast cancer treatment. SK-BR-3-LR, a lapatinib-resistant cell clone, was established from HER2-positive SK-BR-3 breast cancer cells following chronic exposure to lapatinib. The PI3K/AKT signaling pathway was demonstrated to be resistant to HER2 inhibition in SK-BR-3-LR cells. However, both small-molecular Recepteur d'Origine Nantais (RON) inhibitors and RON-targeted small interfering RNA (siRNA) effectively restored lapatinib sensitivity in these cells by inhibiting PI3K/AKT activation. Our results demonstrate for the first time the important role of RON in mediating lapatinib resistance and suggest that RON-targeted therapy may become a novel, promising therapeutic strategy after the failure of lapatinib treatment in patients with HER2-positive breast cancer.

  1. A systematic review of dual targeting in HER2-positive breast cancer

    DEFF Research Database (Denmark)

    Kümler, Iben; Tuxen, Malgorzata K; Nielsen, Dorte Lisbet

    2014-01-01

    BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is overexpresed in 15-20% of all breast cancers. Treatment with trastuzumab has led to an improved outcome and prolonged survival of HER2-positive breast cancer patients and today the drug is established as standard of care in both...... the adjuvant and metastatic settings. However, trastuzumab resistance is common and a major focus in the treatment of HER2-positive breast cancer has been developing therapeutic agents to either potentiate the effect of trastuzumab or to target cells which have become resistant to trastuzumab. The present...... review addresses efficacy and toxicity of dual targeting in HER2-positive breast cancer. MATERIALS AND METHODS: A computer-based literature search was carried out using PubMed; data reported at international meetings and clinicaltrials.gov was included. RESULTS: This paper describes efficacy and safety...

  2. HER2-targeted therapy in breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors

    DEFF Research Database (Denmark)

    Nielsen, Dorte Lisbet; Andersson, Michael; Kamby, Claus

    2008-01-01

    There is strong clinical evidence that trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor (HER) two tyrosine kinase receptor, is an important component of first-line treatment of patients with HER2-positive metastatic breast cancer. In particular the combination...... with taxanes and vinorelbine has been established. In the preoperative setting inclusion of trastuzumab has significantly increased the pathological complete response rate. Results from large phase III trials evaluating adjuvant therapy in HER2-positive early breast cancer indicate that the addition...... of trastuzumab to chemotherapy improves disease-free and overall survival. The use of lapatinib, a dual tyrosine kinase inhibitor of both HER1 and HER2, in combination with capecitabine in the second-line treatment of HER2-positive patients with metastatic breast cancer previously treated with trastuzumab has...

  3. Antitumor efficacy of piperine in the treatment of human HER2-overexpressing breast cancer cells.

    Science.gov (United States)

    Do, Minh Truong; Kim, Hyung Gyun; Choi, Jae Ho; Khanal, Tilak; Park, Bong Hwan; Tran, Thu Phuong; Jeong, Tae Cheon; Jeong, Hye Gwang

    2013-12-01

    Piperine is a bioactive component of black pepper, Piper nigrum Linn, commonly used for daily consumption and in traditional medicine. Here, the molecular mechanisms by which piperine exerts antitumor effects in HER2-overexpressing breast cancer cells was investigated. The results showed that piperine strongly inhibited proliferation and induced apoptosis through caspase-3 activation and PARP cleavage. Furthermore, piperine inhibited HER2 gene expression at the transcriptional level. Blockade of ERK1/2 signaling by piperine significantly reduced SREBP-1 and FAS expression. Piperine strongly suppressed EGF-induced MMP-9 expression through inhibition of AP-1 and NF-κB activation by interfering with ERK1/2, p38 MAPK, and Akt signaling pathways resulting in a reduction in migration. Finally, piperine pretreatment enhanced sensitization to paclitaxel killing in HER2-overexpressing breast cancer cells. Our findings suggest that piperine may be a potential agent for the prevention and treatment of human breast cancer with HER2 overexpression.

  4. Analysis of EGFR and HER-2 expressions in ductal carcinomas in situ in canine mammary glands

    Directory of Open Access Journals (Sweden)

    I.L.D. Silva

    2014-06-01

    Full Text Available Biomolecular evidence has shown that ductal carcinoma in situ (DCIS may develop into invasive carcinoma of the canine mammary gland, and mutations in proto-oncogenes HER2 and EGFR; two members of the family of epidermal growth factor receptors, may be involved in this process. The purpose of this study was the characterization of the immunohistochemical expression of the EGFR and HER2 proteins in the process of neoplastic transformation, supposedly present in ductal carcinomas in situ in canine mammary glands. Fifteen cases of DCIS were evaluated, with a higher expression of HER2 and EGFR being observed in low-grade carcinomas when compared with high-grade neoplasms, and with a high positive statistical correlation in the latter. Results suggest that aggressive tumors tend to lose the expression of EGFR and HER2 simultaneously. The loss of the expression of these markers may be related to the process of neoplastic progression in canine mammary tumors.

  5. Afatinib and its encapsulated polymeric micelles inhibits HER2-overexpressed colorectal tumor cell growth in vitro and in vivo.

    Science.gov (United States)

    Guan, Siao-Syun; Chang, Jungshan; Cheng, Chun-Chia; Luo, Tsai-Yueh; Ho, Ai-Sheng; Wang, Chia-Chi; Wu, Cheng-Tien; Liu, Shing-Hwa

    2014-07-15

    Colorectal cancer (CRC) is known as a common malignant neoplasm worldwide. The role of EGFR/HER2 in CRC is unclear. Afatinib is an irreversible EGFR/HER2 inhibitor. There were few studies of afatinib on CRC. Here, we investigated the protein levels/expressions of HER2 in sera and tumors from CRC patients and the therapeutic effect of afatinib on HER2-overexpressed CRC in vitro and in vivo. The increased HER2 levels were detected in the collected sera and tumors of patients with CRC. The serological HER2 levels were correlated with the tumor HER2 expressions in patients. Afatinib also inhibited the HER2-positive tumor cell growth and caused apoptosis in HER2-overexpressed human colorectal cancer HCT-15 cells but not in low HER2 expressed human gastric cancer MKN45 cells. In vivo study showed that afatinib reduced tumor growth in HER2-overexpressed xenografts. Moreover, afatinib-encapsulated micelles displayed higher cytotoxic activity in HCT-15 cells and were more effective for tumor growth suppression in HCT-15-induced tumor xenografts than afatinib performance alone. Taken together, these findings suggest that higher serum HER2 levels reflect the higher HER2 contents in tumors of CRC patients, and the improved afatinib-encapsulated micelles possess high therapeutic efficacy in HER2-overexpressed CRC in vitro and in vivo.