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Sample records for pemetrexed alimta ly231514

  1. Potential role of pemetrexed in metastatic breast cancer patients pre-treated with anthracycline or taxane

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    Li-Yan Zhou

    2015-03-01

    Full Text Available Objectives: This article reviews pharmacology, pharmacokinetic properties, clinical efficacy, and safety in metastatic breast cancer patients, as well as the predictive biomarkers for outcome of treatment with pemetrexed-based regimens. Methods: PubMed, Embase, OVID, and the Cochrane Library databases were searched from the beginning of each database without any limitations to the date of publication. Search terms were ‘‘pemetrexed’’ or ‘‘LY231514’’ or “Alimta”, “metastatic breast cancer”, and “advanced breast cancer”. Results: There were 15 studies (n = 1002 meeting our criteria for evaluation. Eight single-agent trials (n = 551 and seven using combinations with other agents (n = 451 were identified that evaluated pemetrexed for use in patients with metastatic breast cancer. Response rates to pemetrexed as a single agent varied from 8% to 31%, and with combination therapy have been reported to be between 15.8% and 55.7%. With routine supplementation of patients with folic acid, dexamethasone, and vitamin B12, the toxicity profile of these patients was mild, including dose-limiting neutropenia and thrombocytopenia, as well as lower grades of reversible hepatotoxicity and gastrointestinal toxicity. Expression of thymidylate synthase (TS and other biomarkers are associated with the prognosis and sensitivity for pemetrexed in breast cancer. Conclusion: Pemetrexed has shown remarkable activity with acceptable toxicities for treatment of metastatic breast cancer patients. Translational research on pemetrexed in breast cancer identified biomarkers as well as additional genes important to its clinical activity and toxicity. Further research is needed to clarify the role of pemetrexed in breast cancer treatment in order to guide oncologists. Keywords: Metastatic breast cancer, Chemotherapy, Pemetrexed, Anthracycline, Taxane

  2. Potential role of pemetrexed in metastatic breast cancer patients pre-treated with anthracycline or taxane

    Institute of Scientific and Technical Information of China (English)

    Li-Yan Zhou; Ye-Hui Shi; Yong-Sheng Jia; Zhong-Sheng Tong

    2015-01-01

    Objectives: This article reviews pharmacology, pharmacokinetic properties, clinical efficacy, and safety in metastatic breast cancer patients, as well as the predictive biomarkers for outcome of treatment with pemetrexed-based regimens. Methods: PubMed, Embase, OVID, and the Cochrane Library databases were searched from the beginning of each database without any limitations to the date of publication. Search terms were‘‘pemetrexed’’ or‘‘LY231514’’ or“Alimta”,“metastatic breast cancer”, and“advanced breast cancer”. Results: There were 15 studies (n ¼ 1002) meeting our criteria for evaluation. Eight single-agent trials (n ¼ 551) and seven using combinations with other agents (n ¼ 451) were identified that evaluated pemetrexed for use in patients with metastatic breast cancer. Response rates to pemetrexed as a single agent varied from 8%to 31%, and with combination therapy have been reported to be between 15.8% and 55.7%. With routine supplementation of patients with folic acid, dexamethasone, and vitamin B12, the toxicity profile of these patients was mild, including dose-limiting neutropenia and thrombocytopenia, as well as lower grades of reversible hepatotoxicity and gastrointestinal toxicity. Expression of thymidylate synthase (TS) and other biomarkers are associated with the prognosis and sensitivity for pemetrexed in breast cancer. Conclusion: Pemetrexed has shown remarkable activity with acceptable toxicities for treatment of metastatic breast cancer patients. Translational research on pemetrexed in breast cancer identified biomarkers as well as additional genes important to its clinical activity and toxicity. Further research is needed to clarify the role of pemetrexed in breast cancer treatment in order to guide oncologists. Copyright © 2015, Chinese Medical Association Production. Production and hosting by Elsevier B.V. on behalf of KeAi Com-munications Co., Ltd. This is an open access article under the CC BY-NC-ND license

  3. Phase I dose-escalation study to examine the safety and tolerability of LY2603618, a checkpoint 1 kinase inhibitor, administered 1 day after pemetrexed 500 mg/m(2) every 21 days in patients with cancer.

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    Weiss, Glen J; Donehower, Ross C; Iyengar, Tara; Ramanathan, Ramesh K; Lewandowski, Karen; Westin, Eric; Hurt, Karla; Hynes, Scott M; Anthony, Stephen P; McKane, Scott

    2013-02-01

    This phase I study aims at assessing the safety and tolerability of LY2603618, a selective inhibitor of Checkpoint Kinase 1, in combination with pemetrexed and determining the maximum tolerable dose and the pharmacokinetic parameters. This was an open-label, multicenter, dose-escalation study in patients with advanced solid tumors. Increasing doses of LY2603618 (40-195 mg/m(2)) were combined with 500 mg/m(2) of pemetrexed. LY2603618 was administered on Days 1 and 9 and pemetrexed on Day 8 in a 28-day cycle. For all subsequent 21-day cycles, pemetrexed was administered on Day 1 and LY2603618 on Day 2. Antitumor activity was evaluated as per Response Evaluation Criteria in Solid Tumors 1.0. A total of 31 patients were enrolled into six cohorts (three at 40 mg/m(2) over 4.5-hour infusion, 1-hour infusion in subsequent cohorts: three each at 40 mg/m(2), 70 mg/m(2), and 195 mg/m(2); 13 at 105 mg/m(2); six at 150 mg/m(2)). Four patients experienced a dose-limiting toxicity: diarrhea (105 mg/m(2)); reversible infusion-related reaction (150 mg/m(2)); thrombocytopenia (195 mg/m(2)); and fatigue (195 mg/m(2)). The maximum tolerated dose was defined as 150 mg/m(2). The pharmacokinetic data demonstrated that the exposure of LY2603618 increased in a dose-dependent manner, displayed a suitable half-life for maintaining required human exposures while minimizing the intra- and inter-cycle accumulation, and was unaffected by the pemetrexed administration. The pharmacokinetic-defined biologically efficacious dose was achieved at doses ≥105 mg/m(2). LY2603618 administered approximately 24 h after pemetrexed showed acceptable safety and pharmacokinetic profiles.

  4. FLT-PET/CT as a Biomarker of Therapeutic Response in Pemetrexed Therapy for Non-Small Cell Lung Cancer

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    2016-12-01

    Teva Pharmaceuticals , Petach Tikva Israel) were provided freshly prepared as a 1mg/ml sterile saline solution by the Abramson Cancer Center...human and murine, pemetrexed (ALIMTA; Eli Lilly and Company, Indianapolis, IN) and cisplatin (Teva Pharmaceuticals , PetachTikva Israel) were provided...Griffiths JR, Doblas S, Sinkus R, Laverman P, Oyen WJ, Heerschap A, Boerman OC. Response Monitoring with [18F]FLT PET and Diffusion-Weighted MRI

  5. New Polymorphic Forms of Pemetrexed Diacid and Their Use for the Preparation of Pharmaceutically Pure Amorphous and Hemipentahydrate Forms of Pemetrexed Disodium

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    Michalak, Olga; Łaszcz, Marta; Jatczak, Kamil; Witkowska, Anna; Bujak, Iwona; Groman, Aleksandra; Cybulski, Marcin

    2015-01-01

    The preparation of stable amorphous pemetrexed disodium of pharmaceutical purity as well as the process optimization for the preparation of the hemipentahydrate form of pemetrexed disodium are described. Analytical methods for the polymorphic and chemical purity studies of pemetrexed disodium and pemetrexed diacid forms were developed. The physicochemical properties of the amorphous and hydrate forms of pemetrexed disodium, as well as new forms of pemetrexed diacid (a key synthetic intermedia...

  6. New Polymorphic Forms of Pemetrexed Diacid and Their Use for the Preparation of Pharmaceutically Pure Amorphous and Hemipentahydrate Forms of Pemetrexed Disodium

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    Olga Michalak

    2015-07-01

    Full Text Available The preparation of stable amorphous pemetrexed disodium of pharmaceutical purity as well as the process optimization for the preparation of the hemipentahydrate form of pemetrexed disodium are described. Analytical methods for the polymorphic and chemical purity studies of pemetrexed disodium and pemetrexed diacid forms were developed. The physicochemical properties of the amorphous and hydrate forms of pemetrexed disodium, as well as new forms of pemetrexed diacid (a key synthetic intermediate were studied by thermal analysis and powder X-ray diffraction. High-performance liquid chromatography and gas chromatography methods were used for the chemical purity and residual solvents determination. In order to study the polymorphic and chemical stability of the amorphous and hemipentahydrate forms, a hygroscopicity test (25 °C, 80% RH was performed. Powder diffraction and high-performance liquid chromatography analyses revealed that the amorphous character and high chemical purity were preserved after the hygroscopicity test. The hemipentahydrate form transformed completely to the heptahydrate form of pemetrexed disodium. Both pemetrexed disodium forms were produced with high efficiency and pharmaceutical purity in a small commercial scale. Amorphous pemetrexed disodium was selected for further pharmaceutical development. Two new polymorphs (forms 1 and 2 of pemetrexed diacid were used for the preparation of high purity amorphous pemetrexed disodium.

  7. Caffeine markedly sensitizes human mesothelioma cell lines to pemetrexed

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    Min, Sang Hee; Goldman, I. David; Zhao, Rongbao

    2013-01-01

    Pemetrexed is a new generation antifolate approved for the treatment of mesothelioma and non-small cell lung cancer. Caffeine is known to augment radiation or chemotherapeutic drug-induced cell killing. The current study addresses the impact of caffeine on the activity of pemetrexed in mesothelioma cell lines. Caffeine enhanced pemetrexed activity in all four mesothelioma cell lines tested (H2052, H2373, H28 and MSTO-211H). Caffeine sensitized H2052 cells in a dose- and schedule-dependent manner, and was associated with a markedly decreased clonogenic survival. Caffeine sensitization occurred only in cells subjected to pulse, but not continuous, exposure to pemetrexed. Similar pemetrexed sensitization was also observed with the clinically better tolerated caffeine analog, theobromine. Pemetrexed sensitization by caffeine was associated with an increase in pemetrexed-induced phosphorylation of ataxia-telangiectasia-mutated (ATM) and Chk1. These data indicate that caffeine and its analog, theobromine, may be a useful approach to enhance pemetrexed-based chemotherapy. PMID:17594092

  8. High plasma exposure to pemetrexed leads to severe hyponatremia in patients with advanced non small cell lung cancer receiving pemetrexed-platinum doublet chemotherapy

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    Gota, Vikram; Kavathiya, Krunal; Doshi, Kartik; Gurjar, Murari; Damodaran, Solai E; Noronha, Vanita; Joshi, Amit; Prabhash, Kumar

    2014-01-01

    Pemetrexed-platinum doublet therapy is a standard treatment for stage IIIb/IV nonsquamous non small cell lung cancer (NSCLC). While the regimen is associated with several grade ≥3 toxicities, hyponatremia is not a commonly reported adverse effect. Here we report an unusually high incidence of grade ≥3 hyponatremia in Indian patients receiving pemetrexed-platinum doublet, and the pharmacological basis for this phenomenon. Forty-six patients with advanced NSCLC were enrolled for a bioequivalence study of two pemetrexed formulations. All patients received the pemetrexed-platinum doublet for six cycles followed by single-agent pemetrexed maintenance until progression. Pharmacokinetic blood samples were collected at predefined time points during the first cycle and the concentration-time profile of pemetrexed was investigated by noncompartmental analysis. Hyponatremic episodes were investigated with serum electrolytes, serum osmolality, urinary sodium, and urine osmolality. Sixteen of 46 patients (35%) had at least one episode of grade ≥3 hyponatremia. Twenty-four episodes of grade ≥3 hyponatremia were observed in 200 cycles of doublet chemotherapy. Plasma exposure to pemetrexed was significantly higher in patients with high-grade hyponatremia than in those with low-grade or no hyponatremia (P=0.063 and P=0.001, respectively). Pemetrexed clearance in high-grade hyponatremia was quite low compared with normal and low-grade hyponatremia (P=0.001 and P=0.055, respectively). Median pemetrexed exposure in this cohort was much higher than that reported in the literature from Western studies. Higher exposure to pemetrexed is associated with grade ≥3 hyponatremia. The pharmacogenetic basis for higher exposure to pemetrexed in Indian patients needs further investigation

  9. Physical and chemical stability of pemetrexed in infusion solutions.

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    Zhang, Yanping; Trissel, Lawrence A

    2006-06-01

    Pemetrexed is a multitargeted, antifolate, antineoplastic agent that is indicated for single-agent use in locally advanced or metastatic non-small-cell lung cancer after prior chemotherapy and in combination with cisplatin for the treatment of malignant pleural mesothelioma not treatable by surgery. Currently, there is no information on the long-term stability of pemetrexed beyond 24 hours. To evaluate the longer-term physical and chemical stability of pemetrexed 2, 10, and 20 mg/mL in polyvinyl chloride (PVC) bags of dextrose 5% injection and NaCl 0.9% injection. Triplicate samples of pemetrexed were prepared in the concentrations and infusion solutions required. Evaluations for physical and chemical stability were performed initially and over 2 days at 23 degrees C protected from light and exposed to fluorescent light, and over 31 days of storage at 4 degrees C protected from light. Physical stability was assessed using turbidimetric and particulate measurement as well as visual observation. Chemical stability was evaluated by HPLC. All pemetrexed solutions remained chemically stable, with little or no loss of pemetrexed over 2 days at 23 degrees C, protected from light and exposed to fluorescent light, and over 31 days of storage at 4 degrees C, protected from light. The room temperature samples were physically stable throughout the 48 hour test period. However, pemetrexed admixtures developed large numbers of microparticulates during refrigerated storage exceeding 24 hours. Pemetrexed is chemically stable for 2 days at room temperature and 31 days refrigerated in dextrose 5% injection and NaCl 0.9% injection. However, substantial numbers of microparticulates may form in pemetrexed diluted in the infusion solutions in PVC bags, especially during longer periods of refrigerated storage. Limiting the refrigerated storage period to the manufacturer-recommended 24 hours will limit particulate formation.

  10. Cost-effectiveness of pemetrexed in combination with cisplatin as first line treatment for patients with advanced non-squamous non-small-cell

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    Jonathan González García

    2017-01-01

    Full Text Available Introduction: Lung cancer is the third most frequent neoplastic tumour in Spain, with around 27 000 new cases diagnosed per year; 80-95% of these are non-small-cell cancer (NSCLC, and the majority of cases are diagnosed in advanced stages of the disease, and for this reason it is one of the oncologic conditions with higher mortality rates (21.4% mean survival at 5 years. The main treatment regimens used for first-line treatment of NSCLC are: isplatin/pemetrexed (cis/pem, cisplatin/gemcitabine/ bevacizumab (cis/gem/bev, and carboplatin/paclitaxel/ bevacizumab (carb/pac/bev. The objective of this study was to evaluate the cost-effectiveness ratio of antineoplastic 1st line NSCLC treatment regimens, from the point of view of hospital management. Methodology: A cost-efficacy mathematical model was prepared, based on a decision tree. The efficacy variable was Progression Free Survival, obtained from the PARAMOUNT, AVAIL and SAIL Phase III clinical trials. The study was conducted from the perspective of the hospital management, considering only the direct costs of drug acquisition. A deterministic sensitivity analysis was conducted to confirm the robustness of outcomes. Results: The PFS obtained in clinical trials with cis/pem, cis/ gem/bev and carb/pac/bev was: 6.9, 6.7 and 6.2 months, respectively. Based on our model, the mean cost of treatment per patient for these regimens was: 19 942 €, 15 594 € and 36 095 €, respectively. The incremental cost-effectiveness ratio per month of additional PFS between cis/pem and cis/gem/bev was 19 303 €. Estimating a 30% reduction in acquisition costs for pemetrexed (Alimta®Eli Lilly Nederland B.V., due to the forthcoming launch of generic medications, the cis/pem treatment would become the predominant alternative for 1st line treatment of NSCLC patients, by offering the best health results at a lower cost.

  11. Pemetrexed disodium (Eli Lilly).

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    Norman, P

    2001-11-01

    Pemetrexed, a thymidylate synthase (TS) and transferase inhibitor, is in phase III trials with Eli Lilly as a potential treatment for several common solid tumors, including non-small cell lung cancer (NSCLC) and mesothelioma [321789], [410731]. Studies on pemetrexed have concluded that not only is the compound a TS inhibitor but also a potent inhibitor of human dihydrofolate reductase (DHFR). The results suggest that pemetrexed acts upon multiple intracellular targets and that the antitumor effect may be derived from its simultaneous inhibition of multiple folate-requiring enzymes [203662]: this compound has been designated as a multitargeted antifolate (MTA) [386680]. The drug also causes concentration- and time-dependent apoptosis [284380]. Other studies in which the 4-oxo group of the pyrimidine ring portion of pemetrexed was replaced with a hydrogen atom, demonstrated that the resulting analogs were potent DHFR inhibitors with very little activity against the enzymes glycinamide ribonucleotide formyltransferase (GARFT) and TS [310674]. In phase II European studies in 64 patients with advanced breast cancer, encouraging responses were seen in anthracycline-failure (23%) and anthracycline-refractory (19%) patients. Responses were observed in 28% of patients who had been previously treated with a taxane [326097]. Data from a phase II trial of pemetrexed (500 mg/m2 once every 21 days as a 10 min i.v. infusion) as a salvage therapy in advanced breast cancer showed that supplementation of the treatment regime with folic acid (FA) and vitamin B12 reduced its already manageable and tolerable toxicities [408821], [409650]. At doses of 500 mg/m2, the drug was also safely administered to 35 patients with impaired renal function [409953]. Phase I and II trials have shown that the main side effects include neutropenia, thrombocytopenia, mucositis, nausea and vomiting [203666], [272241]. Princeton University holds the patent rights to this drug under EP-00432677. In June

  12. Pemetrexed safety and pharmacokinetics in patients with third-space fluid

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    Dickgreber, Nicolas J; Sorensen, Jens Benn; Paz-Ares, Luis G

    2010-01-01

    Pemetrexed is established as first-line treatment with cisplatin for malignant pleural mesothelioma and advanced nonsquamous non-small-cell lung cancer (NSCLC) and as single-agent second-line treatment for nonsquamous NSCLC. Because the structure and pharmacokinetics of pemetrexed are similar to ...... to those of methotrexate, and methotrexate is associated with severe toxicity in patients with third-space fluid (TSF), the safety of pemetrexed in patients with TSF was evaluated....

  13. Critical appraisal of pemetrexed in the treatment of NSCLC and metastatic pulmonary nodules

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    Li X

    2014-06-01

    Full Text Available Xin Li, Sen Wei, Jun ChenTianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Heping District, Tianjin, People's Republic of ChinaAbstract: Pemetrexed, a new multitarget antifolate antineoplastic agent, has significantly improved the overall survival in nonsquamous non-small-cell lung cancer patients. Presently, pemetrexed is recommended for first line treatment in combination with platinum derivatives, for second line treatment as a single agent and, more recently, as maintenance treatment after first line chemotherapy. In this article we critically appraise the status of pemetrexed including pharmacodynamics, pharmacokinetics, toxicity, and the cost effectiveness of pemetrexed, as well as the predictive biomarkers for pemetrexed based chemotherapy.Keywords: chemotherapy, non-small-cell lung cancer, pemetrexed

  14. Molecular mechanism implicated in Pemetrexed-induced apoptosis in human melanoma cells

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    Buqué Aitziber

    2012-04-01

    Full Text Available Abstract Background Metastatic melanoma is a lethal skin cancer and its incidence is rising every year. It represents a challenge for oncologist, as the current treatment options are non-curative in the majority of cases; therefore, the effort to find and/or develop novel compounds is mandatory. Pemetrexed (Alimta®, MTA is a multitarget antifolate that inhibits folate-dependent enzymes: thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase, required for de novo synthesis of nucleotides for DNA replication. It is currently used in the treatment of mesothelioma and non-small cell lung cancer (NSCLC, and has shown clinical activity in other tumors such as breast, colorectal, bladder, cervical, gastric and pancreatic cancer. However, its effect in human melanoma has not been studied yet. Results In the current work we studied the effect of MTA on four human melanoma cell lines A375, Hs294T, HT144 and MeWo and in two NSCLC cell lines H1299 and Calu-3. We have found that MTA induces DNA damage, S-phase cell cycle arrest, and caspase- dependent and –independent apoptosis. We show that an increment of the intracellular reactive oxygen species (ROS and p53 is required for MTA-induced cytotoxicity by utilizing N-Acetyl-L-Cysteine (NAC to blockage of ROS and p53-defective H1299 NSCLC cell line. Pretreatment of melanoma cells with NAC significantly decreased the DNA damage, p53 up-regulation and cytotoxic effect of MTA. MTA was able to induce p53 expression leading to up-regulation of p53-dependent genes Mcl-1 and PIDD, followed by a postranscriptional regulation of Mcl-1 improving apoptosis. Conclusions We found that MTA induced DNA damage and mitochondrial-mediated apoptosis in human melanoma cells in vitro and that the associated apoptosis was both caspase-dependent and –independent and p53-mediated. Our data suggest that MTA may be of therapeutic relevance for the future treatment of human malignant melanoma.

  15. Pemetrexed safety and pharmacokinetics in patients with third-space fluid

    DEFF Research Database (Denmark)

    Dickgreber, Nicolas J; Sørensen, Jens Benn; Paz-Ares, Luis G

    2010-01-01

    Pemetrexed is established as first-line treatment with cisplatin for malignant pleural mesothelioma and advanced nonsquamous non-small-cell lung cancer (NSCLC) and as single-agent second-line treatment for nonsquamous NSCLC. Because the structure and pharmacokinetics of pemetrexed are similar...

  16. Cost-effectiveness of continuation maintenance pemetrexed after cisplatin and pemetrexed chemotherapy for advanced nonsquamous non-small-cell lung cancer: estimates from the perspective of the Chinese health care system.

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    Zeng, Xiaohui; Peng, Liubao; Li, Jianhe; Chen, Gannong; Tan, Chongqing; Wang, Siying; Wan, Xiaomin; Ouyang, Lihui; Zhao, Ziying

    2013-01-01

    Continuation maintenance treatment with pemetrexed is approved by current clinical guidelines as a category 2A recommendation after induction therapy with cisplatin and pemetrexed chemotherapy (CP strategy) for patients with advanced nonsquamous non-small-cell lung cancer (NSCLC). However, the cost-effectiveness of the treatment remains unclear. We completed a trial-based assessment, from the perspective of the Chinese health care system, of the cost-effectiveness of maintenance pemetrexed treatment after a CP strategy for patients with advanced nonsquamous NSCLC. A Markov model was developed to estimate costs and benefits. It was based on a clinical trial that compared continuation maintenance pemetrexed therapy plus best supportive care (BSC) versus placebo plus BSC after a CP strategy for advanced nonsquamous NSCLC. Sensitivity analyses were conducted to assess the stability of the model. The model base case analysis suggested that continuation maintenance pemetrexed therapy after a CP strategy would increase benefits in a 1-, 2-, 5-, or 10-year time horizon, with incremental costs of $183,589.06, $126,353.16, $124,766.68, and $124,793.12 per quality-adjusted life-year gained, respectively. The most sensitive influential variable in the cost-effectiveness analysis was the utility of the progression-free survival state, followed by proportion of patients with postdiscontinuation therapy in both arms, proportion of BSC costs for PFS versus progressed survival state, and cost of pemetrexed. Probabilistic sensitivity analysis indicated that the cost-effective probability of adding continuation maintenance pemetrexed therapy to BSC was zero. One-way and probabilistic sensitivity analyses revealed that the Markov model was robust. Continuation maintenance of pemetrexed after a CP strategy for patients with advanced nonsquamous NSCLC is not cost-effective based on a recent clinical trial. Decreasing the price or adjusting the dosage of pemetrexed may be a better option

  17. Pharmacokinetic evaluation of pemetrexed

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    Sørensen, Jens Benn

    2011-01-01

    correlates with renal function and it may be safely used with vitamin supplementation in patients with creatinine clearance ≥ 45 ml/min. The pharmacokinetics of pemetrexed is also largely unchanged in third-space fluids and can be feasibly and safely administered in combination with several other cytotoxic...

  18. Pharmacokinetic evaluation of pemetrexed

    DEFF Research Database (Denmark)

    Sørensen, Jens Benn

    2011-01-01

    correlates with renal function and it may be safely used with vitamin supplementation in patients with creatinine clearance = 45 ml/min. The pharmacokinetics of pemetrexed is also largely unchanged in third-space fluids and can be feasibly and safely administered in combination with several other cytotoxic...

  19. Pemetrexed in maintenance treatment of advanced non-squamous non-small-cell lung cancer

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    Minami S

    2015-01-01

    Full Text Available Seigo Minami,1 Takashi Kijima2 1Department of Respiratory Medicine, Osaka Police Hospital, 2Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan Abstract: Pemetrexed, a multitargeting antifolate cytotoxic drug, plays a leading role in front-line chemotherapy for patients with advanced non-squamous non-small-cell lung cancer (NSCLC. Following its approval as second-line monotherapy for locally advanced or metastatic non-squamous NSCLC, pemetrexed has established itself as the first-line regimen in combination with cisplatin, and its powerful antitumor effects and less cumulative toxicities were then taken advantage of in the JMEN and PARAMOUNT trials, respectively, to pioneer a new treatment strategy of switch and continuation maintenance monotherapy. These developments have brought about a marked paradigm shift, and made pemetrexed indispensable in the treatment for non-squamous NSCLC. So far, only three drugs have been approved for maintenance therapy; pemetrexed both by switch and continuation maintenance, erlotinib by switch maintenance, and bevacizumab by continuation maintenance. Compared with observation alone after defined cycles of the first-line chemotherapy, subsequent pemetrexed maintenance therapy has provided significantly longer survival and infrequent severe adverse events. The cost-effectiveness of pemetrexed maintenance therapy is controversial, as well as the other two maintenance drugs, bevacizumab and erlotinib. The latest attractive attention is a combination maintenance therapy. We may have to consider epidermal growth factor receptor (EGFR mutation status for selection of a combination pattern. A combination maintenance therapy of pemetrexed plus bevacizumab is potential for patients with wild-type EGFR status, while a EGFR tyrosine kinase inhibitor-containing combination is promising for patients with active EGFR mutation status. Pemetrexed will be

  20. Development of liposomal pemetrexed for enhanced therapy against multidrug resistance mediated by ABCC5 in breast cancer

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    Bai F

    2018-03-01

    Full Text Available Fang Bai,1–3,* You Yin,4,* Ting Chen,1,* Jihui Chen,1 Meixin Ge,2 Yunshu Lu,2 Fangyuan Xie,5 Jian Zhang,1 Kejin Wu,3 Yan Liu1,6 1Department of Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 2Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 3Department of Breast Surgery, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, 4Department of Neurology, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, 5Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 6Department of Pharmacy, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, People’s Republic of China *These authors contributed equally to this work Purpose: Breast cancer is the most common cancer among women. Pemetrexed, a new generation antifolate drug, is one of the primary treatments for breast cancer. However, multidrug resistance (MDR in breast cancer greatly hampers the therapeutic efficacy of chemotherapies such as pemetrexed. Nanomedicine is emerging as a promising alternative technique to overcome cancer MDR. Thus, pemetrexed-loaded d-alpha tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS liposomes (liposomal pemetrexed were developed as a strategy to overcome MDR to pemetrexed in breast cancer. Materials and methods: Liposomal pemetrexed was developed using the calcium acetate gradient method. The cytotoxic effects, apoptosis-inducing activity, in vivo distribution, and antitumor activity of liposomal pemetrexed were investigated. Results: Liposomal pemetrexed was small in size (160.77 nm, with a small polydispersity of <0.1. The encapsulation efficacy of liposomal pemetrexed was 63.5%, which is rather high for water-soluble drugs in liposomes. The IC50 of liposomal pemetrexed following treatment with MDR breast cancer cells (MCF-7 cells overexpressing ABCC5

  1. Re-challenge with pemetrexed in advanced mesothelioma: a multi-institutional experience

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    Bearz Alessandra

    2012-09-01

    Full Text Available Abstract Background Although first-line therapy for patients affected by advanced mesothelioma is well established, there is a lack of data regarding the impact of second-line treatment. Methods We retrospectively collected data of patients affected by advanced mesothelioma, already treated with first-line therapy based on pemetrexed and platin, with a response (partial response or stable disease lasting at least 6 months, and re-treated with a pemetrexed-based therapy at progression. The primary objective was to describe time to progression and overall survival after re-treatment. Results Overall across several Italian oncological Institutions we found 30 patients affected by advanced mesothelioma, in progression after a 6-month lasting clinical benefit following a first-line treatment with cisplatin and pemetrexed, and re-challenged with a pemetrexed-based therapy. In these patients we found a disease control rate of 66%, with reduction of pain in 43% of patients. Overall time to progression and survival were promising for a second-line setting of patients with advanced mesothelioma, being 5.1 and 13.6 months, respectively. Conclusions In our opinion, when a patient has a long-lasting benefit from previous treatment with pemetrexed combined with a platin compound, the same treatment should be offered at progression.

  2. Pemetrexed in maintenance treatment of advanced non-squamous non-small-cell lung cancer.

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    Minami, Seigo; Kijima, Takashi

    2015-01-01

    Pemetrexed, a multitargeting antifolate cytotoxic drug, plays a leading role in front-line chemotherapy for patients with advanced non-squamous non-small-cell lung cancer (NSCLC). Following its approval as second-line monotherapy for locally advanced or metastatic non-squamous NSCLC, pemetrexed has established itself as the first-line regimen in combination with cisplatin, and its powerful antitumor effects and less cumulative toxicities were then taken advantage of in the JMEN and PARAMOUNT trials, respectively, to pioneer a new treatment strategy of switch and continuation maintenance monotherapy. These developments have brought about a marked paradigm shift, and made pemetrexed indispensable in the treatment for non-squamous NSCLC. So far, only three drugs have been approved for maintenance therapy; pemetrexed both by switch and continuation maintenance, erlotinib by switch maintenance, and bevacizumab by continuation maintenance. Compared with observation alone after defined cycles of the first-line chemotherapy, subsequent pemetrexed maintenance therapy has provided significantly longer survival and infrequent severe adverse events. The cost-effectiveness of pemetrexed maintenance therapy is controversial, as well as the other two maintenance drugs, bevacizumab and erlotinib. The latest attractive attention is a combination maintenance therapy. We may have to consider epidermal growth factor receptor (EGFR) mutation status for selection of a combination pattern. A combination maintenance therapy of pemetrexed plus bevacizumab is potential for patients with wild-type EGFR status, while a EGFR tyrosine kinase inhibitor-containing combination is promising for patients with active EGFR mutation status. Pemetrexed will be a pivotal drug when a combination maintenance therapy is used in practice. For future maintenance therapy, we need to explore reliable predictive selection or exclusion markers that can predict who will really benefit from maintenance therapy.

  3. Pemetrexed plus carboplatin versus pemetrexed in pretreated patients with advanced non-squamous non-small-cell lung cancer : treating the right patients based on individualized treatment effect prediction

    NARCIS (Netherlands)

    van Kruijsdijk, R. C. M.; Visseren, F. L. J.; Boni, L.; Groen, H. J. M.; Dingemans, A. M. C.; Aerts, J. G. J. V.; van der Graaf, Y.; Ardizzoni, A.; Smit, E. F.

    In this study, it is shown that there is important heterogeneity in the effects of pemetrexed-carboplatin versus pemetrexed on progression-free survival in pretreated patients with advanced non-squamous non-small-cell lung cancer. Treatment effect can be predicted for individual patients using a

  4. Schedule-dependent cytotoxic synergism of pemetrexed and erlotinib in BXPC-3 and PANC-1 human pancreatic cancer cells.

    Science.gov (United States)

    Wang, Lin; Zhu, Zhi-Xia; Zhang, Wen-Ying; Zhang, Wei-Min

    2011-09-01

    Previous studies have shown that both pemetrexed, a cytotoxic drug, and erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), inhibit the cell growth of pancreatic cancer cells. However, whether they exert a synergistic antitumor effect on pancreatic cancer cells remains unknown. The present study aimed to assess the synergistic effect of erlotinib in combination with pemetrexed using different sequential administration schedules on the proliferation of human pancreatic cancer BXPC-3 and PANC-1 cells and to probe its cellular mechanism. The EGFR and K-ras gene mutation status was examined by quantitative PCR high-resolution melting (qPCR-HRM) analysis. BXPC-3 and PANC-1 cells were incubated with pemetrexed and erlotinib using different administration schedules. MTT assay was used to determine cytotoxicity, and cell cycle distribution was determined by flow cytometry. The expression and phosphorylation of EGFR, HER3, AKT and MET were determined using Western blotting. Both pemetrexed and erlotinib inhibited the proliferation of BXPC-3 and PANC-1 cells in a dose- and time-dependent manner in vitro. Synergistic effects on cell proliferation were observed when pemetrexed was used in combination with erlotinib. The degree of the synergistic effects depended on the administration sequence, which was most obvious when erlotinib was sequentially administered at 24-h interval following pemetrexed. Cell cycle studies revealed that pemetrexed induced S arrest and erlotinib induced G(0)/G(1) arrest. The sequential administration of erlotinib following pemetrexed induced S arrest. Western blot analyses showed that pemetrexed increased and erlotinib decreased the phosphorylation of EGFR, HER3 and AKT, respectively. However, both pemetrexed and erlotinib exerted no significant effects on the phosphorylation of c-MET. The phosphorylation of EGFR, HER3 and AKT was significantly suppressed by scheduled incubation with pemetrexed followed by erlotinib

  5. Radiation recall dermatitis with soft tissue necrosis following pemetrexed therapy: a case report

    Directory of Open Access Journals (Sweden)

    Spirig Christian

    2009-11-01

    Full Text Available Abstract Introduction Radiation recall dermatitis is a well known but still poorly understood inflammatory reaction. It can develop in previously irradiated areas and has been shown to be triggered by a variety of different drugs, including cytostatic agents. Pemetrexed may cause radiation recall dermatitis in pre-irradiated patients. Case presentation We present the case of a 49-year-old Caucasian woman with non-small cell lung cancer who was initially treated with carboplatin and paclitaxel concomitant with radiotherapy after suffering a painful plexus brachialis infiltration. Due to disease progression, a second-line treatment with pemetrexed was started. A severe soft tissue necrosis developed despite steroid treatment and plastic surgery. Conclusion To the best of our knowledge, we present the first case of a patient with severe soft tissue necrosis in a pre-irradiated area after pemetrexed therapy. We believe that physicians treating patients with pemetrexed should be aware of the severe, possibly life-threatening effects that may be induced by pemetrexed after previous radiation therapy.

  6. Maximizing Benefits from Maintenance Pemetrexed with Stereotactic Ablative Radiotherapy in Oligoprogressive Non-Squamous Non-Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Shao-Lun Lu

    2016-08-01

    Full Text Available Maintenance pemetrexed offers survival benefit with well-tolerated toxicities for advanced non-squamous non-small cell lung cancer (NSCLC. We present 3 consecutively enrolled patients with advanced non-squamous NSCLC, receiving stereotactic ablative radiotherapy (SABR for oligoprogressive disease during maintenance pemetrexed. All of them had sustained local control of thoracic oligoprogression after the SABR, while maintenance pemetrexed were kept for additionally long progression-free interval. SABR targeting oligoprogression with continued pemetrexed is an effective and safe approach to extend exposure of maintenance pemetrexed, thus maximizing the benefit from it.

  7. Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3.

    Science.gov (United States)

    Ikemura, Kenji; Hamada, Yugo; Kaya, Chinatsu; Enokiya, Tomoyuki; Muraki, Yuichi; Nakahara, Hiroki; Fujimoto, Hajime; Kobayashi, Tetsu; Iwamoto, Takuya; Okuda, Masahiro

    2016-10-01

    Pemetrexed, a multitargeted antifolate, is eliminated by tubular secretion via human organic anion transporter 3 (hOAT3). Although proton pump inhibitors (PPIs) are frequently used in cancer patients, the drug interaction between PPIs and pemetrexed remains to be clarified. In this study, we examined the drug interaction between pemetrexed and PPIs in hOAT3-expressing cultured cells, and retrospectively analyzed the impact of PPIs on the development of hematologic toxicity in 108 patients who received pemetrexed and carboplatin treatment of nonsquamous non-small cell lung cancer for the first time between January 2011 and June 2015. We established that pemetrexed was transported via hOAT3 (Km = 68.3 ± 11.1 µM). Lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan inhibited hOAT3-mediated uptake of pemetrexed in a concentration-dependent manner. The inhibitory effect of lansoprazole was much greater than those of other PPIs and the apparent IC50 value of lansoprazole against pemetrexed transport via hOAT3 was 0.57 ± 0.17 µM. The inhibitory type of lansoprazole was competitive. In a retrospective study, multivariate analysis revealed that coadministration of lansoprazole, but not other PPIs, with pemetrexed and carboplatin was an independent risk factor significantly contributing to the development of hematologic toxicity (odds ratio: 10.004, P = 0.005). These findings demonstrated that coadministration of lansoprazole could exacerbate the hematologic toxicity associated with pemetrexed, at least in part, by competitive inhibition of hOAT3. Our results would aid clinicians to make decisions of coadministration drugs to avoid drug interaction-induced side effects for achievement of safe and appropriate chemotherapy with pemetrexed. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  8. Sequentially administrated of pemetrexed with icotinib/erlotinib in lung adenocarcinoma cell lines in vitro.

    Science.gov (United States)

    Feng, Xiuli; Zhang, Yan; Li, Tao; Li, Yu

    2017-12-26

    Combination of chemotherapy and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) had been proved to be a potent anti-drug for the treatment of tumors. However, survival time was not extended for the patients with lung adenocarcinoma (AdC) compared with first-line chemotherapy. In the present study, we attempt to assess the optimal schedule of the combined administration of pemetrexed and icotinib/erlotinib in AdC cell lines. Human lung AdC cell lines with wild-type (A549), EGFR T790M (H1975) and activating EGFR mutation (HCC827) were applied in vitro to assess the differential efficacy of various sequential regimens on cell viability, cell apoptosis and cell cycle distribution. The results suggested that the antiproliferative effect of the sequence of pemetrexed followed by icotinib/erlotinib was more effective than that of icotinib/erlotinib followed by pemetrexed. Additionally, a reduction of G1 phase and increased S phase in sequence of pemetrexed followed by icotinib/erlotinib was also observed, promoting cell apoptosis. Thus, the sequential administration of pemetrexed followed by icotinib/erlotinib exerted a synergistic effect on HCC827 and H1975 cell lines compared with the reverse sequence. The sequential treatment of pemetrexed followed by icotinib/erlotinib has been demonstrated promising results. This treatment strategy warrants further confirmation in patients with advanced lung AdC.

  9. Review of pemetrexed in combination with cisplatin for the treatment of malignant pleural mesothelioma

    Directory of Open Access Journals (Sweden)

    Ranjit K Goudar

    2008-03-01

    Full Text Available Ranjit K GoudarDepartment of Medicine, Division of Hematology, Medical Oncology and Cellular Therapy, Duke University Medical Center, Durham, NC, USAAbstract: Malignant pleural mesothelioma is a resistant form of lung cancer, and its incidence continues to rise in Europe and Australia. Until recently, chemotherapy had not been shown to be effective in the treatment of this slowly progressive disease. In 2004, the combination of pemetrexed and cisplatin was shown to induce high response rates in MPM. This article reviews the published literature describing the development and testing of this therapeutic combination in mesothelioma, and examines in detail the key phase III clinical trial that led to the approval of pemetrexed by the US FDA. Ongoing research will further define the role of pemetrexed plus cisplatin in the treatment of MPM.Keywords: malignant pleural mesothelioma, mesothelioma, pemetrexed, cisplatin

  10. Pemetrexed-carboplatin with intercalated icotinib in the treatment of patient with advanced EGFR wild-type lung adenocarcinoma

    Science.gov (United States)

    Xu, Tongpeng; Wu, Hao; Jin, Shidai; Min, Huang; Zhang, Zhihong; Shu, Yongqian; Wen, Wei; Guo, Renhua

    2017-01-01

    Abstract Rationale: Tyrosine kinase inhibitors (TKIs) are known to have greater efficacy in epidermal growth factor receptor (EGFR) mutation nonsmall cell lung cancer (NSCLC). However, about 10% of EGFR wild-type (wt) patients respond to TKIs. Patient concerns: Several strategies to increase the efficacy of TKIs in wt NSCLC are the subjects of ongoing investigations. One of them is combining EGFR TKI with intercalated chemotherapy. Diagnoses: We describe a patient with EGFR wt NSCLC, who was found with ovarian and lung metastasis, was treated with pemetrexed and intercalated icotinib. Interventions: In this case, we reported the successful long-term maintenance treatment of a patient with EGFR wt NSCLC with pemetrexed and Icotinib. The patient (40-year-old female) was found with ovarian masses and lung masses. Pathological, immunohistochemical, and amplification refractory mutation system (ARMS) assay examinations of ovarian specimen suggested the expression of metastatic lung adenocarcinoma with wt EGFR. After failure treatment with paclitaxel-carboplatin, the patient received 4 cycles of pemetrexed plus platinum with intercalated icotinib and then remained on pemetrexed and icotinib. Outcomes: A partial response was achieved after the treatment. The patient's condition had remained stable on pemetrexed and icotinib for more than 20 months, with no evidence of progression. Lessons: To our knowledge, this is the first report using the long-term maintenance treatment with pemetrexed and intercalated icotinib in EGFR wt patient. The therapeutic strategies warrant further exploration in selected populations of NSCLC. PMID:28816950

  11. Pemetrexed With Platinum Combination as a Backbone for Targeted Therapy in Non-Small-Cell Lung Cancer.

    Science.gov (United States)

    Stinchcombe, Thomas E; Borghaei, Hossein; Barker, Scott S; Treat, Joseph Anthony; Obasaju, Coleman

    2016-01-01

    Standard platinum-based chemotherapy combinations for advanced non-small-cell lung cancer (NSCLC) have reached a plateau in terms of the survival benefit they offer for patients. In addition, the emerging clinical trend of tailored treatment based on patient characteristics has led to the development of therapeutic strategies that target specific cancer-related molecular pathways, including epidermal growth factor receptor (EGFR), angiogenesis, and anaplastic lymphoma kinase inhibitors. Current research is focused on combining targeted therapy with platinum-based chemotherapy in an endeavor to achieve an additional benefit in specific patient populations. Currently, pemetrexed is indicated for use in the first-line, maintenance, and second-line settings for the treatment of nonsquamous NSCLC. The combination of pemetrexed and cisplatin is well tolerated and is the approved standard first-line therapy. Thus, the pemetrexed-platinum backbone provides an attractive option for combination with targeted therapies. This review aims to summarize the current knowledge and future prospects of the use of pemetrexed-platinum as a backbone for combination with targeted therapies for NSCLC. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Lyα Profile, Dust, and Prediction of Lyα Escape Fraction in Green Pea Galaxies

    Science.gov (United States)

    Yang, Huan; Malhotra, Sangeeta; Gronke, Max; Rhoads, James E.; Leitherer, Claus; Wofford, Aida; Jiang, Tianxing; Dijkstra, Mark; Tilvi, V.; Wang, Junxian

    2017-08-01

    We studied Lyman-α (Lyα) escape in a statistical sample of 43 Green Peas with HST/COS Lyα spectra. Green Peas are nearby star-forming galaxies with strong [O III]λ5007 emission lines. Our sample is four times larger than the previous sample and covers a much more complete range of Green Pea properties. We found that about two-thirds of Green Peas are strong Lyα line emitters with rest-frame Lyα equivalent width > 20 \\mathringA . The Lyα profiles of Green Peas are diverse. The Lyα escape fraction, defined as the ratio of observed Lyα flux to intrinsic Lyα flux, shows anti-correlations with a few Lyα kinematic features—both the blue peak and red peak velocities, the peak separations, and the FWHM of the red portion of the Lyα profile. Using properties measured from Sloan Digital Sky Survey optical spectra, we found many correlations—the Lyα escape fraction generally increases at lower dust reddening, lower metallicity, lower stellar mass, and higher [O III]/[O II] ratio. We fit their Lyα profiles with the H I shell radiative transfer model and found that the Lyα escape fraction is anti-correlated with the best-fit N H I . Finally, we fit an empirical linear relation to predict {f}{esc}{Lyα } from the dust extinction and Lyα red peak velocity. The standard deviation of this relation is about 0.3 dex. This relation can be used to isolate the effect of intergalactic medium (IGM) scatterings from Lyα escape and to probe the IGM optical depth along the line of sight of each z> 7 Lyα emission-line galaxy in the James Webb Space Telescope era.

  13. c-FLIP and the NOXA/Mcl-1 axis participate in the synergistic effect of pemetrexed plus cisplatin in human choroidal melanoma cells.

    Science.gov (United States)

    Zhao, Xiaofei; Kong, Feng; Wang, Lei; Zhang, Han

    2017-01-01

    Choroidal melanoma is the most common primary malignant intraocular tumor, and very few effective therapies are available to treat it. Our study aimed to understand whether pemetrexed plus cisplatin exerts a beneficial synergistic effect in human choroidal melanoma cells and to delineate the underlying molecular mechanism. To accomplish these aims, we treated choroidal melanoma cells with pemetrexed and cisplatin and assessed cell survival with SRB and MTT assays. Proteins were detected using western blotting analysis. NOXA and CHOP were knocked down with siRNA. We found that pemetrexed or cisplatin alone inhibited survival and induced apoptosis in human choroidal melanoma cells. Furthermore, the expression levels of c-FLIP, an anti-apoptotic protein in the extrinsic apoptosis pathway, and Mcl-1, an anti-apoptotic protein in the intrinsic apoptosis pathway, were decreased by pemetrexed or cisplatin respectively, while the expression of a pro-apoptotic protein in the intrinsic apoptosis pathway, NOXA, was up-regulated. Moreover, pemetrexed or cisplatin alone increased the protein expression of the endoplasmic reticulum stress markers IRE1α, Bip and CHOP. Silencing CHOP expression reduced NOXA expression. These findings suggest that the pemetrexed or cisplatin induced intrinsic apoptosis via activation of the ER stress response. Importantly, combining the two compounds more strongly induced apoptosis. Following the cotreatment, CHOP and NOXA expression increased, while c-FLIP and Mcl-1 expression decreased, and these effects were more pronounced than when using either compound alone. This result suggests that pemetrexed and cisplatin synergistically activate ER stress response-induced apoptosis in choroidal melanoma cells. To summarize, the c-FLIP and NOXA/Mcl-1 axis participated in the synergistic effect of pemetrexed plus cisplatin in human choroidal melanoma cells. Intrinsic apoptosis was induced via activation of the ER stress response. Our study provides

  14. Adjuvant Bidirectional Chemotherapy with Intraperitoneal Pemetrexed Combined with Intravenous Cisplatin for Diffuse Malignant Peritoneal Mesothelioma

    Directory of Open Access Journals (Sweden)

    Lana Bijelic

    2012-01-01

    Full Text Available Cytoreductive surgery (CRS with heated intraoperative intraperitoneal chemotherapy (HIPEC has emerged as optimal treatment for diffuse malignant peritoneal mesothelioma (DMPM showing median survivals of 36–92 months. However, recurrences occur frequently even in patients undergoing optimal cytreduction and are often confined to the abdomen. We initiated a Phase II study of adjuvant intraperitoneal pemetrexed combined with intravenous cisplatin for patients undergoing CRS and HIPEC for DMPM. The treatment consisted of pemetrexed 500 mg/m2 intraperitoneally and cisplatin 50 mg/m2 intravenously given simultaneously on day 1 of every 21 day cycle for 6 cycles. The primary endpoint of the study was treatment related toxicity. From July 2007 until July 2009 ten patients were enrolled. Nine of 10 completed all 6 cycles of adjuvant treatment per protocol. The most common toxicities were fatigue, nausea and abdominal pain grade 1 or 2. There was one grade 3 toxicity consisting of a catheter infection. The median survival for all 10 patients was 33.5 months. Pharmacokinetic analysis of intraperitoneal pemetrexed showed a peritoneal to plasma area under the curve ratio of 70. Our study shows that adjuvant intravenous cisplatin and intraperitoneal pemetrexed can be used following CRS and HIPEC for DMPM with low morbidity.

  15. Pemetrexed-carboplatin with intercalated icotinib in the treatment of patient with advanced EGFR wild-type lung adenocarcinoma: A case report.

    Science.gov (United States)

    Xu, Tongpeng; Wu, Hao; Jin, Shidai; Min, Huang; Zhang, Zhihong; Shu, Yongqian; Wen, Wei; Guo, Renhua

    2017-08-01

    Tyrosine kinase inhibitors (TKIs) are known to have greater efficacy in epidermal growth factor receptor (EGFR) mutation nonsmall cell lung cancer (NSCLC). However, about 10% of EGFR wild-type (wt) patients respond to TKIs. Several strategies to increase the efficacy of TKIs in wt NSCLC are the subjects of ongoing investigations. One of them is combining EGFR TKI with intercalated chemotherapy. We describe a patient with EGFR wt NSCLC, who was found with ovarian and lung metastasis, was treated with pemetrexed and intercalated icotinib. In this case, we reported the successful long-term maintenance treatment of a patient with EGFR wt NSCLC with pemetrexed and Icotinib. The patient (40-year-old female) was found with ovarian masses and lung masses. Pathological, immunohistochemical, and amplification refractory mutation system (ARMS) assay examinations of ovarian specimen suggested the expression of metastatic lung adenocarcinoma with wt EGFR. After failure treatment with paclitaxel-carboplatin, the patient received 4 cycles of pemetrexed plus platinum with intercalated icotinib and then remained on pemetrexed and icotinib. A partial response was achieved after the treatment. The patient's condition had remained stable on pemetrexed and icotinib for more than 20 months, with no evidence of progression. To our knowledge, this is the first report using the long-term maintenance treatment with pemetrexed and intercalated icotinib in EGFR wt patient. The therapeutic strategies warrant further exploration in selected populations of NSCLC.

  16. Treatment rationale and study design for a phase III, double-blind, placebo-controlled study of maintenance pemetrexed plus best supportive care versus best supportive care immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Jaime Jesús

    2010-03-01

    Full Text Available Abstract Background To improve the efficacy of first-line therapy for advanced non-small cell lung cancer (NSCLC, additional maintenance chemotherapy may be given after initial induction chemotherapy in patients who did not progress during the initial treatment, rather than waiting for disease progression to administer second-line treatment. Maintenance therapy may consist of an agent that either was or was not present in the induction regimen. The antifolate pemetrexed is efficacious in combination with cisplatin for first-line treatment of advanced NSCLC and has shown efficacy as a maintenance agent in studies in which it was not included in the induction regimen. We designed a phase III study to determine if pemetrexed maintenance therapy improves progression-free survival (PFS and overall survival (OS after cisplatin/pemetrexed induction therapy in patients with advanced nonsquamous NSCLC. Furthermore, since evidence suggests expression levels of thymidylate synthase, the primary target of pemetrexed, may be associated with responsiveness to pemetrexed, translational research will address whether thymidylate synthase expression correlates with efficacy outcomes of pemetrexed. Methods/Design Approximately 900 patients will receive four cycles of induction chemotherapy consisting of pemetrexed (500 mg/m2 and cisplatin (75 mg/m2 on day 1 of a 21-day cycle. Patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 who have not progressed during induction therapy will randomly receive (in a 2:1 ratio one of two double-blind maintenance regimens: pemetrexed (500 mg/m2 on day 1 of a 21-day cycle plus best supportive care (BSC or placebo plus BSC. The primary objective is to compare PFS between treatment arms. Secondary objectives include a fully powered analysis of OS, objective tumor response rate, patient-reported outcomes, resource utilization, and toxicity. Tumor specimens for translational research will be obtained from

  17. Treatment rationale and study design for a phase III, double-blind, placebo-controlled study of maintenance pemetrexed plus best supportive care versus best supportive care immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer

    International Nuclear Information System (INIS)

    Paz-Ares, Luis G; Altug, Sedat; Vaury, Alexandra Thareau; Jaime, Jesús Corral; Russo, Francesca; Visseren-Grul, Carla

    2010-01-01

    To improve the efficacy of first-line therapy for advanced non-small cell lung cancer (NSCLC), additional maintenance chemotherapy may be given after initial induction chemotherapy in patients who did not progress during the initial treatment, rather than waiting for disease progression to administer second-line treatment. Maintenance therapy may consist of an agent that either was or was not present in the induction regimen. The antifolate pemetrexed is efficacious in combination with cisplatin for first-line treatment of advanced NSCLC and has shown efficacy as a maintenance agent in studies in which it was not included in the induction regimen. We designed a phase III study to determine if pemetrexed maintenance therapy improves progression-free survival (PFS) and overall survival (OS) after cisplatin/pemetrexed induction therapy in patients with advanced nonsquamous NSCLC. Furthermore, since evidence suggests expression levels of thymidylate synthase, the primary target of pemetrexed, may be associated with responsiveness to pemetrexed, translational research will address whether thymidylate synthase expression correlates with efficacy outcomes of pemetrexed. Approximately 900 patients will receive four cycles of induction chemotherapy consisting of pemetrexed (500 mg/m 2 ) and cisplatin (75 mg/m 2 ) on day 1 of a 21-day cycle. Patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 who have not progressed during induction therapy will randomly receive (in a 2:1 ratio) one of two double-blind maintenance regimens: pemetrexed (500 mg/m 2 on day 1 of a 21-day cycle) plus best supportive care (BSC) or placebo plus BSC. The primary objective is to compare PFS between treatment arms. Secondary objectives include a fully powered analysis of OS, objective tumor response rate, patient-reported outcomes, resource utilization, and toxicity. Tumor specimens for translational research will be obtained from consenting patients before induction

  18. Comparison of erlotinib and pemetrexed as second-/third-line treatment for lung adenocarcinoma patients with asymptomatic brain metastases

    Directory of Open Access Journals (Sweden)

    He YY

    2016-04-01

    Full Text Available Yayi He,1,* Wenwen Sun,2,* Yan Wang,3,* Shengxiang Ren,1 Xuefei Li,3 Jiayu Li,3 Christopher J Rivard,4 Caicun Zhou,1 Fred R Hirsch4 1Department of Oncology, Shanghai Pulmonary Hospital, 2Clinic and Research Center of Tuberculosis, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, 3Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, People’s Republic of China; 4Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO, USA *These authors contributed equally to this work Objective: Brain metastases occur in one-third of all non-small-cell lung cancer patients. Due to restrictive transport at the blood–brain barrier, many drugs provide poor control of metastases in the brain. The aim of this study was to compare erlotinib with pemetrexed as second-/third-line treatment in patients with lung adenocarcinoma with asymptomatic brain metastases.Methods: From January 2012 to June 2014, all lung adenocarcinoma patients with asymptomatic brain metastases who received treatment with erlotinib or pemetrexed as second-/third-line treatment were retrospectively reviewed. Chi-square and log-rank tests were used to perform statistical analysis.Results: The study enrolled 99 patients, of which 44 were positive for EGFR mutation. Median progression-free survival (PFS in months was not significantly different between the erlotinib- and pemetrexed-treated groups (4.2 vs 3.4 months; 95% confidence interval [CI]: 2.01–6.40 vs 2.80–5.00, respectively; P=0.635. Median PFS was found to be significantly longer in EGFR mutation–positive patients in the erlotinib-treated group (8.0 months; 95% CI 5.85–10.15 compared to the pemetrexed group (3.9 months; 95% CI: 1.25–6.55; P=0.032. The most common treatment-related side effect was mild-to-moderate rash and the most common drug-related side

  19. Phase i study of 'dose-dense' pemetrexed plus carboplatin/radiotherapy for locally advanced non-small cell lung carcinoma

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    Treat Joseph

    2011-02-01

    Full Text Available Abstract Background This phase I study investigates the feasibility of carboplatin plus dose-dense (q2-week pemetrexed given concurrently with radiotherapy (XRT for locally advanced and oligometastatic non-small cell lung cancer (NSCLC. Methods Eligible patients had Stage III or IV (oligometastatic NSCLC. Patients received XRT to 63 Gy in standard fractionation. Patients received concurrent carboplatin (AUC = 6 during weeks 1 and 5 of XRT, and pemetrexed during weeks 1, 3, 5, and 7 of XRT. The starting dose level (level 1 of pemetrexed was 300 mg/m2. Following the finding of dose limiting toxicity (DLT in dose level 1, an amended dose level (level 1A continued pemetrexed at 300 mg/m2, but with involved field radiation instead of extended nodal irradiation. Consolidation consisted of carboplatin (AUC = 6 and pemetrexed (500 mg/m2 q3 weeks × 2 -3 cycles. Results Eighteen patients were enrolled. Fourteen patients are evaluable for toxicity analysis. Of the initial 6 patients treated on dose level 1, two experienced DLTs (one grade 4 sepsis, one prolonged grade 3 esophagitis. There was one DLT (grade 5 pneumonitis in the 8 patients treated on dose level 1A. In 16 patients evaluable for response (4 with oligometastatic stage IV disease and 12 with stage III disease, the median follow-up time is 17.8 months. Thirteen of 16 patients had in field local regional response. The actuarial median survival time was 28.6 months in all patients and 34.7 months (estimated in stage III patients. Conclusions Concurrent carboplatin with dose-dense (q2week pemetrexed at 300 mg/m2 with involved field XRT is feasible and encouraging in patients with locally advanced and oligometastatic NSCLC. Trial Registration ClinicalTrials.gov NCT00330044

  20. Pretreatment Red Blood Cell Total Folate Concentration Is Associated With Response to Pemetrexed in Stage IV Nonsquamous Non-Small-cell Lung Cancer.

    Science.gov (United States)

    Bagley, Stephen J; Vitale, Steven; Zhang, Suhong; Aggarwal, Charu; Evans, Tracey L; Alley, Evan W; Cohen, Roger B; Langer, Corey J; Blair, Ian A; Vachani, Anil; Whitehead, Alexander S

    2017-03-01

    Pemetrexed inhibits folate-dependent enzymes involved in pyrimidine and purine synthesis. Previous studies of genetic variation in these enzymes as predictors of pemetrexed efficacy have yielded inconsistent results. We investigated whether red blood cell (RBC) total folate, a phenotypic rather than genotypic, marker of cellular folate status was associated with the response to pemetrexed-based chemotherapy in advanced nonsquamous non-small-cell lung cancer (NSCLC). We conducted a prospective cohort study of patients with stage IV nonsquamous NSCLC receiving first-line chemotherapy containing pemetrexed. The pretreatment RBC total folate level was quantified using liquid chromatography mass spectrometry. We then compared the objective response rate (ORR) between patients with RBC total folate concentrations greater than and less than an optimal cutoff value determined from the receiver operating characteristic curve. A logistic regression model was used to adjust for age, sex, and the use of bevacizumab. The ORR was 62% (32 of 52 patients). Receiver operating characteristic analysis was used to establish that a RBC total folate cutoff value of 364.6 nM optimally discriminated between pemetrexed responders and nonresponders. Patients with RBC total folate  364.5 nM (P = .01). This difference persisted after adjusting for age, sex, and the use of bevacizumab (odds ratio, 0.07; 95% confidence interval, 0.01-0.57; P = .01). A low pretreatment RBC total folate was associated with an inferior response to pemetrexed-based chemotherapy in stage IV nonsquamous NSCLC. Larger, multicenter studies are needed to validate RBC total folate as a predictive marker of pemetrexed response. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study.

    Science.gov (United States)

    Shi, Y K; Wang, L; Han, B H; Li, W; Yu, P; Liu, Y P; Ding, C M; Song, X; Ma, Z Y; Ren, X L; Feng, J F; Zhang, H L; Chen, G Y; Han, X H; Wu, N; Yao, C; Song, Y; Zhang, S C; Song, W; Liu, X Q; Zhao, S J; Lin, Y C; Ye, X Q; Li, K; Shu, Y Q; Ding, L M; Tan, F L; Sun, Y

    2017-10-01

    Icotinib has been previously shown to be non-inferior to gefitinib in non-selected advanced non-small-cell lung cancer patients when given as second- or further-line treatment. In this open-label, randomized, phase 3 CONVINCE trial, we assessed the efficacy and safety of first-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance in lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation. Eligible participants were adults with stage IIIB/IV lung adenocarcinoma and exon 19/21 EGFR mutations. Participants were randomly allocated (1 : 1) to receive oral icotinib or 3-week cycle of cisplatin plus pemetrexed for up to four cycles; non-progressive patients after four cycles were maintained with pemetrexed until disease progression or intolerable toxicity. The primary end point was progression-free survival (PFS) assessed by independent response evaluation committee. Other end points included overall survival (OS) and safety. Between January 2013 and August 2014, 296 patients were randomized, and 285 patients were treated (148 to icotinib, 137 to chemotherapy). Independent response evaluation committee-assessed PFS was significantly longer in the icotinib group (11.2 versus 7.9 months; hazard ratio, 0.61, 95% confidence interval 0.43-0.87; P = 0.006). No significant difference for OS was observed between treatments in the overall population or in EGFR-mutated subgroups (exon 19 Del/21 L858R). The most common grade 3 or 4 adverse events (AEs) in the icotinib group were rash (14.8%) and diarrhea (7.4%), compared with nausea (45.9%), vomiting (29.2%), and neutropenia (10.9%) in the chemotherapy group. AEs (79.1% versus 94.2%; P icotinib group than in the chemotherapy group. First-line icotinib significantly improves PFS of advanced lung adenocarcinoma patients with EGFR mutation with a tolerable and manageable safety profile. Icotinib should be considered as a first-line treatment for this patient population. © The Author

  2. Budget impact analysis of pemetrexed introduction: case study from a teaching hospital perspective, Thailand.

    Science.gov (United States)

    Chanjaruporn, Farsai; Roughead, Elizabeth E; Sooksriwong, Cha-oncin; Kaojarern, Sming

    2011-09-01

    Thailand does not currently require Budget Impact Analysis (BIA) assessment. The present study aimed to estimate the annual drug cost and the incremental impact on the hospital pharmaceutical budget of the introduction of pemetrexed to a Thai teaching hospital. The budget impact model was conducted in accordance with the Guidelines for preparing submissions to the Pharmaceutical Benefits Advisory Committee (PBAC). The model variables consisted of number of patients, growth rate of lung cancer, uptake rate of pemetrexed over time, unit prices of drugs, and the length and cost of treatment. Sensitivity analysis was performed to determine changes in budgetary impact due to variation of parameters or assumptions in the model. The introduction of pemetrexed was estimated to cause considerable costs for the teaching hospital. In the base-case analysis, the incremental costs were estimated at 8,553,984 Baht in the first year increasing to 12, 118, 144 Baht, 17,820,800 Baht and 17,820,800 Baht in the following years. The 4-year net budgetary impact was 20,154,480 Baht or approximately 127,560 Baht per patient. Sensitivity analyses found that number of treatment cycles andproportion of patients assumed to be treated with pemetrexed were the two most important influencing factors in the model. New costly innovative interventions should be evaluated using the BIA model to determine whether they are affordable. The Thai government should consider requiring the BIA study as one of the requirements for drug submission to assist in the determination of listing and subsidizing decision for medicines.

  3. Analisi di costo di pemetrexed vs docetaxel nel trattamento di seconda linea del carcinoma polmonare non a piccole cellule

    Directory of Open Access Journals (Sweden)

    Roberto Ravasio

    2005-06-01

    Full Text Available OBJECTIVES: to compare costs of pemetrexed versus docetaxel in patients with non-small cell lung cancer previously treated with chemotherapy paying special attention to the adverse events. MATERIALS AND METHODS: a cost analysis was carried out performing comparison between pemetrexed and docetaxel. Clinical data (overall survival and resource consumption (chemotherapy drugs, G-CSF, and hospitalizations due to adverse events were obtained from a randomized phase III trial. The economic evaluation was based on direct costs using local Italian unit costs (euro 2005. The perspective was the National Health Service’s. RESULTS: the study results showed that mean survival of pemetrexed (8,3 months; 0,69 years was higher than mean survival of docetaxel (7,9 months; 0,66 years. The mean cost of treatment with pemetrexed was 8.684,26 euros and with docetaxel was 6.182,87 euros. This difference was nearly offset by the difference in the costs of adverse events: the mean cost of adverse events due to chemotherapy treatment with pemetrexed (493,93 euros turned out to be lower than with docetaxel (2.394,34 euros. CONCLUSION: the present cost-analysis could be a stable ground for a further cost-utility analysis, aimed at reaching a more cost-effectiveness management of the chemotherapy-related adverse effects in patients with NSCLC.

  4. Pretreatment red blood cell total folate is associated with response to pemetrexed in stage IV non-squamous non-small-cell lung cancer

    Science.gov (United States)

    Bagley, Stephen J.; Vitale, Steven; Zhang, Suhong; Aggarwal, Charu; Evans, Tracey L.; Alley, Evan W.; Cohen, Roger B.; Langer, Corey J.; Blair, Ian A.; Vachani, Anil; Whitehead, Alexander S.

    2016-01-01

    Objectives Pemetrexed inhibits folate-dependent enzymes involved in pyrimidine and purine synthesis. Prior studies of genetic variation in these enzymes as predictors of pemetrexed efficacy have yielded inconsistent results. We investigated whether red blood cell (RBC) total folate, a phenotypic rather than genotypic marker of cellular folate status, was associated with response to pemetrexed-based chemotherapy in advanced non-squamous non-small-cell lung cancer (NSCLC). Materials and methods We conducted a prospective cohort study of patients with stage IV non-squamous NSCLC receiving first-line chemotherapy containing pemetrexed. Pretreatment RBC total folate was quantified using liquid chromatography/mass spectrometry. We then compared objective response rate (ORR) between patients with RBC total folate concentrations above and below an optimal cut-off value determined from the receiver operating characteristic (ROC) curve. A logistic regression model was used to adjust for age, sex, and use of bevacizumab. Results The ORR was 62% (32 of 52 patients). ROC analysis was used to establish that a RBC total folate cutoff value of 364.6 nM optimally discriminated between pemetrexed responders and non-responders. Patients with RBC total folate below 364.5 nM had an ORR of 27%, compared to 71% in patients with RBC total folate above this value (p=0.01). This difference persisted after adjusting for age, sex, and use of bevacizumab (OR 0.07, 95% CI 0.01 - 0.57, p=0.01). Conclusions Low pretreatment RBC total folate is associated with inferior response to pemetrexed-based chemotherapy in stage IV non-squamous NSCLC. Larger, multicenter studies are needed to validate RBC total folate as a predictive marker of pemetrexed response. PMID:27863923

  5. Pemetrexed induced thymidylate synthase inhibition in non-small cell lung cancer patients: a pilot study with 3'-deoxy-3'-[¹⁸F]fluorothymidine positron emission tomography.

    Directory of Open Access Journals (Sweden)

    Virginie Frings

    Full Text Available OBJECTIVES: Pemetrexed is a thymidylate synthase (TS inhibitor and is effective in non-small cell lung cancer (NSCLC. 3'-deoxy-3'-[¹⁸F]fluorothymidine (¹⁸F-FLT, a proliferation marker, could potentially identify tumor specific TS-inhibition. The aim of this study was to investigate the effect of pemetrexed-induced TS-inhibition on ¹⁸F-FLT uptake 4 hours after pemetrexed administration in metastatic NSCLC patients. METHODS: Fourteen NSCLC patients underwent dynamic ¹⁸F-FLT positron emission tomography (PET scans at baseline and 4 hours after the first dose of pemetrexed. Volumes of interest were defined with a 41%, 50% and 70% threshold of the maximum pixel. Kinetic analysis and simplified measures were performed. At one, two, four and six hours after pemetrexed, plasma deoxyuridine was measured as systemic indicator of TS-inhibition. Tumor response measured with response evaluation criteria in solid tumors (RECIST, time to progression (TTP and overall survival (OS were determined. RESULTS: Eleven patients had evaluable ¹⁸F-FLT PET scans at baseline and 4 hours after pemetrexed. Two patients had increased ¹⁸F-FLT uptake of 35% and 31% after pemetrexed, whereas two other patients had decreased uptake of 31%. In the remaining seven patients ¹⁸F-FLT uptake did not change beyond test-retest borders. In all patients deoxyuridine levels raised after administration of pemetrexed, implicating pemetrexed-induced TS-inhibition. ¹⁸F-FLT uptake in bone marrow was significantly increased 4 hours after pemetrexed administration. Six weeks after the start of treatment 5 patients had partial response, 4 stable disease and 2 progressive disease. Median TTP was 4.2 months (range 3.0-7.4 months; median OS was 13.0 months (range 5.1-30.8 months. Changes in ¹⁸F-FLT uptake were not predictive for tumor response, TTP or OS. CONCLUSIONS: Measuring TS-inhibition in a clinical setting 4 hours after pemetrexed revealed a non-systematic change in

  6. Sequential treatment of icotinib after first-line pemetrexed in advanced lung adenocarcinoma with unknown EGFR gene status.

    Science.gov (United States)

    Zheng, Yulong; Fang, Weijia; Deng, Jing; Zhao, Peng; Xu, Nong; Zhou, Jianying

    2014-07-01

    In non-small cell lung cancer (NSCLC), the well-developed epidermal growth factor receptor (EGFR) is an important therapeutic target. EGFR activating gene mutations have been proved strongly predictive of response to EGFR-tyrosine kinase inhibitors (TKI) in NSCLC. However, both in daily clinical practice and clinical trials, patients with unknown EGFR gene status (UN-EGFR-GS) are very common. In this study, we assessed efficacy and tolerability of sequential treatment of first-line pemetrexed followed by icotinib in Chinese advanced lung adenocarcinoma with UN-EGFR-GS. We analyzed 38 patients with advanced lung adenocarcinoma with UN-EGFR-GS treated with first-line pemetrexed-based chemotherapy followed by icotinib as maintenance or second-line therapy. The response rates to pemetrexed and icotinib were 21.1% and 42.1%, respectively. The median overall survival was 27.0 months (95% CI, 19.7-34.2 months). The 12-month overall survival probability was 68.4%. The most common toxicities observed in icotinib phase were rashes, diarrheas, and elevated aminotransferase. Subgroup analysis indicated that the overall survival is correlated with response to icotinib. The sequence of first-line pemetrexed-based chemotherapy followed by icotinib treatment is a promising option for advanced lung adenocarcinoma with UN-EGFR-GS in China.

  7. What is the physical origin of strong Lyα emission? I. Demographics of Lyα emitter structures

    International Nuclear Information System (INIS)

    Shibuya, Takatoshi; Ouchi, Masami; Yuma, Suraphong; Nakajima, Kimihiko; Hashimoto, Takuya; Shimasaku, Kazuhiro; Mori, Masao; Umemura, Masayuki

    2014-01-01

    We present the results of structure analyses for a large sample of 426 Lyα emitters (LAEs) at z ∼ 2.2 that are observed with the Hubble Space Telescope/Advanced Camera for Surveys and WFC3-IR during deep extra-galactic legacy surveys. We confirm that the merger fraction and the average ellipticity of LAE's stellar component are 10%-30% and 0.4-0.6, respectively, that are comparable with previous study results. We successfully identify that some LAEs have a spatial offset between Lyα and stellar-continuum emission peaks, δ Lyα , by ∼2.5-4 kpc beyond our statistical errors. To uncover the physical origin of strong Lyα emission found in LAEs, we investigate the Lyα equivalent width (EW) dependences of three structural parameters: merger fraction, δ Lyα , and ellipticity of stellar distribution in the range of EW(Lyα) = 20-250 Å. Contrary to expectations, we find that the merger fraction does not significantly increase with Lyα EW. We reveal an anti-correlation between δ Lyα and EW(Lyα) using a Kolmogorov-Smirnov (K-S) test. There is a trend that the LAEs with a large Lyα EW have a small ellipticity. This is consistent with the recent theoretical claims that Lyα photons can more easily escape from face-on disks having a small ellipticity, due to less inter-stellar gas along the line of sight, although our K-S test indicates that this trend is not statistically significant. Our results of Lyα-EW dependence generally support the idea that an H I column density is a key quantity determining Lyα emissivity.

  8. The Lyα Reference Sample

    DEFF Research Database (Denmark)

    Ostlin, Goran; Hayes, Matthew; Duval, Florent

    2014-01-01

    The Lyα Reference Sample (LARS) is a substantial program with the Hubble Space Telescope (HST) that provides a sample of local universe laboratory galaxies in which to study the detailed astrophysics of the visibility and strength of the Lyαline of neutral hydrogen. Lyα is the dominant spectral...... are produced (whether or not they escape), we demanded an Hα equivalent width W(Hα) ≥100 Å. The final sample of 14 galaxies covers far-UV (FUV, λ ~ 1500 Å) luminosities that overlap with those of high-z Lyα emitters (LAEs) and Lyman break galaxies (LBGs), making LARS a valid comparison sample. We present......) but strongly asymmetric Lyα emission. Spectroscopy from the Cosmic Origins Spectrograph on board HST centered on the brightest UV knot shows a moderate outflow in the neutral interstellar medium (probed by low ionization stage absorption features) and Lyα emission with an asymmetric profile. Radiative transfer...

  9. Phase i study of 'dose-dense' pemetrexed plus carboplatin/radiotherapy for locally advanced non-small cell lung carcinoma

    International Nuclear Information System (INIS)

    Shen, Xinglei; DeNittis, Albert; Werner-Wasik, Maria; Axelrod, Rita; Gilman, Paul; Meyer, Thomas; Treat, Joseph; Curran, Walter J; Machtay, Mitchell

    2011-01-01

    This phase I study investigates the feasibility of carboplatin plus dose-dense (q2-week) pemetrexed given concurrently with radiotherapy (XRT) for locally advanced and oligometastatic non-small cell lung cancer (NSCLC). Eligible patients had Stage III or IV (oligometastatic) NSCLC. Patients received XRT to 63 Gy in standard fractionation. Patients received concurrent carboplatin (AUC = 6) during weeks 1 and 5 of XRT, and pemetrexed during weeks 1, 3, 5, and 7 of XRT. The starting dose level (level 1) of pemetrexed was 300 mg/m 2 . Following the finding of dose limiting toxicity (DLT) in dose level 1, an amended dose level (level 1A) continued pemetrexed at 300 mg/m 2 , but with involved field radiation instead of extended nodal irradiation. Consolidation consisted of carboplatin (AUC = 6) and pemetrexed (500 mg/m 2 ) q3 weeks × 2 -3 cycles. Eighteen patients were enrolled. Fourteen patients are evaluable for toxicity analysis. Of the initial 6 patients treated on dose level 1, two experienced DLTs (one grade 4 sepsis, one prolonged grade 3 esophagitis). There was one DLT (grade 5 pneumonitis) in the 8 patients treated on dose level 1A. In 16 patients evaluable for response (4 with oligometastatic stage IV disease and 12 with stage III disease), the median follow-up time is 17.8 months. Thirteen of 16 patients had in field local regional response. The actuarial median survival time was 28.6 months in all patients and 34.7 months (estimated) in stage III patients. Concurrent carboplatin with dose-dense (q2week) pemetrexed at 300 mg/m 2 with involved field XRT is feasible and encouraging in patients with locally advanced and oligometastatic NSCLC.

  10. A z = 3 Lyα BLOB ASSOCIATED WITH A DAMPED Lyα SYSTEM PROXIMATE TO ITS BACKGROUND QUASAR

    International Nuclear Information System (INIS)

    Hennawi, Joseph F.; Prochaska, J. Xavier; Kollmeier, Juna; Zheng Zheng

    2009-01-01

    We report on the discovery of a bright Lyα blob associated with the z = 3 quasar SDSS J124020.91+145535.6 which is also coincident with strong damped Lyα absorption from a foreground galaxy (a so-called proximate damped Lyα (PDLA) system). The one-dimensional spectrum acquired by the Sloan Digital Sky Survey (SDSS) shows a broad Lyα emission line with a FWHM ≅500 km s -1 and a luminosity of L Lyα = 3.9 x 10 43 erg s -1 superposed on the trough of the PDLA. Follow-up observations using the Keck/LRIS spectrometer confirm that this source has a Lyα nebula with spatial extent exceeding 5'', corresponding to a proper size >39 kpc. Mechanisms for powering the large Lyα luminosity in this nebula are discussed. We use a Monte Carlo radiative transfer simulation to investigate the possibility that the line emission is fluorescent recombination radiation from a kpc-scale PDLA galaxy powered by the ionizing flux of the quasar, but find that the predicted Lyα flux is several orders of magnitude lower than observed. We conclude that the Lyα emission is not associated with the PDLA galaxy at all, but instead is intrinsic to the quasar's host and similar to the extended Lyα f uzzwhich is detected around many active galactic nuclei. PDLAs are natural coronagraphs that block their background quasar at Lyα and we discuss how systems similar to SDSS J124020.91+145535.6 might be used to image the neutral hydrogen in the PDLA galaxy in silhouette against the screen of extended Lyα emission from the background quasar.

  11. Pemetrexed plus dendritic cells as third-line therapy for metastatic esophageal squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Zhang B

    2016-06-01

    Full Text Available Bin Zhang,1,* Rui Li,2,3,* Chun-Xiao Chang,2,3 Yong Han,2,3 Sheng-Bin Shi,2,3 Jing Tian2,3 1Department of Medical Oncology, Shandong Ji Ning First People’s Hospital, 2Department of Medical Oncology, Shandong Cancer Hospital, Shandong University, Shandong 3Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, People’s Republic of China*These authors contributed equally to this workAbstract: This study was conducted to evaluate the toxicity and efficacy of pemetrexed plus dendritic cells (DCs when administered as third-line treatment for metastatic esophageal squamous cell carcinoma (ESCC. All patients in the study group had previously failed first-line treatment with 5-fluorouracil and cisplatin-based regimens, as well as second-line treatment with taxane-based regimens. A total of 31 patients were treated with pemetrexed (500 mg/m2 plus DCs on day 1, every 3 weeks. DCs were given for one cycle of 21 days. Thirty patients were evaluated for their response. No patient had a complete response, three patients (10.0% had a partial response, ten patients (33.3% had stable disease, and 17 patients (56.7% had progressive disease. The overall response rate was 10.0%. The median progression-free survival (PFS time was 2.9 months (95% CI, 2.7–3.2, and the median overall survival (OS time was 7.1 months (95% CI, 6.4–7.9. The median PFS and OS times among patients with high and low levels of miR-143 expression in their blood serum were significantly different: median PFS times =3.2 months (95% CI, 2.9–3.4 and 2.7 months (95% CI, 2.4–3.0, respectively (P=0.017, and median OS times =7.8 months (95% CI, 6.8–8.9 and 6.3 months (95% CI, 5.3–7.3, respectively (P=0.036. No patient experienced Grade 4 toxicity. Combined third-line treatment with pemetrexed and DCs was marginally effective and well tolerated in patients with advanced ESCC. Serum miR-143 levels are a potential

  12. Novel drug-resistance mechanisms of pemetrexed-treated non-small cell lung cancer.

    Science.gov (United States)

    Tanino, Ryosuke; Tsubata, Yukari; Harashima, Nanae; Harada, Mamoru; Isobe, Takeshi

    2018-03-30

    Pemetrexed (PEM) improves the overall survival of patients with advanced non-small cell lung cancer (NSCLC) when administered as maintenance therapy. However, PEM resistance often appears during the therapy. Although thymidylate synthase is known to be responsible for PEM resistance, no other mechanisms have been investigated in detail. In this study, we explored new drug resistance mechanisms of PEM-treated NSCLC using two combinations of parental and PEM-resistant NSCLC cell lines from PC-9 and A549. PEM increased the apoptosis cells in parental PC-9 and the senescent cells in parental A549. However, such changes were not observed in the respective PEM-resistant cell lines. Quantitative RT-PCR analysis revealed that, besides an increased gene expression of thymidylate synthase in PEM-resistant PC-9 cells, the solute carrier family 19 member1 ( SLC19A1) gene expression was markedly decreased in PEM-resistant A549 cells. The siRNA-mediated knockdown of SLC19A1 endowed the parental cell lines with PEM resistance. Conversely, PEM-resistant PC-9 cells carrying an epidermal growth factor receptor (EGFR) mutation acquired resistance to a tyrosine kinase inhibitor erlotinib. Although erlotinib can inhibit the phosphorylation of EGFR and Erk, it is unable to suppress the phosphorylation of Akt in PEM-resistant PC-9 cells. Additionally, PEM-resistant PC-9 cells were less sensitive to the PI3K inhibitor LY294002 than parental PC-9 cells. These results indicate that SLC19A1 negatively regulates PEM resistance in NSCLC, and that EGFR-tyrosine-kinase-inhibitor resistance was acquired with PEM resistance through Akt activation in NSCLC harboring EGFR mutations.

  13. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer

    DEFF Research Database (Denmark)

    Scagliotti, G.V.; Parikh, P.; Pawel, J. von

    2008-01-01

    , in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/ gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ... neutropenia (P = .002); and alopecia (P

  14. Randomized, phase II trial of pemetrexed and carboplatin with or without enzastaurin versus docetaxel and carboplatin as first-line treatment of patients with stage IIIB/IV non-small cell lung cancer.

    Science.gov (United States)

    Socinski, Mark A; Raju, Robert N; Stinchcombe, Thomas; Kocs, Darren M; Couch, Linda S; Barrera, David; Rousey, Steven R; Choksi, Janak K; Jotte, Robert; Patt, Debra A; Periman, Phillip O; Schlossberg, Howard R; Weissman, Charles H; Wang, Yunfei; Asmar, Lina; Pritchard, Sharon; Bromund, Jane; Peng, Guangbin; Treat, Joseph; Obasaju, Coleman K

    2010-12-01

    Enzastaurin is an oral serine/threonine kinase inhibitor that targets protein kinase C-beta (PKC-β) and the phosphatidylinositol-3-kinase/AKT pathway. This trial assessed pemetrexed-carboplatin ± enzastaurin to docetaxel-carboplatin in advanced non-small cell lung cancer. Patients with stage IIIB (with pleural effusion) or IV non-small cell lung cancer and performance status 0 or 1 were randomized to one of the three arms: (A) pemetrexed 500 mg/m and carboplatin area under the curve 6 once every 3 weeks for up to 6 cycles with a loading dose of enzastaurin 1125 or 1200 mg followed by 500 mg daily until disease progression, (B) the same regimen of pemetrexed-carboplatin without enzastaurin, or (C) docetaxel 75 mg/m and carboplatin area under the curve 6 once every 3 weeks for up to six cycles. The primary end point was time to disease progression (TTP). Between March 2006 and May 2008, 218 patients were randomized. Median TTP was 4.6 months for pemetrexed-carboplatin-enzastaurin, 6.0 months for pemetrexed-carboplatin, and 4.1 months for docetaxel-carboplatin (differences not significant). Median survival was 7.2 months for pemetrexed-carboplatin-enzastaurin, 12.7 months for pemetrexed-carboplatin, and 9.2 months for docetaxel-carboplatin (log-rank p = 0.05). Compared with the other arms, docetaxel-carboplatin was associated with lower rates of grade 3 thrombocytopenia and anemia but a higher rate of grade 3 or 4 febrile neutropenia. There was no difference in TTP between the three arms, but survival was longer with pemetrexed-carboplatin compared with docetaxel-carboplatin. Enzastaurin did not add to the activity of pemetrexed-carboplatin.

  15. GREEN PEA GALAXIES REVEAL SECRETS OF Lyα ESCAPE

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Huan; Wang, Junxian [CAS Key Laboratory for Research in Galaxies and Cosmology, Department of Astronomy, University of Science and Technology of China (China); Malhotra, Sangeeta; Rhoads, James E. [Arizona State University, School of Earth and Space Exploration (United States); Gronke, Max; Dijkstra, Mark [Institute of Theoretical Astrophysics, University of Oslo (Norway); Jaskot, Anne [Smith College, Northampton, MA (United States); Zheng, Zhenya, E-mail: yanghuan@mail.ustc.edu.cn, E-mail: huan.y@asu.edu, E-mail: Sangeeta.Malhotra@asu.edu, E-mail: James.Rhoads@asu.edu [Pontificia Universidad Católica de Chile, Santiago (Chile)

    2016-04-01

    We analyze archival Lyα spectra of 12 “Green Pea” galaxies observed with the Hubble Space Telescope, model their Lyα profiles with radiative transfer models, and explore the dependence of the Lyα escape fraction on various properties. Green Pea galaxies are nearby compact starburst galaxies with [O iii] λ5007 equivalent widths (EWs) of hundreds of Å. All 12 Green Pea galaxies in our sample show Lyα lines in emission, with an Lyα EW distribution similar to high-redshift Lyα emitters. Combining the optical and UV spectra of Green Pea galaxies, we estimate their Lyα escape fractions and find correlations between Lyα escape fraction and kinematic features of Lyα profiles. The escape fraction of Lyα in these galaxies ranges from 1.4% to 67%. We also find that the Lyα escape fraction depends strongly on metallicity and moderately on dust extinction. We compare their high-quality Lyα profiles with single H i shell radiative transfer models and find that the Lyα escape fraction anticorrelates with the derived H i column densities. Single-shell models fit most Lyα profiles well, but not the ones with the highest escape fractions of Lyα. Our results suggest that low H i column density and low metallicity are essential for Lyα escape and make a galaxy an Lyα emitter.

  16. What is the physical origin of strong Lyα emission? II. Gas kinematics and distribution of Lyα emitters

    Energy Technology Data Exchange (ETDEWEB)

    Shibuya, Takatoshi; Ouchi, Masami; Ono, Yoshiaki [Institute for Cosmic Ray Research, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8582 (Japan); Nakajima, Kimihiko; Hashimoto, Takuya; Shimasaku, Kazuhiro; Goto, Ryosuke [Department of Astronomy, Graduate School of Science, The University of Tokyo, Tokyo 113-0033 (Japan); Rauch, Michael [Observatories of the Carnegie Institution of Washington, 813 Santa Barbara Street, Pasadena, CA 91101 (United States); Gauthier, Jean-Rene [Cahill Center for Astronomy and Astrophysics, California Institute of Technology, MS 249-17, Pasadena, CA 91125 (United States); Mori, Masao; Umemura, Masayuki, E-mail: shibyatk@icrr.u-tokyo.ac.jp [Center for Computational Sciences, The University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577 (Japan)

    2014-06-10

    We present a statistical study of velocities of Lyα, interstellar (IS) absorption, and nebular lines and gas covering fraction for Lyα emitters (LAEs) at z ≅ 2. We make a sample of 22 LAEs with a large Lyα equivalent width (EW) of ≳ 50 Å based on our deep Keck/Low Resolution Imaging Spectrometer (LRIS) observations, in conjunction with spectroscopic data from the Subaru/Fiber Multi Object Spectrograph program and the literature. We estimate the average velocity offset of Lyα from a systemic redshift determined with nebular lines to be Δv {sub Lyα} = 234 ± 9 km s{sup –1}. Using a Kolmogorov-Smirnov test, we confirm the previous claim of Hashimoto et al. that the average Δv {sub Lyα} of LAEs is smaller than that of Lyman break galaxies (LBGs). Our LRIS data successfully identify blueshifted multiple IS absorption lines in the UV continua of four LAEs on an individual basis. The average velocity offset of IS absorption lines from a systemic redshift is Δv {sub IS} = 204 ± 27 km s{sup –1}, indicating LAEs' gas outflow with a velocity comparable to typical LBGs. Thus, the ratio R{sub IS}{sup Lyα}≡Δv{sub Lyα}/Δv{sub IS} of LAEs is around unity, suggestive of low impacts on Lyα transmission by resonant scattering of neutral hydrogen in the IS medium. We find an anti-correlation between Lyα EW and the covering fraction, f{sub c} , estimated from the depth of absorption lines, where f{sub c} is an indicator of average neutral hydrogen column density, N {sub H} {sub I}. The results of our study support the idea that N {sub H} {sub I} is a key quantity determining Lyα emissivity.

  17. Preliminary Safety, Pharmacokinetics, and Efficacy of Regorafenib, Cisplatin, and Pemetrexed in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancers.

    Science.gov (United States)

    Hellmann, Matthew D; Sturm, Isrid; Trnkova, Zuzana Jirakova; Lettieri, John; Diefenbach, Konstanze; Rizvi, Naiyer A; Gettinger, Scott N

    2015-11-01

    Regorafenib is an oral multitargeted kinase inhibitor with potent antiangiogenic activity. In this phase I trial we evaluated the safety, pharmacokinetics, and efficacy of regorafenib with cisplatin and pemetrexed for patients with advanced nonsquamous non-small-cell lung cancers (nsNSCLCs). Nine patients enrolled before premature termination of the study. Five of 9 (56%) patients had a partial response and the median progression-free survival was 7 months (range, 1.5-15.1 months). Regorafenib had acceptable tolerability and minor pharmacokinetic interactions in combination with standard doses of cisplatin and pemetrexed in patients with advanced nsNSCLCs. The combination of bevacizumab, an antiangiogenesis agent, with cytotoxic chemotherapy improves survival in patients with advanced nonsquamous non-small-cell lung cancers (nsNSCLCs). Regorafenib is an oral multitargeted kinase inhibitor with potent antiangiogenic activity that is approved for patients with advanced colorectal cancer and gastrointestinal stromal tumors. In this phase I trial we evaluated the safety, pharmacokinetics (PK), and efficacy of regorafenib with cisplatin and pemetrexed for patients with advanced nsNSCLCs. Chemotherapy-naive patients with advanced nsNSCLCs were treated with regorafenib 60 mg/d continuously and cisplatin 75 mg/m(2) with pemetrexed 500 mg/m(2) once every 21 days for up to 6 cycles. Thereafter, regorafenib with or without pemetrexed could be continued as maintenance. Nine patients enrolled before premature termination of the study because of slow recruitment and a change in the development strategy of regorafenib by the study sponsor. Five patients experienced at least 1 treatment-related Grade 3 adverse event. No Grade 4 or 5 toxicity occurred. Five of 9 (56%) patients had a partial response and the median progression-free survival was 7 months (range, 1.5-15.1 months). Minor PK interactions between regorafenib and chemotherapy were observed. Regorafenib had acceptable

  18. LY-293558. Eli Lilly & Co.

    Science.gov (United States)

    Gilron, I

    2001-09-01

    Lilly is developing the racemic compound LY-215490, a selective and competitive AMPA antagonist, as a potential treatment for cerebral infarction, cerebrovascular ischemia, epilepsy and as an analgesic [135089], [158980], [254029], [278691]. By January 2000, LY-293558 was undergoing phase II trials for pain [414000].

  19. Ly α and UV Sizes of Green Pea Galaxies

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Huan; Wang, Junxian [CAS Key Laboratory for Research in Galaxies and Cosmology, Department of Astronomy, University of Science and Technology of China (China); Malhotra, Sangeeta; Rhoads, James E.; Jiang, Tianxing [Arizona State University, School of Earth and Space Exploration (United States); Leitherer, Claus [Space Telescope Science Institute, 3700 San Martin Dr, Baltimore, MD 21218 (United States); Wofford, Aida, E-mail: huan.y@asu.edu [National Autonomous University of Mexico, Institute of Astronomy (Mexico)

    2017-03-20

    Green Peas are nearby analogs of high-redshift Ly α -emitting galaxies (LAEs). To probe their Ly α escape, we study the spatial profiles of Ly α and UV continuum emission of 24 Green Pea galaxies using the Cosmic Origins Spectrograph (COS) on the Hubble Space Telescope . We extract the spatial profiles of Ly α emission from their 2D COS spectra, and of the UV continuum from both 2D spectra and NUV images. The Ly α emission shows more extended spatial profiles than the UV continuum, in most Green Peas. The deconvolved full width at half maximum of the Ly α spatial profile is about 2–4 times that of the UV continuum, in most cases. Because Green Peas are analogs of high z LAEs, our results suggest that most high- z LAEs probably have larger Ly α sizes than UV sizes. We also compare the spatial profiles of Ly α photons at blueshifted and redshifted velocities in eight Green Peas with sufficient data quality, and find that the blue wing of the Ly α line has a larger spatial extent than the red wing in four Green Peas with comparatively weak blue Ly α line wings. We show that Green Peas and MUSE z = 3–6 LAEs have similar Ly α and UV continuum sizes, which probably suggests that starbursts in both low- z and high- z LAEs drive similar gas outflows illuminated by Ly α light. Five Lyman continuum (LyC) leakers in this sample have similar Ly α to UV continuum size ratios (∼1.4–4.3) to the other Green Peas, indicating that their LyC emissions escape through ionized holes in the interstellar medium.

  20. Crystal Structure of the FGFR4/LY2874455 Complex Reveals Insights into the Pan-FGFR Selectivity of LY2874455.

    Science.gov (United States)

    Wu, Daichao; Guo, Ming; Philips, Michael A; Qu, Lingzhi; Jiang, Longying; Li, Jun; Chen, Xiaojuan; Chen, Zhuchu; Chen, Lin; Chen, Yongheng

    2016-01-01

    Aberrant FGFR4 signaling has been documented abundantly in various human cancers. The majority of FGFR inhibitors display significantly reduced potency toward FGFR4 compared to FGFR1-3. However, LY2874455 has similar inhibition potency for FGFR1-4 with IC50 less than 6.4 nM. To date, there is no published crystal structure of LY2874455 in complex with any kinase. To better understand the pan-FGFR selectivity of LY2874455, we have determined the crystal structure of the FGFR4 kinase domain bound to LY2874455 at a resolution of 2.35 Å. LY2874455, a type I inhibitor for FGFR4, binds to the ATP-binding pocket of FGFR4 in a DFG-in active conformation with three hydrogen bonds and a number of van der Waals contacts. After alignment of the kinase domain sequence of 4 FGFRs, and superposition of the ATP binding pocket of 4 FGFRs, our structural analyses reveal that the interactions of LY2874455 to FGFR4 are largely conserved in 4 FGFRs, explaining at least partly, the broad inhibitory activity of LY2874455 toward 4 FGFRs. Consequently, our studies reveal new insights into the pan-FGFR selectivity of LY2874455 and provide a structural basis for developing novel FGFR inhibitors that target FGFR1-4 broadly.

  1. Polymorphisms in folate pathway and pemetrexed treatment outcome in patients with malignant pleural mesothelioma

    International Nuclear Information System (INIS)

    Goricar, Katja; Kovac, Viljem; Dolzan, Vita

    2014-01-01

    A combination of pemetrexed and cisplatin has been shown to improve the outcome in patients with malignant pleural mesothelioma (MPM), however, there is a great heterogeneity in treatment response among patients. The aim of our study was to evaluate the influence of polymorphisms in folate pathway and transporter genes on pemetrexed treatment outcome in Slovenian patients with MPM. MPM patients treated with pemetrexed in the course of a prospective randomized clinical trial were genotyped for nineteen polymorphisms in five genes of folate pathway and six transporter genes. Logistic regression was used to assess the influence of polymorphisms on treatment efficacy and toxicity, while Cox regression was used to determine their influence on progression-free and overall survival. Patients with at least one polymorphic MTHFD1 rs2236225 allele had a significantly lower response rate (p = 0.005; odds ratio [OR] = 0.12; 95% confidence interval [CI] = 0.03−0.54) and shorter progression-free survival (p = 0.032; hazard ratio [HR] = 3.10; 95% CI = 1.10−8.74) than non-carriers. Polymorphisms in transporter genes did not influence survival; however, several were associated with toxicity. Liver toxicity was significantly lower in carriers of polymorphic ABCC2 rs2273697 (p = 0.028; OR = 0.23; 95% CI = 0.06−0.85), SLCO1B1 rs4149056 (p = 0.028; OR = 0.23; 95% CI = 0.06−0.85) and rs11045879 (p = 0.014; OR = 0.18; 95% CI = 0.05−0.71) alleles compared to non-carriers, as well as in patients with SLCO1B1 GCAC haplotype (p = 0.048; OR = 0.17; 95% CI = 0.03−0.98). Gastrointestinal toxicity was much more common in patients with polymorphic ABCC2 rs717620 allele (p = 0.004; OR = 10.67; 95% CI = 2.15−52.85) and ABCC2 CAG haplotype (p = 0.006; OR = 5.67; 95% CI = 1.64−19.66). MTHFD1 polymorphism affected treatment response and survival, while polymorphisms in ABCC2 and SLCO1B1 transporter genes influenced the risk for toxicity. These polymorphisms could serve as potential

  2. Phase I Trial of Radiation With Concurrent and Consolidation Pemetrexed and Cisplatin in Patients With Unresectable Stage IIIA/B Non-Small-Cell Lung Cancer

    International Nuclear Information System (INIS)

    Brade, Anthony; Bezjak, Andrea; MacRae, Robert; Laurie, Scott; Sun, Alex; Cho, John; Leighl, Natasha; Pearson, Shannon; Southwood, Bernadette; Wang, Lisa; McGill, Shauna; Iscoe, Neill; Shepherd, Frances A.

    2011-01-01

    Purpose: To evaluate the feasibility and safety of concurrent pemetrexed/cisplatin/thoracic radiotherapy followed by consolidation pemetrexed/cisplatin for unresectable Stage IIIA/B non-small-cell lung cancer (NSCLC). Methods and Materials: Eligible patients with 2 on Days 1 and 22 for Dose Levels 1, 2, and 3/4, respectively) and cisplatin (25 mg/m 2 Days 1-3 for Dose Levels 1-3; 20 mg/m 2 Days 1-5 for Dose Level 4) concurrent with thoracic radiation (61-66 Gy in 31-35 fractions). Consolidation consisted of two cycles of pemetrexed/cisplatin (500 mg/m 2 , 75 mg/m 2 ) 21 days apart, after concurrent therapy. Results: Between January 2006 and October 2007, 16 patients entered the study. Median follow-up was 17.2 months. No dose-limiting toxicities were observed. Median radiation dose was 64 Gy (range, 45-66 Gy). Rates of significant Grade 3/4 hematologic toxicity were 38% and 7%, respectively. One patient experienced Grade 3 acute esophagitis, and 2 experienced late (Grade 3) esophageal stricture, successfully managed with dilation. One patient experienced Grade 3 pneumonitis. The overall response rate was 88%. One-year overall survival was 81%. Conclusions: Full systemic dose pemetrexed seems to be safe with full-dose cisplatin and thoracic radiation in Stage IIIA/B NSCLC. Pemetrexed is the first third-generation cytotoxic agent tolerable at full dose in this setting. A Phase II study evaluating Dose Level 4 is ongoing.

  3. Combination chemotherapy with intermittent erlotinib and pemetrexed for pretreated patients with advanced non-small cell lung cancer: a phase I dose-finding study

    International Nuclear Information System (INIS)

    Minami, Seigo; Tachibana, Isao; Komuta, Kiyoshi; Kawase, Ichiro; Kijima, Takashi; Takahashi, Ryo; Kida, Hiroshi; Nakatani, Takeshi; Hamaguchi, Masanari; Takeuchi, Yoshiko; Nagatomo, Izumi; Yamamoto, Suguru

    2012-01-01

    Erlotinib and pemetrexed have been approved for the second-line treatment of non-small cell lung cancer (NSCLC). These two agents have different mechanisms of action. Combined treatment with erlotinib and pemetrexed could potentially augment the antitumor activity of either agent alone. In the present study, we investigated the safety profile of combined administration of the two agents in pretreated NSCLC patients. A phase I dose-finding study (Trial registration: UMIN000002900) was performed in patients with stage III/IV nonsquamous NSCLC whose disease had progressed on or after receiving first-line chemotherapy. Patients received 500 mg/m 2 of pemetrexed intravenously every 21 days and erlotinib (100 mg at Level 1 and 150 mg at Level 2) orally on days 2–16. Twelve patients, nine males and three females, were recruited. Patient characteristics included a median age of 66 years (range, 48–78 years), stage IV disease (nine cases), adenocarcinoma (seven cases) and activating mutation-positives in the epidermal growth factor receptor gene (two cases). Treatment was well-tolerated, and the recommended dose of erlotinib was fixed at 150 mg. Dose-limiting toxicities were experienced in three patients and included: grade 3 elevation of serum alanine aminotransferase, repetitive grade 4 neutropenia that required reduction of the second dose of pemetrexed and grade 3 diarrhea. No patient experienced drug-induced interstitial lung disease. Three patients achieved a partial response and stable disease was maintained in five patients. Combination chemotherapy of intermittent erlotinib with pemetrexed was well-tolerated, with promising efficacy against pretreated advanced nonsquamous NSCLC

  4. An Open-Label, Multicenter, Randomized, Phase II Study of Pazopanib in Combination with Pemetrexed in First-Line Treatment of Patients with Advanced-Stage Non-Small-Cell Lung Cancer

    DEFF Research Database (Denmark)

    Scagliotti, Giorgio V; Felip, Enriqueta; Besse, Benjamin

    2013-01-01

    This randomized open-label phase II study evaluated the efficacy, safety, and tolerability of pazopanib in combination with pemetrexed compared with the standard cisplatin/pemetrexed doublet in patients with previously untreated, advanced, nonsquamous non-small-cell lung cancer....

  5. Pemetrexed combined with paclitaxel in patients with advanced or metastatic non-small-cell lung cancer: a phase I-II trial.

    Science.gov (United States)

    Stathopoulos, George P; Dimitroulis, John; Toubis, Michael; Katis, Costas; Karaindros, Dimitris; Stathopoulos, John; Koutandos, John

    2007-07-01

    Pemetrexed, a novel multi-targeted agent established for the treatment of mesothelioma, has been under investigation for other malignancies, and in recent years particularly for non-small-cell lung cancer (NSCLC). In the present trial we investigated pemetrexed in combination with paclitaxel as front-line treatment in advanced or metastatic NSCLC. Our objectives were to determine the response rate, median and overall survival and toxicity. From April 2005 until May 2006, 51 patients with advanced or metastatic NSCLC were enrolled and 48 were considered evaluable. There were 39 males and nine females, median age 62 years (range 37-81 years), one patient stage IIIA N(2), 23 patients, IIIB and 24, stage IV. All patients had a cytologically- or histologically-confirmed diagnosis. Pemetrexed was administered at a standard dose of 500mg/m(2) and paclitaxel at an escalating dose starting at 135mg/m(2), then 150mg/m(2) and ending at a dose of 175mg/m(2); the level was increased every three patients. Both agents were administered on day 1, repeated every 3 weeks for six courses. A 39.6% partial response rate was observed with a median survival of 14 months. Toxicity was mild with 8.3% grade 3 and 4 neutropenia and other very mild hematologic and non-hematologic adverse reactions. The combination of pemetrexed and paclitaxel at doses of 500mg/m(2) and 175mg/m(2), respectively, has been shown to be an effective combination with very limited toxicity.

  6. Locus specificity in the mutability of mouse lymphoma strain LY-S

    International Nuclear Information System (INIS)

    Evans, H.H.; Mencl, J.; Horng, M.F.

    1985-01-01

    Mouse lymphoma L5178Y strains, LY-R and LY-S, are closely related but differ in their sensitivity to the lethal effects of radiation and various chemicals. Strain LY-S was originally isolated in 1961 following a spontaneous change in the sensitivity of cultured LY-R cells to ionizing radiation. The authors previously reported that, although strain LY-S is more sensitive to the lethal effects of ionizing radiation and alkylating agents than strain LY-R, it is markedly less mutable than strain LY-R at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus. The isolated sublines of strains LY-R and LY-S which are heterozygous at the thymidine kinase (TK) locus. The LY-S TK+/- heterozygote, like its TK+/+ parent, is more sensitive to the lethal effects of ionizing radiation and alkylating agents and less mutable at the HGPRT locus by these agents than the LY-R TK+/- heterozygote. However, the LY-S heterozygote is 100 times more mutable by these agents at the TK locus than at the HGRT locus. In contrast to LY-R, the majority of the spontaneous and induced LY-S TK-/- mutants form small colonies in the presence of trifluorothymidine, indicating that in the LY-S heterozygote, the inactivation of the TK gene is accompanied by damage to, or rearrangement of neighboring genes

  7. TensorLy: Tensor Learning in Python

    NARCIS (Netherlands)

    Kossaifi, Jean; Panagakis, Yannis; Pantic, Maja

    2016-01-01

    Tensor methods are gaining increasing traction in machine learning. However, there are scant to no resources available to perform tensor learning and decomposition in Python. To answer this need we developed TensorLy. TensorLy is a state of the art general purpose library for tensor learning.

  8. Ly49Q, a member of the Ly49 family that is selectively expressed on myeloid lineage cells and involved in regulation of cytoskeletal architecture

    Science.gov (United States)

    Toyama-Sorimachi, Noriko; Tsujimura, Yusuke; Maruya, Mikako; Onoda, Atsuko; Kubota, Toshiyuki; Koyasu, Shigeo; Inaba, Kayo; Karasuyama, Hajime

    2004-01-01

    Here, we identified and characterized a Ly49 family member, designated as Ly49Q. The Ly49q gene encodes a 273-aa protein with an immunoreceptor tyrosine-based inhibitory motif (ITIM) at the N terminus of its cytoplasmic domain. We show that the ITIM of Ly49Q can recruit SHP-2 and SHP-1 in a tyrosine phosphorylation-dependent manner. In contrast to other known members of the Ly49 family, Ly49Q was found not to be expressed on NK1.1+ cells, but instead was detectable on virtually all Gr-1+ cells, such as myeloid precursors in bone marrow. Monocytes/macrophages also expressed low levels of Ly49Q, and the expression was enhanced by the treatment of cells with IFN-γ. Treatment of activated macrophages with anti-Ly49Q mAb induced rapid formation of polarized actin structures, showing filopodia-like structure on one side and lamellipodial-like structure on the other side. A panel of proteins became tyrosine-phosphorylated in myeloid cells when treated with the mAb. Induction of the phosphorylation depends on the ITIM of Ly49Q. Thus, Ly49Q has unique features different from other known Ly49 family members and appears to be involved in regulation of cytoskeletal architecture of macrophages through ITIM-mediated signaling. PMID:14732700

  9. Cost-effectiveness of gefitinib, icotinib, and pemetrexed-based chemotherapy as first-line treatments for advanced non-small cell lung cancer in China.

    Science.gov (United States)

    Lu, Shun; Ye, Ming; Ding, Lieming; Tan, Fenlai; Fu, Jie; Wu, Bin

    2017-02-07

    Tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR) are becoming the standard treatment option for patients with advanced non-small cell lung cancer (NSCLC) harboring an EGFR mutation, but the economic impact of this practice is unclear, especially in a health resource-limited setting. A decision-analytic model was developed to simulate 21-day patient transitions in a 10-year time horizon. The health and economic outcomes of four first-line strategies (pemetrexed plus cisplatin [PC] alone, PC followed by maintenance with pemetrexed, or initial treatment with gefitinib or icotinib) among patients harboring EGFR mutations were estimated and assessed via indirect comparisons. Costs in the Chinese setting were estimated. The primary outcome was the incremental cost-effectiveness ratio (ICER). Sensitivity analyses were performed. The icotinib strategy resulted in greater health benefits than the other three strategies in NSCLC patients harboring EGFR mutations. Relative to PC alone, PC followed by pemetrexed maintenance, gefitinib and icotinib resulted in ICERs of $104,657, $28,485 and $19,809 per quality-adjusted life-year gained, respectively. The cost of pemetrexed, the EGFR mutation prevalence and the utility of progression-free survival were factors that had a considerable impact on the model outcomes. When the icotinib Patient Assistance Program was available, the economic outcome of icotinib was more favorable. These results indicate that gene-guided therapy with icotinib might be a more cost-effective treatment option than traditional chemotherapy.

  10. Co-delivery of pemetrexed and miR-21 antisense oligonucleotide by lipid-polymer hybrid nanoparticles and effects on glioblastoma cells.

    Science.gov (United States)

    Küçüktürkmen, Berrin; Devrim, Burcu; Saka, Ongun M; Yilmaz, Şükran; Arsoy, Taibe; Bozkir, Asuman

    2017-01-01

    Combination therapy using anticancer drugs and nucleic acid is a more promising strategy to overcome multidrug resistance in cancer and to enhance apoptosis. In this study, lipid-polymer hybrid nanoparticles (LPNs), which contain both pemetrexed and miR-21 antisense oligonucleotide (anti-miR-21), have been developed for treatment of glioblastoma, the most aggressive type of brain tumor. Prepared LPNs have been well characterized by particle size distribution and zeta potential measurements, determination of encapsulation efficiency, and in vitro release experiments. Morphology of LPNs was determined by transmission electron microscopy. LPNs had a hydrodynamic size below 100 nm and exhibited sustained release of pemetrexed up to 10 h. Encapsulation of pemetrexed in LPNs increased cellular uptake from 6% to 78%. Results of confocal microscopy analysis have shown that co-delivery of anti-miR-21 significantly improved accumulation of LPNs in the nucleus of U87MG cells. Nevertheless, more effective cytotoxicity results could not be obtained due to low concentration of anti-miR-21, loaded in LPNs. We expect that the effective drug delivery systems can be obtained with higher concentration of anti-miR-21 for the treatment of glioblastoma.

  11. Phase II Study of Biweekly Pemetrexed Plus Irinotecan as Second-Line Therapy for Metastatic Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    C. Louvet

    2010-01-01

    Conclusion. Pemetrexed plus irinotecan administered every two weeks is an active and well-tolerated regimen in mCRC patients pretreated with FOLFOX regimen. However, this regimen does not seem to provide clinically relevant advantage over historical data of a classical FOLFIRI regimen.

  12. Expression of the Ly-6 family proteins Lynx1 and Ly6H in the rat brain is compartmentalized, cell-type specific, and developmentally regulated

    DEFF Research Database (Denmark)

    Thomsen, Morten Skøtt; Cinar, Betül; Jensen, Majbrit Myrup

    2014-01-01

    regarding the distribution and developmental regulation of these proteins in the brain. We use protein cross-linking and synaptosomal fractions to demonstrate that the Ly-6 proteins Lynx1 and Ly6H are membrane-bound proteins in the brain, which are present on the cell surface and localize to synaptic...... demonstrate that Lynx1 and Ly6H are expressed in cultured neurons, but not cultured micro- or astroglial cultures. In addition, Lynx1, but not Ly6H was detected in the CSF. Finally, we show that the Ly-6 proteins Lynx1, Lynx2, Ly6H, and PSCA, display distinct expression patterns during postnatal development...

  13. Specific binding of [3H]LY186126, an analogue of indolidan (LY195115), to cardiac membranes enriched in sarcoplasmic reticulum vesicles

    International Nuclear Information System (INIS)

    Kauffman, R.F.; Utterback, B.G.; Robertson, D.W.

    1989-01-01

    LY186126 was found to be a potent inhibitor of type IV cyclic AMP phosphodiesterase located in the sarcoplasmic reticulum of canine cardiac muscle. This compound, a close structural analogue of indolidan (LY195115), was prepared in high specific activity, tritiated form to study the positive inotropic receptor(s) for cardiotonic phosphodiesterase inhibitors such as indolidan and milrinone. A high-affinity binding site for [ 3 H]LY186126 was observed (Kd = 4 nM) in purified preparations of canine cardiac sarcoplasmic reticulum vesicles. Binding was proportional to vesicle protein, was inactivated by subjecting membranes to proteolysis or boiling, and was dependent on added Mg2+. Scatchard analysis suggested the presence of a single class of binding sites in the membrane preparation. Indolidan, milrinone, and LY186126 (all at 1 microM) produced essentially complete displacement of bound [ 3 H]LY186126, while nifedipine, propranolol, and prazosin had little or no effect at this concentration. This represents the first reported use of a radioactive analogue to label the inotropic receptor for cardiotonic phosphodiesterase inhibitors. The results suggest that [ 3 H]LY186126 is a useful radioligand for examining the subcellular site(s) responsible for positive inotropic effects of these drugs

  14. Preliminary safety, pharmacokinetics, and efficacy of regorafenib, cisplatin, and pemetrexed in patients with advanced non-squamous non-small cell lung cancers

    Science.gov (United States)

    Hellmann, Matthew D; Sturm, Isrid; Trnkova, Zuzana Jirakova; Lettieri, John; Diefenbach, Konstanze; Rizvi, Naiyer A.; Gettinger, Scott N.

    2016-01-01

    Structured Abstract Purpose The addition of bevacizumab, an anti-angiogenesis agent, to cytotoxic chemotherapy improves survival in patients with advanced non-squamous non-small cell lung cancers (nsNSCLCs). Regorafenib is an oral multi-targeted kinase inhibitor with potent anti-angiogenic activity that is approved for patients with advanced colorectal cancer and gastrointestinal stromal tumors. This phase I trial evaluated the safety, pharmacokinetics, and efficacy of regorafenib with cisplatin and pemetrexed for patients with advanced nsNSCLCs. Methods Chemotherapy-naïve patients with advanced nsNSCLCs were treated with regorafenib 60mg/day continuously and cisplatin 75mg/m2 plus pemetrexed 500mg/m2 once every three weeks for up to six cycles. Thereafter, regorafenib with or without pemetrexed could be continued as maintenance. Results Nine patients enrolled prior to premature termination of the study due to slow recruitment and a change in the development strategy of regorafenib by the study sponsor, partially due to slow enrollment. Five patients experienced at least one treatment-related Grade 3 adverse event. No grade 4–5 toxicity occurred. 5 of 9 (56%) patients had a partial response and the median progression-free survival was 7 months (range 1.5–15.1). Minor pharmacokinetic (PK) interactions between regorafenib and chemotherapy were observed. Conclusions Regorafenib had acceptable tolerability and minor PK interactions in combination with standard doses of cisplatin and pemetrexed in patients with advanced nsNSCLCs. Encouraging activity was appreciated in chemotherapy-naïve patients with advanced nsNSCLCs. However, the small number of patients treated limits conclusions that can be drawn from these results. PMID:26003007

  15. THE LINE POLARIZATION WITHIN A GIANT Lyα NEBULA

    International Nuclear Information System (INIS)

    Prescott, Moire K. M.; Smith, Paul S.; Schmidt, Gary D.; Dey, Arjun

    2011-01-01

    Recent theoretical work has suggested that Lyα nebulae could be substantially polarized in the Lyα emission line, depending on the geometry, kinematics, and powering mechanism at work. Polarization observations can therefore provide a useful constraint on the source of ionization in these systems. In this Letter, we present the first Lyα polarization measurements for a giant Lyα nebula at z∼ 2.656. We do not detect any significant linear polarization of the Lyα emission: P Lyα = 2.6% ± 2.8% (corrected for statistical bias) within a single large aperture. The current data also do not show evidence for the radial polarization gradient predicted by some theoretical models. These results rule out singly scattered Lyα (e.g., from the nearby active galactic nucleus, AGN) and may be inconsistent with some models of backscattering in a spherical outflow. However, the effects of seeing, diminished signal-to-noise ratio, and angle averaging within radial bins make it difficult to put strong constraints on the radial polarization profile. The current constraints may be consistent with higher density outflow models, spherically symmetric infall models, photoionization by star formation within the nebula or the nearby AGN, resonant scattering, or non-spherically symmetric cold accretion (i.e., along filaments). Higher signal-to-noise ratio data probing to higher spatial resolution will allow us to harness the full diagnostic power of polarization observations in distinguishing between theoretical models of giant Lyα nebulae.

  16. Regulation of Akt and Wnt signaling by the group II metabotropic glutamate receptor antagonist LY341495 and agonist LY379268.

    Science.gov (United States)

    Sutton, Laurie P; Rushlow, Walter J

    2011-06-01

    Metabotropic glutamate receptors 2/3 (mGlu(2/3)) have been implicated in schizophrenia and as a novel treatment target for schizophrenia. The current study examined whether mGlu(2/3) regulates Akt (protein kinase B) and Wnt (Wingless/Int-1) signaling, two cascades associated with schizophrenia and modified by antipsychotics. Western blotting revealed increases in phosphorylated Akt (pAkt) and phosphorylated glycogen synthase kinase-3 (pGSK-3) following acute and repeated treatment of LY379268 (mGlu(2/3) agonist), whereas increases in dishevelled-2 (Dvl-2), dishevelled-3 (Dvl-3), GSK-3 and β-catenin were only observed following repeated treatment. LY341495 (mGlu(2/3) antagonist) induced the opposite response compared with LY379268. Co-immunoprecipitation experiments showed an association between the mGlu(2/3) complex and Dvl-2 providing a possible mechanism to explain how the mGlu(2/3) can mediate changes in Wnt signaling. However, there was no association between the mGlu(2/3) complex and Akt suggesting that changes in Akt signaling following LY341495 and LY379268 treatments may not be directly mediated by the mGlu(2/3) . Finally, an increase in locomotor activity induced by LY341495 treatment correlated with increased pAkt and pGSK-3 levels and was attenuated by the administration of the GSK-3 inhibitor, SB216763. Overall, the results suggest that mGlu(2/3) regulates Akt and Wnt signaling and LY379268 treatment has overlapping effects with D(2) dopamine receptor antagonists (antipsychotic drugs). © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

  17. The mGlu2/3 Receptor Agonists LY354740 and LY379268 Differentially Regulate Restraint-Stress-Induced Expression of c-Fos in Rat Cerebral Cortex

    Directory of Open Access Journals (Sweden)

    M. M. Menezes

    2013-01-01

    Full Text Available Metabotropic glutamate 2/3 (mGlu2/3 receptors have emerged as potential therapeutic targets due to the ability of mGlu2/3 receptor agonists to modulate excitatory transmission at specific synapses. LY354740 and LY379268 are selective and potent mGlu2/3 receptor agonists that show both anxiolytic- and antipsychotic-like effects in animal models. We compared the efficacy of LY354740 and LY379268 in attenuating restraint-stress-induced expression of the immediate early gene c-Fos in the rat prelimbic (PrL and infralimbic (IL cortex. LY354740 (10 and 30 mg/kg, i.p. showed statistically significant and dose-related attenuation of stress-induced increase in c-Fos expression, in the rat cortex. By contrast, LY379268 had no effect on restraint-stress-induced c-Fos upregulation (0.3–10 mg/kg, i.p.. Because both compounds inhibit serotonin 2A receptor (5-HT2AR-induced c-Fos expression, we hypothesize that LY354740 and LY379268 have different in vivo properties and that 5-HT2AR activation and restraint stress induce c-Fos through distinct mechanisms.

  18. Spectroscopy of z ~ 6 i-Dropout Galaxies: Frequency of Lyα Emission and the Sizes of Lyα-emitting Galaxies1,

    Science.gov (United States)

    Dow-Hygelund, C. C.; Holden, B. P.; Bouwens, R. J.; Illingworth, G. D.; van der Wel, A.; Franx, M.; van Dokkum, P. G.; Ford, H.; Rosati, P.; Magee, D.; Zirm, A.

    2007-05-01

    We report on deep spectroscopy, using LRIS on Keck I and FORS2 on the VLT, of a sample of 22 candidate z~6 Lyman break galaxies (LBGs) selected by the i775-z850>1.3 dropout criterion. Redshifts could be measured for eight objects. These redshifts are all in the range z=5.5-6.1, confirming the efficiency of the i775-z850 color selection technique. Six of the confirmed galaxies show Lyα emission. Assuming that the 14 objects without redshifts are z~6 LBGs that lack detectable Lyα emission lines, we infer that the fraction of Lyα-emitting LBGs with Lyα equivalent widths greater than 20 Å among z~6 LBGs is ~30%, similar to that found at z~3. Every Lyα-emitting object in our sample is compact, with half-light radii rhldropout sample (332 candidate z~6 objects). We can reject the hypothesis that the Lyα-emitting population is a subset of the rest of the z~6 LBG population at >97% confidence. We speculate that the small sizes of the Lyα-emitting LBGs are due to these objects being less massive than other LBGs at z~6. Based on observations made with the NASA/ESA Hubble Space Telescope, which is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS 5-26555. These observations are associated with programs 7817, 9270, 9301, 9583, and 9803. Based on observations collected at the European Southern Observatory, Paranal, Chile (LP166.A-0701 and 169.A-045).

  19. BROADBAND IMAGING SEGREGATION OF z ∼ 3 Lyα EMITTING AND Lyα ABSORBING GALAXIES

    International Nuclear Information System (INIS)

    Cooke, Jeff

    2009-01-01

    The spectral properties of Lyman break galaxies (LBGs) offer a means to isolate pure samples displaying either dominant Lyα in absorption or Lyα in emission using broadband information alone. We present criteria developed using a large z ∼ 3 LBG spectroscopic sample from the literature that enables large numbers of each spectral type to be gathered in photometric data, providing good statistics for multiple applications. In addition, we find that the truncated faint, blue-end tail of z ∼ 3 LBG population overlaps and leads directly into an expected Lyα emitter (LAE) population. As a result, we present simple criteria to cleanly select large numbers of z ∼ 3 LAEs in deep broadband surveys. We present the spectroscopic results of 32r' ∼< 25.5 LBGs and r' ∼< 27.0 LAEs at z ∼ 3 preselected in the Canada-France-Hawaii Telescope Legacy Survey that confirm these criteria.

  20. Safety of Neoadjuvant Bevacizumab plus Pemetrexed and Carboplatin 
in Patients with IIIa Lung Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Songliang ZHANG

    2015-06-01

    Full Text Available Background and objective Bevacizumab has showed its efficacy in advanced non-squamous lung cancer. The aim of this study is to assess the safety of bevacizumab plus pemetrexed and carboplatin neoadjuvant chemotherapy in patients with lung adenocarcinoma. Methods 25 patients with IIIa lung adenocarcinoma undergoing lobectemy or pneumonectomy with mediastinal lymphadenectomy after induction bevacizumab (Bev plus pemetrexed/carboplatin (PC were selected. Toxicity of chemotherapy and postoperative complications were analyzed. Results Grade 3 or 4 neoadjuvant-related adverse events included fatigue (3 patients, neutropenia (3 patients, hypertension (1 patient. The adverse events thought to be related to bevacizumab included epistaxis in 2 patients (grade 1: 1; grade 2: 1 and hypertension in 3 patients (grade 1: 2; grade 3: 1. Postoperative complications included pneumonia in 2 patients, bronchial stump insufficiency in 1 case, atelectasis in 2 cases, and arrhythmia in 1 case. Hemorrhage events, thromboembolic events and wound-healing problems were not observed in the perioperative period. Conclusion The treatment modality of neoadjuvant Bev-PC appears to be safe and tolerant in patients with stage IIIa lung adenocarcinoma.

  1. Icotinib antagonizes ABCG2-mediated multidrug resistance, but not the pemetrexed resistance mediated by thymidylate synthase and ABCG2.

    Science.gov (United States)

    Wang, De-Shen; Patel, Atish; Shukla, Suneet; Zhang, Yun-Kai; Wang, Yi-Jun; Kathawala, Rishil J; Robey, Robert W; Zhang, Li; Yang, Dong-Hua; Talele, Tanaji T; Bates, Susan E; Ambudkar, Suresh V; Xu, Rui-Hua; Chen, Zhe-Sheng

    2014-06-30

    ABCG2 is a potential biomarker causing multidrug resistance (MDR) in Non-Small Cell Lung Cancer (NSCLC). We conducted this study to investigate whether Icotinib, a small-molecule inhibitor of EGFR tyrosine kinase, could interact with ABCG2 transporter in NSCLC. Our results showed that Icotinib reversed ABCG2-mediated MDR by antagonizing the drug efflux function of ABCG2. Icotinib stimulated the ATPase activity in a concentration-dependent manner and inhibited the photolabeling of ABCG2 with [125I]-Iodoarylazidoprazosin, demonstrating that it interacts at the drug-binding pocket. Homology modeling predicted the binding conformation of Icotinib at Asn629 centroid-based grid of ABCG2. However, Icotinib at reversal concentration did not affect the expression levels of AKT and ABCG2. Furthermore, a combination of Icotinib and topotecan exhibited significant synergistic anticancer activity against NCI-H460/MX20 tumor xenografts. However, the inhibition of transport activity of ABCG2 was insufficient to overcome pemetrexed resistance in NCI-H460/MX20 cells, which was due to the co-upregulated thymidylate synthase (TS) and ABCG2 expression. This is the first report to show that the up-regulation of TS in ABCG2-overexpressing cell line NCI-H460/MX20 may play a role of resistance to pemetrexate. Our findings suggested different possible strategies of overcoming the resistance of topotecan and pemetrexed in the NSCLC patients.

  2. Synthesis of[11C]LY186126, an inhibitor of phosphodiesterase

    International Nuclear Information System (INIS)

    Prenant, C.; Crouzel, C.; Comar, D.; Robertson, D.W.

    1992-01-01

    LY186126 [1,3-dihydro-1,3,3-trimethyl-5-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyriddazinyl)-2H-indol-2-one ], an analogue of the cardiotonic agent indolidan, is a potent, selective and competitive inhibitor of an isozymic form of cyclic AMP phosphodiesterase. LY186126 was labelled with carbon-11 to permit pharmacological studies in the dog myocardium by positron emission tomography. Alkylation with [ 11 C]methyl iodide of N-norLY186126 (LY-197055) allowed the production of 1.7 GBq (50mCi) of [ 11 C]LY-186126 in 40 min. The product, was purified by HPLC. (author)

  3. Specific binding of (/sup 3/H)LY186126, an analogue of indolidan (LY195115), to cardiac membranes enriched in sarcoplasmic reticulum vesicles

    Energy Technology Data Exchange (ETDEWEB)

    Kauffman, R.F.; Utterback, B.G.; Robertson, D.W.

    1989-05-01

    LY186126 was found to be a potent inhibitor of type IV cyclic AMP phosphodiesterase located in the sarcoplasmic reticulum of canine cardiac muscle. This compound, a close structural analogue of indolidan (LY195115), was prepared in high specific activity, tritiated form to study the positive inotropic receptor(s) for cardiotonic phosphodiesterase inhibitors such as indolidan and milrinone. A high-affinity binding site for (/sup 3/H)LY186126 was observed (Kd = 4 nM) in purified preparations of canine cardiac sarcoplasmic reticulum vesicles. Binding was proportional to vesicle protein, was inactivated by subjecting membranes to proteolysis or boiling, and was dependent on added Mg2+. Scatchard analysis suggested the presence of a single class of binding sites in the membrane preparation. Indolidan, milrinone, and LY186126 (all at 1 microM) produced essentially complete displacement of bound (/sup 3/H)LY186126, while nifedipine, propranolol, and prazosin had little or no effect at this concentration. This represents the first reported use of a radioactive analogue to label the inotropic receptor for cardiotonic phosphodiesterase inhibitors. The results suggest that (/sup 3/H)LY186126 is a useful radioligand for examining the subcellular site(s) responsible for positive inotropic effects of these drugs.

  4. LY-354740 (Eli Lilly).

    Science.gov (United States)

    Pilc, Andrzej

    2003-01-01

    Lilly is developing LY-354740, the lead compound in a series of derivatives of the metabotropic glutamate receptor group II agonist L-CCG-1, for the potential treatment of anxiety [212536], [276941], [276942].

  5. Giant Ly α Nebulae in the Illustris Simulation

    Energy Technology Data Exchange (ETDEWEB)

    Gronke, Max [Institute of Theoretical Astrophysics, University of Oslo, Postboks 1029 Blindern, NO-0315 Oslo (Norway); Bird, Simeon, E-mail: maxbg@astro.uio.no [Department of Physics and Astronomy, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218 (United States)

    2017-02-01

    Several “giant” Ly α nebulae with an extent ≳300 kpc and observed Ly α luminosity of ≳10{sup 44} erg s{sup −1} cm{sup −2} arcsec{sup −2} have recently been detected, and it has been speculated that their presence hints at a substantial cold gas reservoir in small cool clumps not resolved in modern hydrodynamical simulations. We use the Illustris simulation to predict the Ly α emission emerging from large halos ( M > 10{sup 11.5} M {sub ⊙}) at z ∼ 2 and thus test this model. We consider both active galactic nucleus (AGN) and star driven ionization, and compare the simulated surface brightness maps, profiles, and Ly α spectra to a model where most gas is clumped below the simulation resolution scale. We find that with Illustris, no additional clumping is necessary to explain the extents, luminosities, and surface brightness profiles of the “giant Ly α nebulae” observed. Furthermore, the maximal extents of the objects show a wide spread for a given luminosity and do not correlate significantly with any halo properties. We also show how the detected size depends strongly on the employed surface brightness cutoff, and predict that further examples of such objects will be found in the near future.

  6. TensorLy: Tensor Learning in Python

    OpenAIRE

    Kossaifi, Jean; Panagakis, Yannis; Pantic, Maja

    2016-01-01

    Tensors are higher-order extensions of matrices. While matrix methods form the cornerstone of machine learning and data analysis, tensor methods have been gaining increasing traction. However, software support for tensor operations is not on the same footing. In order to bridge this gap, we have developed \\emph{TensorLy}, a high-level API for tensor methods and deep tensorized neural networks in Python. TensorLy aims to follow the same standards adopted by the main projects of the Python scie...

  7. Extinction Correction Significantly Influences the Estimate of the Lyα Escape Fraction

    Science.gov (United States)

    An, Fang Xia; Zheng, Xian Zhong; Hao, Cai-Na; Huang, Jia-Sheng; Xia, Xiao-Yang

    2017-02-01

    The Lyα escape fraction is a key measure to constrain the neutral state of the intergalactic medium and then to understand how the universe was fully reionized. We combine deep narrowband imaging data from the custom-made filter NB393 and the {{{H}}}2S1 filter centered at 2.14 μm to examine the Lyα emitters and Hα emitters at the same redshift z = 2.24. The combination of these two populations allows us to determine the Lyα escape fraction at z = 2.24. Over an area of 383 arcmin2 in the Extended Chandra Deep Field South (ECDFS), 124 Lyα emitters are detected down to NB393 = 26.4 mag at the 5σ level, and 56 Hα emitters come from An et al. Of these, four have both Lyα and Hα emissions (LAHAEs). We also collect the Lyα emitters and Hα emitters at z = 2.24 in the COSMOS field from the literature, and increase the number of LAHAEs to 15 in total. About one-third of them are AGNs. We measure the individual/volumetric Lyα escape fraction by comparing the observed Lyα luminosity/luminosity density to the extinction-corrected Hα luminosity/luminosity density. We revisit the extinction correction for Hα emitters using the Galactic extinction law with color excess for nebular emission. We also adopt the Calzetti extinction law together with an identical color excess for stellar and nebular regions to explore how the uncertainties in extinction correction affect the estimate of individual and global Lyα escape fractions. In both cases, an anti-correlation between the Lyα escape fraction and dust attenuation is found among the LAHAEs, suggesting that dust absorption is responsible for the suppression of the escaping Lyα photons. However, the estimated Lyα escape fraction of individual LAHAEs varies by up to ˜3 percentage points between the two methods of extinction correction. We find the global Lyα escape fraction at z = 2.24 to be (3.7 ± 1.4)% in the ECDFS. The variation in the color excess of the extinction causes a discrepancy of ˜1 percentage point

  8. Comparing the Antiseizure and Neuroprotective Efficacy of LY293558, Diazepam, Caramiphen, and LY293558-Caramiphen Combination against Soman in a Rat Model Relevant to the Pediatric Population

    Science.gov (United States)

    Apland, James P.; Aroniadou-Anderjaska, Vassiliki; Figueiredo, Taiza H.; Pidoplichko, Volodymyr I.; Rossetti, Katia

    2018-01-01

    The currently Food and Drug Administration–approved anticonvulsant for the treatment of status epilepticus (SE) induced by nerve agents is the benzodiazepine diazepam; however, diazepam does not appear to offer neuroprotective benefits. This is of particular concern with respect to the protection of children because, in the developing brain, synaptic transmission mediated via GABAA receptors, the target of diazepam, is weak. In the present study, we exposed 21-day-old male rats to 1.2 × LD50 soman and compared the antiseizure, antilethality, and neuroprotective efficacy of diazepam (10 mg/kg), LY293558 (an AMPA/GluK1 receptor antagonist; 15 mg/kg), caramiphen (CRM, an antimuscarinic with NMDA receptor-antagonistic properties; 50 mg/kg), and LY293558 (15 mg/kg) + CRM (50 mg/kg), administered 1 hour after exposure. Diazepam, LY293558, and LY293558 + CRM, but not CRM alone, terminated SE; LY293558 + CRM treatment acted significantly faster and produced a survival rate greater than 85%. Thirty days after soman exposure, neurodegeneration in limbic regions was most severe in the CRM-treated group, minimal to severe—depending on the region—in the diazepam group, absent to moderate in the LY293558-treated group, and totally absent in the LY293558 + CRM group. Amygdala and hippocampal atrophy, a severe reduction in spontaneous inhibitory activity in the basolateral amygdala, and increased anxiety-like behavior in the open-field and acoustic startle response tests were present in the diazepam and CRM groups, whereas the LY293558 and LY293558 + CRM groups did not differ from controls. The combined administration of LY293558 and CRM, by blocking mainly AMPA, GluK1, and NMDA receptors, is a very effective anticonvulsant and neuroprotective therapy against soman in young rats. PMID:29467308

  9. Comparing the Antiseizure and Neuroprotective Efficacy of LY293558, Diazepam, Caramiphen, and LY293558-Caramiphen Combination against Soman in a Rat Model Relevant to the Pediatric Population.

    Science.gov (United States)

    Apland, James P; Aroniadou-Anderjaska, Vassiliki; Figueiredo, Taiza H; Pidoplichko, Volodymyr I; Rossetti, Katia; Braga, Maria F M

    2018-05-01

    The currently Food and Drug Administration-approved anticonvulsant for the treatment of status epilepticus (SE) induced by nerve agents is the benzodiazepine diazepam; however, diazepam does not appear to offer neuroprotective benefits. This is of particular concern with respect to the protection of children because, in the developing brain, synaptic transmission mediated via GABA A receptors, the target of diazepam, is weak. In the present study, we exposed 21-day-old male rats to 1.2 × LD 50 soman and compared the antiseizure, antilethality, and neuroprotective efficacy of diazepam (10 mg/kg), LY293558 (an AMPA/GluK1 receptor antagonist; 15 mg/kg), caramiphen (CRM, an antimuscarinic with NMDA receptor-antagonistic properties; 50 mg/kg), and LY293558 (15 mg/kg) + CRM (50 mg/kg), administered 1 hour after exposure. Diazepam, LY293558, and LY293558 + CRM, but not CRM alone, terminated SE; LY293558 + CRM treatment acted significantly faster and produced a survival rate greater than 85%. Thirty days after soman exposure, neurodegeneration in limbic regions was most severe in the CRM-treated group, minimal to severe-depending on the region-in the diazepam group, absent to moderate in the LY293558-treated group, and totally absent in the LY293558 + CRM group. Amygdala and hippocampal atrophy, a severe reduction in spontaneous inhibitory activity in the basolateral amygdala, and increased anxiety-like behavior in the open-field and acoustic startle response tests were present in the diazepam and CRM groups, whereas the LY293558 and LY293558 + CRM groups did not differ from controls. The combined administration of LY293558 and CRM, by blocking mainly AMPA, GluK1, and NMDA receptors, is a very effective anticonvulsant and neuroprotective therapy against soman in young rats. U.S. Government work not protected by U.S. copyright.

  10. The physical properties and evolution of Lyα emitting galaxies

    Science.gov (United States)

    Pentericci, L.; Grazian, A.; Fontana, A.

    2009-05-01

    A significant fraction of high redshift starburst galaxies presents strong Lyα emission. Understanding the nature of these galaxies is important to assess the role they played in the early Universe and to shed light on the relation between the narrow band selected Lyα emitters and the Lyman break galaxies: are the Lyα emitters a subset of the general LBG population? or do they represent the youngest galaxies in their early phases of formation? We studied a sample of UV continuum selected galaxies from z~2.5 to z~6 (U, B, V and i-dropouts) from the GOODS-South survey, that have been observed spectroscopically. Using the GOODS-MUSIC catalog we investigated their physical properties, such as total masses, ages, SFRs, extinction etc as determined from a spectrophotometric fit to the multi-wavelength (U band to mid-IR) SEDs, and their dependence on the emission line characteristics. In particular we determined the nature of the LBGs with Lyα in emission and compared them to the properties of narrow band selected Lyα emitters. For U and B-dropouts we also compared the properties of LBGs with and without the Lyα emission line.

  11. A New Method to Measure the Post-reionization Ionizing Background from the Joint Distribution of Lyα and Lyβ Forest Transmission

    Science.gov (United States)

    Davies, Frederick B.; Hennawi, Joseph F.; Eilers, Anna-Christina; Lukić, Zarija

    2018-03-01

    The amplitude of the ionizing background that pervades the intergalactic medium (IGM) at the end of the epoch of reionization provides a valuable constraint on the emissivity of the sources that reionized the universe. While measurements of the ionizing background at lower redshifts rely on a simulation-calibrated mapping between the photoionization rate and the mean transmission of the Lyα forest, at z ≳ 6 the IGM becomes increasingly opaque and transmission arises solely in narrow spikes separated by saturated Gunn–Peterson troughs. In this regime, the traditional approach of measuring the average transmission over large ∼50 Mpc/h regions is less sensitive and suboptimal. In addition, the five times smaller oscillator strength of the Lyβ transition implies that the Lyβ forest is considerably more transparent at z ≳ 6, even in the presence of contamination by foreground z ∼ 5 Lyα forest absorption. In this work we present a novel statistical approach to analyze the joint distribution of transmission spikes in the cospatial z ∼ 6 Lyα and Lyβ forests. Our method relies on approximate Bayesian computation (ABC), which circumvents the necessity of computing the intractable likelihood function describing the highly correlated Lyα and Lyβ transmission. We apply ABC to mock data generated from a large-volume hydrodynamical simulation combined with a state-of-the-art model of ionizing background fluctuations in the post-reionization IGM and show that it is sensitive to higher IGM neutral hydrogen fractions than previous techniques. As a proof of concept, we apply this methodology to a real spectrum of a z = 6.54 quasar and measure the ionizing background from 5.4 ≤ z ≤ 6.4 along this sightline with ∼0.2 dex statistical uncertainties. Some of the data presented herein were obtained at the W. M. Keck Observatory, which is operated as a scientific partnership among the California Institute of Technology, the University of California, and the

  12. DIFFUSE Lyα EMITTING HALOS: A GENERIC PROPERTY OF HIGH-REDSHIFT STAR-FORMING GALAXIES

    International Nuclear Information System (INIS)

    Steidel, Charles C.; Bogosavljevic, Milan; Shapley, Alice E.; Kollmeier, Juna A.; Reddy, Naveen A.; Erb, Dawn K.; Pettini, Max

    2011-01-01

    Using a sample of 92 UV continuum-selected, spectroscopically identified galaxies with (z) = 2.65, all of which have been imaged in the Lyα line with extremely deep narrow-band imaging, we examine galaxy Lyα emission profiles to very faint surface brightness limits. The galaxy sample is representative of spectroscopic samples of Lyman break galaxies (LBGs) at similar redshifts in terms of apparent magnitude, UV luminosity, inferred extinction, and star formation rate and was assembled without regard to Lyα emission properties. Approximately 45% (55%) of the galaxy spectra have Lyα appearing in net absorption (emission), with ≅ 20% satisfying commonly used criteria for the identification of 'Lyα emitters' (LAEs; W 0 (Lyα) ≥ 20 A). We use extremely deep stacks of rest-UV continuum and continuum-subtracted Lyα images to show that all sub-samples exhibit diffuse Lyα emission to radii of at least 10'' (∼80 physical kpc). The characteristic exponential scale lengths for Lyα line emission exceed that of the λ 0 = 1220 A UV continuum light by factors of ∼5-10. The surface brightness profiles of Lyα emission are strongly suppressed relative to the UV continuum light in the inner few kpc, by amounts that are tightly correlated with the galaxies' observed spectral morphology; however, all galaxy sub-subsamples, including that of galaxies for which Lyα appears in net absorption in the spectra, exhibit qualitatively similar diffuse Lyα emission halos. Accounting for the extended Lyα emission halos, which generally would not be detected in the slit spectra of individual objects or with typical narrow-band Lyα imaging, increases the total Lyα flux (and rest equivalent width W 0 (Lyα)) by an average factor of ∼5, and by a much larger factor for the 80% of LBGs not classified as LAEs. We argue that most, if not all, of the observed Lyα emission in the diffuse halos originates in the galaxy H II regions but is scattered in our direction by H I gas in the

  13. Spectral Ly{alpha}, Ly{beta}, and H{alpha} line shapes for the H atom in the presence of a magnetic field in a plasma; Profils des raies spectrales Ly{alpha}, Ly{beta}, et H{alpha} de l'atome H en presence d'un champ magnetique dans un plasma

    Energy Technology Data Exchange (ETDEWEB)

    Nguyen, H; Herman, L [Laboratoire de Recherches Physiques, Faculte des sciences, 9 Quai Saint Bernard, 75 - Paris (France); Drawin, H W [Commissariat a l' Energie Atomique, Fontenay-aux-Roses (France). Centre d' Etudes Nucleaires

    1967-02-15

    This report contains numerical data of the line shapes of Ly{alpha}, Ly{beta}, and H{alpha} for the following parameters: 1. 10{sup 2} {<=} H [gauss] {<=} 1.2. 10{sup 5} 1. 10{sup 15}{<=} N [cm{sup -3}] {<=} 1. 10{sup 18} cm{sup -3} 1. 10{sup 4} {<=} T [deg. K] {<=} 4. 10{sup 4} where H = magnetic field strength, K = density of plasma ions, T = electron temperature. (authors) [French] Dans ce rapport, on donne les valeurs numeriques des contours des raies spectrales Ly{alpha}, Ly{beta}, et H{alpha} pour les valeurs suivantes des parametres H, N et T 1. 10{sup 2} {<=} H [gauss] {<=} 1.2. 10{sup 5} 1. 10{sup 15}{<=} N [cm{sup -3}] {<=} 1. 10{sup 18} cm{sup -3} 1. 10{sup 4} {<=} T [deg. K] {<=} 4. 10{sup 4} ou H intensite du champ magnetique, N = densite des ions, T = temperature electronique. (auteurs)

  14. LyGDI expression in HeLa cells increased its sensitivity to radiation-induced apoptosis

    International Nuclear Information System (INIS)

    Zhou Xinwen; Xu Yaxiang

    2006-01-01

    Objective: In order to confirm whether LyGDI has apoptotic signal transduction function and can increase the apoptotic rate of radiation-induced cell death, the lyGDI and mutant D19lyGDI gene, which constructed with the pCDNA3. 1 His A, were transfected into no-endogenous lyGDI HeLa cells. Methods Transient expressions of lyGDI and D19lyGDI in HeLa cells were analyzed by Western blot using anti-mono antibody of LyGDI and Xpress tag. Cell apoptosis was assayed with Annexin V-FITC apoptosis kit. To select stable clone, the transferred HeLa cells had been maintained in G418 medium for 3 weeks, then a cell line, which stably expressed LyGDI and mutant D19lyGDI, was selected. The selected cell line was irradiated with 12 Gy 60 Co y-rays. Caspase-3 activity of the cells was determined by Western blot and cell viability by clone-forming assay after 48 hours post-irradiation culture. Results: Western blot and Annexin V-FITC apoptotic analysis revealed that lyGDI and D19lyGDI transient expressions in HeLa cells induced apoptosis; Caspase-3 activity measurement and clone-forming assay showed that lyGDI increased sensitivity to radiation-induced cell apoptosis. Conclusions: lyGDI performs function in apoptosis signal transduction, its expression in HeLa cells can increase the sensitivity to radiation-induced cell apoptosis. (authors)

  15. HUBBLE SPACE TELESCOPE IMAGING OF Lyα EMISSION AT z ∼ 4.4

    International Nuclear Information System (INIS)

    Finkelstein, Steven L.; Finkelstein, Keely D.; Cohen, Seth H.; Windhorst, Rogier A.; Malhotra, Sangeeta; Rhoads, James E.; Ryan, Russell E.; Hathi, Nimish P.; McCarthy, Patrick J.; Anderson, Jay; Grogin, Norman A.; Koekemoer, Anton M.; Mutchler, Max; Bond, Howard E.; O'Connell, Robert W.; Balick, Bruce; Calzetti, Daniela; Disney, Michael J.; Dopita, Michael A.; Frogel, Jay A.

    2011-01-01

    We present the highest redshift detections of resolved Lyα emission, using Hubble Space Telescope (HST)/Advanced Camera for Surveys F658N narrowband-imaging data taken in parallel with the Wide Field Camera 3 Early Release Science program in the GOODS Chandra Deep Field-South. We detect Lyα emission from three spectroscopically confirmed z = 4.4 Lyα emitting galaxies (LAEs), more than doubling the sample of LAEs with resolved Lyα emission. Comparing the light distribution between the rest-frame ultraviolet continuum and narrowband images, we investigate the escape of Lyα photons at high redshift. While our data do not support a positional offset between the Lyα and rest-frame ultraviolet (UV) continuum emission, the half-light radius in one out of the three galaxies is significantly (>1σ) larger in Lyα than in the rest-frame UV continuum. Stacking the three LAEs in both the narrowband and UV continuum images, we find that the Lyα light appears larger than the rest-frame UV at 4.2σ significance. This Lyα flux detected with HST is a factor of 4-10 less than observed in similar filters from the ground. These results together imply that the Lyα emission is not strictly confined to its indigenous star-forming regions. Rather, for at least one object the Lyα emission is more extended, with the missing HST flux possibly existing in a diffuse outer halo. This suggests that the radiative transfer of Lyα photons in high-redshift LAEs is complicated, with the interstellar-medium geometry and/or outflows playing a significant role in galaxies at these redshifts.

  16. Ly49Q, an ITIM-bearing NK receptor, positively regulates osteoclast differentiation

    International Nuclear Information System (INIS)

    Hayashi, Mikihito; Nakashima, Tomoki; Kodama, Tatsuhiko; Makrigiannis, Andrew P.; Toyama-Sorimachi, Noriko; Takayanagi, Hiroshi

    2010-01-01

    Osteoclasts, multinucleated cells that resorb bone, play a key role in bone remodeling. Although immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling is critical for osteoclast differentiation, the significance of immunoreceptor tyrosine-based inhibitory motif (ITIM) has not been well understood. Here we report the function of Ly49Q, an Ly49 family member possessing an ITIM motif, in osteoclastogenesis. Ly49Q is selectively induced by receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) stimulation in bone marrow-derived monocyte/macrophage precursor cells (BMMs) among the Ly49 family of NK receptors. The knockdown of Ly49Q resulted in a significant reduction in the RANKL-induced formation of tartrate-resistance acid phosphatase (TRAP)-positive multinucleated cells, accompanied by a decreased expression of osteoclast-specific genes such as Nfatc1, Tm7sf4, Oscar, Ctsk, and Acp5. Osteoclastogenesis was also significantly impaired in Ly49Q-deficient cells in vitro. The inhibitory effect of Ly49Q-deficiency may be explained by the finding that Ly49Q competed for the association of Src-homology domain-2 phosphatase-1 (SHP-1) with paired immunoglobulin-like receptor-B (PIR-B), an ITIM-bearing receptor which negatively regulates osteoclast differentiation. Unexpectedly, Ly49Q deficiency did not lead to impaired osteoclast formation in vivo, suggesting the existence of a compensatory mechanism. This study provides an example in which an ITIM-bearing receptor functions as a positive regulator of osteoclast differentiation.

  17. A SUCCESSFUL BROADBAND SURVEY FOR GIANT Ly{alpha} NEBULAE. II. SPECTROSCOPIC CONFIRMATION

    Energy Technology Data Exchange (ETDEWEB)

    Prescott, Moire K. M. [Department of Physics, University of California, Broida Hall, Mail Code 9530, Santa Barbara, CA 93106 (United States); Dey, Arjun; Jannuzi, Buell T., E-mail: mkpresco@physics.ucsb.edu [National Optical Astronomy Observatory, 950 North Cherry Avenue, Tucson, AZ 85719 (United States)

    2013-01-01

    Using a systematic broadband search technique, we have carried out a survey for large Ly{alpha} nebulae (or Ly{alpha} {sup b}lobs{sup )} at 2 {approx}< z {approx}< 3 within 8.5 deg{sup 2} of the NOAO Deep Wide-Field Survey Booetes field, corresponding to a total survey comoving volume of Almost-Equal-To 10{sup 8} h {sup -3} {sub 70} Mpc{sup 3}. Here, we present our spectroscopic observations of candidate giant Ly{alpha} nebulae. Of 26 candidates targeted, 5 were confirmed to have Ly{alpha} emission at 1.7 {approx}< z {approx}< 2.7, 4 of which were new discoveries. The confirmed Ly{alpha} nebulae span a range of Ly{alpha} equivalent widths, colors, sizes, and line ratios, and most show spatially extended continuum emission. The remaining candidates did not reveal any strong emission lines, but instead exhibit featureless, diffuse, blue continuum spectra. Their nature remains mysterious, but we speculate that some of these might be Ly{alpha} nebulae lying within the redshift desert (i.e., 1.2 {approx}< z {approx}< 1.6). Our spectroscopic follow-up confirms the power of using deep broadband imaging to search for the bright end of the Ly{alpha} nebula population across enormous comoving volumes.

  18. A Randomized, Controlled, Multicenter Clinical Trial Comparing Pemetrexed/Cisplatin and Gemcitabine/Cisplatin as First-line Treatment for Advanced Nonsquamous Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Yan HUANG

    2012-10-01

    Full Text Available Background and objective Platinum-based doublet chemotherapy is still the standard first-line treatment for non-small cell lung cancer (NSCLC. Previous studies have demonstrated that pemetrexed combined with platinum had promising efficacy and safety profile in NSCLC, especially in patients with nonsquamous NSCLC. This trial was conducted to evaluate the efficacy and safety of pemetrexed made in China as first-line treatment. Methods The present study was a randomized, controlled, multicenter clinical trial. Patients were randomly assigned (1:1 to receive cisplatin plus pemetrexed chemotherapy (PC group or gemcitabine plus cisplatin (GC group every 3 weeks. The primary end point was progression free survival (PFS and the secondary end points included 1 year survival rate, objective response rate (ORR, survival without grade 3/4 toxicity (SWT3/4 and safety profile. Results A total of 288 patients from 20 institutions across China were enrolled into the study. Based on the Full Analyses Set (FAS, the PFS was 168 days (5.6 months vs 140 days (4.7 months (P=0.16, one year survival rate was 50.0% vs 54.9% (P=0.47, ORR was 24.4% vs 14.2% (P=0.06 in the PC group and the GC group, respectively; Survival without grade 3/4 toxicity was 11.3 months in GC group vs 8.1 months in PC group (P=0.23. In terms of the safety, side effects were less observed on the PC group (81.95% vs 93.75%, P=0.003. The main side effects included leukopenia, neutropenia, emesis, anemia, thrombopenia. Conclusion The both regimens have similar efficacy as the treatment for advanced nonsquamous NSCLC, but pemetrexed plus cisplatin regimen has better safety profile and seems to have longer PFS, which makes it a new option as the first line setting.

  19. Sequentially administrated of pemetrexed with icotinib/erlotinib in lung adenocarcinoma cell lines in vitro

    OpenAIRE

    Feng, Xiuli; Zhang, Yan; Li, Tao; Li, Yu

    2017-01-01

    Combination of chemotherapy and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) had been proved to be a potent anti-drug for the treatment of tumors. However, survival time was not extended for the patients with lung adenocarcinoma (AdC) compared with first-line chemotherapy. In the present study, we attempt to assess the optimal schedule of the combined administration of pemetrexed and icotinib/erlotinib in AdC cell lines. Human lung AdC cell lines with wild-type (A54...

  20. A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma.

    Science.gov (United States)

    Nowak, A K; Cook, A M; McDonnell, A M; Millward, M J; Creaney, J; Francis, R J; Hasani, A; Segal, A; Musk, A W; Turlach, B A; McCoy, M J; Robinson, B W S; Lake, R A

    2015-12-01

    Data from murine models suggest that CD40 activation may synergize with cytotoxic chemotherapy. We aimed to determine the maximum tolerated dose (MTD) and toxicity profile and to explore immunological biomarkers of the CD40-activating antibody CP-870,893 with cisplatin and pemetrexed in patients with malignant pleural mesothelioma (MPM). Eligible patients had confirmed MPM, ECOG performance status 0-1, and measurable disease. Patients received cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 and CP-870,893 on day 8 of a 21-day cycle for maximum 6 cycles with up to 6 subsequent cycles single-agent CP-870,893. Immune cell subset changes were examined weekly by flow cytometry. Fifteen patients were treated at three dose levels. The MTD of CP-870,893 was 0.15 mg/kg, and was exceeded at 0.2 mg/kg with one grade 4 splenic infarction and one grade 3 confusion and hyponatraemia. Cytokine release syndrome (CRS) occurred in most patients (80%) following CP-870,893. Haematological toxicities were consistent with cisplatin and pemetrexed chemotherapy. Six partial responses (40%) and 9 stable disease (53%) as best response were observed. The median overall survival was 16.5 months; the median progression-free survival was 6.3 months. Three patients survived beyond 30 months. CD19+ B cells decreased over 6 cycles of chemoimmunotherapy (P CP-870,893 with cisplatin and pemetrexed is safe and tolerable at 0.15 mg/kg, although most patients experience CRS. While objective response rates are similar to chemotherapy alone, three patients achieved long-term survival. ACTRN12609000294257. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  1. 65Plus: open-label study of bevacizumab in combination with pemetrexed or pemetrexed/carboplatin as first-line treatment of patients with advanced or recurrent nonsquamous non-small-cell lung cancer

    Directory of Open Access Journals (Sweden)

    Schuette W

    2017-11-01

    Full Text Available Wolfgang Schuette,1 Claus-Peter Schneider,2,3 Walburga Engel-Riedel,4 Christian Schumann,5,6 Martin Kohlhaeufl,7 Monika Heidi Ursel Serke,8 Gert Hoeffken,9 Cornelius Kortsik,10 Martin Reck11 1Department of Internal Medicine II, Hospital Martha-Maria Halle-Doelau, Halle, 2Department of Pneumonology, Central Hospital, Bad Berka, 3Department of Internal Medicine, DRK Manniske Hospital, Bad Frankenhausen, 4Cologne Clinics, Merheim Lung Hospital, Cologne, 5Pneumonology, Department of Internal Medicine II, University Hospital Ulm, 6Clinic for Pneumology, Thoracic Oncology, Sleep, and Respiratory Critical Care, Kempten-Oberallgäu, 7Center of Pneumonology and Chest Surgery, Hospital Schillerhoehe, Gerlingen, 8Pneumonology, Lung Clinics, Hemer, 9Center of Pneumonology, Chest and Vascular Surgery, Specialty Hospital Coswig, Coswig, 10Department of Pneumonology, Catholic Hospital, Mainz, 11Department of Thoracic Oncology, Lung Clinic, Grosshansdorf, Germany Background: The aim of the study was to investigate in terms of noninferiority the efficacy and safety of a monochemotherapy regimen of pemetrexed plus bevacizumab (BevPem versus carboplatin/pemetrexed plus bevacizumab (BevCPem in elderly patients as first-line treatment for advanced metastatic or recurrent nonsquamous non-small-cell lung cancer (NSCLC.Materials and methods: 65Plus was a Phase III, randomized, open-label study. In total, 253 patients received BevPem (n=119 or BevCPem (n=134. The primary outcome measure was progression-free survival. Secondary end points were overall survival, tumor response, and safety outcomes. Evaluations were performed for the whole study population and stratified according to Eastern Cooperative Oncology Group (ECOG performance status (PS.Results: Noninferiority of BevPem in comparison to BevCPem could not be demonstrated for the overall population (P=0.7864. Significant superiority of the combined treatment BevCPem was seen in patients of ECOG PS 0–1 (median

  2. THE NATURE OF Lyα BLOBS: POWERED BY EXTREME STARBURSTS

    International Nuclear Information System (INIS)

    Cen, Renyue; Zheng, Zheng

    2013-01-01

    We present a new model for the observed Lyα blobs (LABs) within the context of the standard cold dark matter model. In this model, LABs are the most massive halos with the strongest clustering (protoclusters) undergoing extreme starbursts in the high-z universe. Aided by calculations of detailed radiative transfer of Lyα photons through ultrahigh resolution (159 pc), large-scale (≥30 Mpc) adaptive mesh refinement cosmological hydrodynamic simulations with galaxy formation, this model is shown to be able to, for the first time, reproduce simultaneously the global Lyα luminosity function and the luminosity-size relation of the observed LABs. Physically, a combination of dust attenuation of Lyα photons within galaxies, clustering of galaxies, and the complex propagation of Lyα photons through the circumgalactic and intergalactic medium gives rise to the large sizes and the irregular isophotal shapes of LABs that are frequently observed. A generic and unique prediction of this model is that there should be strong far-infrared (FIR) sources within each LAB with the most luminous FIR source likely representing the gravitational center of the protocluster, not necessarily the apparent center of the Lyα emission of the LAB or the most luminous optical source. Upcoming ALMA observations should unambiguously test this prediction. If verified, LABs will provide very valuable laboratories for studying the formation of galaxies in the most overdense regions of the universe at a time when the global star formation was the most vigorous

  3. The Nature of Lyα Blobs: Powered by Extreme Starbursts

    Science.gov (United States)

    Cen, Renyue; Zheng, Zheng

    2013-10-01

    We present a new model for the observed Lyα blobs (LABs) within the context of the standard cold dark matter model. In this model, LABs are the most massive halos with the strongest clustering (protoclusters) undergoing extreme starbursts in the high-z universe. Aided by calculations of detailed radiative transfer of Lyα photons through ultrahigh resolution (159 pc), large-scale (>=30 Mpc) adaptive mesh refinement cosmological hydrodynamic simulations with galaxy formation, this model is shown to be able to, for the first time, reproduce simultaneously the global Lyα luminosity function and the luminosity-size relation of the observed LABs. Physically, a combination of dust attenuation of Lyα photons within galaxies, clustering of galaxies, and the complex propagation of Lyα photons through the circumgalactic and intergalactic medium gives rise to the large sizes and the irregular isophotal shapes of LABs that are frequently observed. A generic and unique prediction of this model is that there should be strong far-infrared (FIR) sources within each LAB with the most luminous FIR source likely representing the gravitational center of the protocluster, not necessarily the apparent center of the Lyα emission of the LAB or the most luminous optical source. Upcoming ALMA observations should unambiguously test this prediction. If verified, LABs will provide very valuable laboratories for studying the formation of galaxies in the most overdense regions of the universe at a time when the global star formation was the most vigorous.

  4. Deep Submillimeter and Radio Observations in the SSA22 Field. I. Powering Sources and the Lyα Escape Fraction of Lyα Blobs

    Science.gov (United States)

    Ao, Y.; Matsuda, Y.; Henkel, C.; Iono, D.; Alexander, D. M.; Chapman, S. C.; Geach, J.; Hatsukade, B.; Hayes, M.; Hine, N. K.; Kato, Y.; Kawabe, R.; Kohno, K.; Kubo, M.; Lehnert, M.; Malkan, M.; Menten, K. M.; Nagao, T.; Norris, R. P.; Ouchi, M.; Saito, T.; Tamura, Y.; Taniguchi, Y.; Umehata, H.; Weiss, A.

    2017-12-01

    We study the heating mechanisms and Lyα escape fractions of 35 Lyα blobs (LABs) at z ≈ 3.1 in the SSA22 field. Dust continuum sources have been identified in 11 of the 35 LABs, all with star formation rates (SFRs) above 100 M ⊙ yr-1. Likely radio counterparts are detected in 9 out of 29 investigated LABs. The detection of submillimeter dust emission is more linked to the physical size of the Lyα emission than to the Lyα luminosities of the LABs. A radio excess in the submillimeter/radio-detected LABs is common, hinting at the presence of active galactic nuclei. Most radio sources without X-ray counterparts are located at the centers of the LABs. However, all X-ray counterparts avoid the central regions. This may be explained by absorption due to exceptionally large column densities along the line-of-sight or by LAB morphologies, which are highly orientation dependent. The median Lyα escape fraction is about 3% among the submillimeter-detected LABs, which is lower than a lower limit of 11% for the submillimeter-undetected LABs. We suspect that the large difference is due to the high dust attenuation supported by the large SFRs, the dense large-scale environment as well as large uncertainties in the extinction corrections required to apply when interpreting optical data.

  5. Probing the Intergalactic Medium with Ly α and 21 cm Fluctuations

    Energy Technology Data Exchange (ETDEWEB)

    Heneka, Caroline [Dark Cosmology Center, Niels Bohr Institute, University of Copenhagen, Juliane Maries Vej 30, DK-2100 Copenhagen (Denmark); Cooray, Asantha; Feng, Chang [Department of Physics and Astronomy, University of California, Irvine, CA 92697 (United States)

    2017-10-10

    We study 21 cm and Ly α fluctuations, as well as H α , while distinguishing between Ly α emission of galactic, diffuse, and scattered intergalactic medium (IGM) origin. Cross-correlation information about the state of the IGM is obtained, testing neutral versus ionized medium cases with different tracers in a seminumerical simulation setup. In order to pave the way toward constraints on reionization history and modeling beyond power spectrum information, we explore parameter dependencies of the cross-power signal between 21 cm and Ly α , which displays a characteristic morphology and a turnover from negative to positive correlation at scales of a couple Mpc{sup −1}. In a proof of concept for the extraction of further information on the state of the IGM using different tracers, we demonstrate the use of the 21 cm and H α cross-correlation signal to determine the relative strength of galactic and IGM emission in Ly α . We conclude by showing the detectability of the 21 cm and Ly α cross-correlation signal over more than one decade in scale at high signal-to-noise ratio for upcoming probes like SKA and the proposed all-sky intensity mapping satellites SPHEREx and CDIM, while also including the Ly α damping tail and 21 cm foreground avoidance in the modeling.

  6. ON THE REDSHIFT EVOLUTION OF THE Lyα ESCAPE FRACTION AND THE DUST CONTENT OF GALAXIES

    International Nuclear Information System (INIS)

    Hayes, Matthew; Schaerer, Daniel; Oestlin, Goeran; Mas-Hesse, J. Miguel; Atek, Hakim; Kunth, Daniel

    2011-01-01

    The Lyα emission line has been proven to be a powerful tool for studying evolving galaxies at the highest redshift. However, in order to use Lyα as a physical probe of galaxies, it becomes vital to know the Lyα escape fraction (f Lyα esc ). Unfortunately, due to the resonant nature of Lyα, f Lyα esc may vary unpredictably and requires empirical measurement. Here, we compile Lyα luminosity functions (LFs) between redshifts z = 0 and 8 and, combined with Hα and ultraviolet data, assess how f Lyα esc evolves with redshift. We find a strong upward evolution in f Lyα esc over the range z = 0.3-6, which is well fit by the power law f Lyα esc ∝(1 + z) ξ with ξ = (2.57 +0.19 -0.12 ). This predicts that f Lyα esc should reach unity at z = 11.1. By comparing f Lyα esc and E B-V in individual galaxies we derive an empirical relationship between f Lyα esc and E B-V , which includes resonance scattering and can explain the redshift evolution of f Lyα esc between z = 0 and 6 purely as a function of the evolution in the dust content of galaxies. Beyond z ∼ 6.5, f Lyα esc drops more substantially, an effect attributed to either ionizing photon leakage, or an increase in the neutral gas fraction of the intergalactic medium. While distinguishing between these two scenarios may be extremely challenging, by framing the problem this way we remove the uncertainty of the halo mass from Lyα-based tests of reionization. We finally derive a new method by which to estimate the dust content of galaxies, based purely upon the observed Lyα and UV LFs. These data are characterized by an exponential with an e-folding scale of z EBV ∼ 3.4.

  7. A Faint Flux-limited Ly α Emitter Sample at z ∼ 0.3

    Energy Technology Data Exchange (ETDEWEB)

    Wold, Isak G. B.; Finkelstein, Steven L. [Department of Astronomy, The University of Texas at Austin, 2515 Speedway, Stop C1400, Austin, TX 78712 (United States); Barger, Amy J.; Rosenwasser, Benjamin [Department of Astronomy, University of Wisconsin-Madison, 475 North Charter Street, Madison, WI 53706 (United States); Cowie, Lennox L., E-mail: wold@astro.as.utexas.edu [Institute for Astronomy, University of Hawaii, 2680 Woodlawn Drive, Honolulu, HI 96822 (United States)

    2017-10-20

    We present a flux-limited sample of z ∼ 0.3 Ly α emitters (LAEs) from Galaxy Evolution Explorer ( GALEX ) grism spectroscopic data. The published GALEX z ∼ 0.3 LAE sample is pre-selected from continuum-bright objects and thus is biased against high equivalent width (EW) LAEs. We remove this continuum pre-selection and compute the EW distribution and the luminosity function of the Ly α emission line directly from our sample. We examine the evolution of these quantities from z ∼ 0.3 to 2.2 and find that the EW distribution shows little evidence for evolution over this redshift range. As shown by previous studies, the Ly α luminosity density from star-forming (SF) galaxies declines rapidly with declining redshift. However, we find that the decline in Ly α luminosity density from z = 2.2 to z = 0.3 may simply mirror the decline seen in the H α luminosity density from z = 2.2 to z = 0.4, implying little change in the volumetric Ly α escape fraction. Finally, we show that the observed Ly α luminosity density from AGNs is comparable to the observed Ly α luminosity density from SF galaxies at z = 0.3. We suggest that this significant contribution from AGNs to the total observed Ly α luminosity density persists out to z ∼ 2.2.

  8. The properties of the brightest Lyα emitters at z=5.7

    Science.gov (United States)

    Lidman, C.; Hayes, M.; Jones, D. H.; Schaerer, D.; Westra, E.; Tapken, C.; Meisenheimer, K.; Verhamme, A.

    2012-03-01

    We use deep Very Large Telescope (VLT) optical and near-infrared spectroscopy and deep Spitzer/IRAC imaging to examine the properties of two of the most luminous Lyα emitters at z= 5.7. The continuum redward of the Lyα line is clearly detected in both objects, thus facilitating a relatively accurate measurement (10-20 per cent uncertainties) of the observed rest-frame equivalent widths, which are around 160 Å for both objects. Through detailed modelling of the profile of the Lyα line with a 3D Monte Carlo radiative transfer code, we estimate the intrinsic rest-frame equivalent width of Lyα and find values that are around 300 Å, which is at the upper end of the range allowed for very young, moderately metal-poor star-forming galaxies. However, the uncertainties are large and values as high as 700 Å are permitted by the data. Both Lyα emitters are detected at 3.6 ?m in deep images taken with the Spitzer Space Telescope. We use these measurements, the measurement of the continuum redward of Lyα and other photometry to constrain the spectral energy distributions of these very luminous Lyα emitters and to compare them with three similar Lyα emitters from the literature. The contribution from nebular emission is included in our models: excluding it results in significantly higher masses. Four of the five Lyα emitters have masses of the order of ˜109 M⊙ and fairly high specific star formation rates (≳10-100 Gyr-1). While our two Lyα emitters appear similar in terms of the observed Lyα rest-frame equivalent width, they are quite distinct from each other in terms of age, mass and star formation history. Evidence for dust is found in all objects, and emission from nebular lines often makes a dominant contribution to the rest-frame 3.6 ?m flux. Rich in emission lines, these objects are prime targets for the next generation of extremely large telescopes, the James Webb Space Telescope (JWST) and the Atacama Large Millimeter Array (ALMA). a Initial 2σ lower

  9. For-LySa: UML for Authentication Analysis

    DEFF Research Database (Denmark)

    Buchholtz, Mikael; Montangero, Carlo; Perrone, Lara

    2005-01-01

    The DEGAS project aims at enriching standard UML-centred development environments in such a way that the developers of global applications can exploit automated formal analyses with minimal overhead. In this paper, we present For-LySa, an instantiation of the DEGAS approach for authentication...... analysis, which exploits an existing analysis tool developed for the process calculus LySa. We discuss what information is needed for the analysis, and how to build the UML model of an authentication protocol in such a way that the needed information can be extracted from the model. We then present our...

  10. The Lyα reference sample. I. Survey outline and first results for Markarian 259

    International Nuclear Information System (INIS)

    Östlin, Göran; Hayes, Matthew; Duval, Florent; Sandberg, Andreas; Rivera-Thorsen, Thøger; Marquart, Thomas; Adamo, Angela; Melinder, Jens; Guaita, Lucia; Micheva, Genoveva; Orlitová, Ivana; Atek, Hakim; Cannon, John M.; Pardy, Stephen A.; Gruyters, Pieter; Herenz, Edmund Christian; Kunth, Daniel; Laursen, Peter; Mas-Hesse, J. Miguel; Otí-Floranes, Héctor

    2014-01-01

    The Lyα Reference Sample (LARS) is a substantial program with the Hubble Space Telescope (HST) that provides a sample of local universe laboratory galaxies in which to study the detailed astrophysics of the visibility and strength of the Lyαline of neutral hydrogen. Lyα is the dominant spectral line in use for characterizing high-redshift (z) galaxies. This paper presents an overview of the survey, its selection function, and HST imaging observations. The sample was selected from the combined GALEX+Sloan Digital Sky Survey catalog at z = 0.028-0.19, in order to allow Lyα to be captured with combinations of long-pass filters in the Solar Blind Channel (SBC) of the Advanced Camera for Surveys (ACS) onboard HST. In addition, LARS utilizes Hα and Hβ narrowband and u, b, i broadband imaging with ACS and the Wide Field Camera 3 (WFC3). In order to study galaxies in which large numbers of Lyα photons are produced (whether or not they escape), we demanded an Hα equivalent width W(Hα) ≥100 Å. The final sample of 14 galaxies covers far-UV (FUV, λ ∼ 1500 Å) luminosities that overlap with those of high-z Lyα emitters (LAEs) and Lyman break galaxies (LBGs), making LARS a valid comparison sample. We present the reduction steps used to obtain the Lyα images, including our LARS eXtraction software (LaXs), which utilizes pixel-by-pixel spectral synthesis fitting of the energy distribution to determine and subtract the continuum at Lyα. We demonstrate that the use of SBC long-pass-filter combinations increase the signal-to-noise ratio by an order of magnitude compared to the nominal Lyα filter available in SBC. To exemplify the science potential of LARS, we also present some first results for a single galaxy, Mrk 259 (LARS #1). This irregular galaxy shows bright and extended (indicative of resonance scattering) but strongly asymmetric Lyα emission. Spectroscopy from the Cosmic Origins Spectrograph on board HST centered on the brightest UV knot shows a moderate

  11. The Lyα reference sample. I. Survey outline and first results for Markarian 259

    Energy Technology Data Exchange (ETDEWEB)

    Östlin, Göran; Hayes, Matthew; Duval, Florent; Sandberg, Andreas; Rivera-Thorsen, Thøger; Marquart, Thomas; Adamo, Angela; Melinder, Jens; Guaita, Lucia; Micheva, Genoveva [Department of Astronomy, Stockholm University, Oscar Klein Centre, AlbaNova, Stockholm SE-106 91 (Sweden); Orlitová, Ivana [Observatoire de Genève, Université de Genève, Chemin des Maillettes 51, 1290 Versoix (Switzerland); Atek, Hakim [Laboratoire d' Astrophysique, Ecole Polytechnique Fédérale de Lausanne, Observatoire de Sauverny, CH-1290 Versoix (Switzerland); Cannon, John M.; Pardy, Stephen A. [Department of Physics and Astronomy, Macalester College, 1600 Grand Avenue, Saint Paul, MN 55105 (United States); Gruyters, Pieter [Department of Physics and Astronomy, Division of Astronomy and Space Physics, Uppsala University, Box 516, 75120 Uppsala (Sweden); Herenz, Edmund Christian [Leibniz-Institute for Astrophysics Potsdam (AIP), innoFSPEC, An der Sternwarte 16, D-14482 Potsdam (Germany); Kunth, Daniel [Institut d' Astrophysique Paris, 98bis Bd Arago, F-75014 Paris (France); Laursen, Peter [Dark Cosmology Centre, Niels Bohr Institute, University of Copenhagen, DK-2100 Copenhagen (Denmark); Mas-Hesse, J. Miguel [Centro de Astrobiologa (CSIC-INTA), Departamento de Astrofsica, POB 78, E-28691, Villanueva de la Cañada (Spain); Otí-Floranes, Héctor [Instituto de Astronoma, Universidad Nacional Autnoma de Mxico, Apdo. Postal 106, Ensenada B. C. 22800 (Mexico); and others

    2014-12-10

    The Lyα Reference Sample (LARS) is a substantial program with the Hubble Space Telescope (HST) that provides a sample of local universe laboratory galaxies in which to study the detailed astrophysics of the visibility and strength of the Lyαline of neutral hydrogen. Lyα is the dominant spectral line in use for characterizing high-redshift (z) galaxies. This paper presents an overview of the survey, its selection function, and HST imaging observations. The sample was selected from the combined GALEX+Sloan Digital Sky Survey catalog at z = 0.028-0.19, in order to allow Lyα to be captured with combinations of long-pass filters in the Solar Blind Channel (SBC) of the Advanced Camera for Surveys (ACS) onboard HST. In addition, LARS utilizes Hα and Hβ narrowband and u, b, i broadband imaging with ACS and the Wide Field Camera 3 (WFC3). In order to study galaxies in which large numbers of Lyα photons are produced (whether or not they escape), we demanded an Hα equivalent width W(Hα) ≥100 Å. The final sample of 14 galaxies covers far-UV (FUV, λ ∼ 1500 Å) luminosities that overlap with those of high-z Lyα emitters (LAEs) and Lyman break galaxies (LBGs), making LARS a valid comparison sample. We present the reduction steps used to obtain the Lyα images, including our LARS eXtraction software (LaXs), which utilizes pixel-by-pixel spectral synthesis fitting of the energy distribution to determine and subtract the continuum at Lyα. We demonstrate that the use of SBC long-pass-filter combinations increase the signal-to-noise ratio by an order of magnitude compared to the nominal Lyα filter available in SBC. To exemplify the science potential of LARS, we also present some first results for a single galaxy, Mrk 259 (LARS #1). This irregular galaxy shows bright and extended (indicative of resonance scattering) but strongly asymmetric Lyα emission. Spectroscopy from the Cosmic Origins Spectrograph on board HST centered on the brightest UV knot shows a moderate

  12. Synthesis of multidrug resistance modulator LY335979 labeled with deuterium and tritium

    International Nuclear Information System (INIS)

    Czeskis, B.A.

    1997-01-01

    DIDEUTERO AND DITRITIOISOTOPOMERS OF THE MULTIDRUG RESISTANCE MODULATOR LY335979 WERE PREPARED BY INITIAL BROMINATION OF 5-HYDROXYQUINOLINE UNDER ACIDIC CONDITIONS FOLLOWED BY MITSUNOBU COUPLING OF 6,8-DIBROMO-5-HYDROXYQUINOLINE WITH (S)-GLYCIDOL. OPENING OF THE RESULTING EPOXIDE WITH DIBENZOSUBERYLPIPERAZINE LY335995 RESULTED IN DIBROMOANALOG OF LY335979, WHICH WAS FINALLY REDUCTIVELY DEBROMINATED WITH DEUTERIUM OR TRITIUM IN THE PRESENCE OF PALLADIUM ON CARBON. (AUTHOR)

  13. Ly6G-mediated depletion of neutrophils is dependent on macrophages.

    Science.gov (United States)

    Bruhn, Kevin W; Dekitani, Ken; Nielsen, Travis B; Pantapalangkoor, Paul; Spellberg, Brad

    2016-01-01

    Antibody-mediated depletion of neutrophils is commonly used to study neutropenia. However, the mechanisms by which antibodies deplete neutrophils have not been well defined. We noticed that mice deficient in complement and macrophages had blunted neutrophil depletion in response to anti-Ly6G monoclonal antibody (MAb) treatment. In vitro, exposure of murine neutrophils to anti-Ly6G MAb in the presence of plasma did not result in significant depletion of cells, either in the presence or absence of complement. In vivo, anti-Ly6G-mediated neutrophil depletion was abrogated following macrophage depletion, but not complement depletion, indicating a requirement for macrophages to induce neutropenia by this method. These results inform the use and limitations of anti-Ly6G antibody as an experimental tool for depleting neutrophils in various immunological settings.

  14. POLARIZED EXTENDED Ly{alpha} EMISSION FROM A z = 2.3 RADIO GALAXY

    Energy Technology Data Exchange (ETDEWEB)

    Humphrey, A. [Centro de Astrofisica da Universidade do Porto, Rua das Estrelas, 4150-762 Porto (Portugal); Vernet, J.; Fosbury, R. A. E. [European Southern Observatory, Karl-Schwarzschild-Strasse 2, D-85748 Garching (Germany); Villar-Martin, M. [Centro de Astrobiologia (INTA-CSIC), Carretera de Ajalvir, km 4, E-28850 Torrejon de Ardoz, Madrid (Spain); Di Serego Alighieri, S. [INAF-Osservatorio Astrofisico di Arcetri, L.go E. Fermi 5, I-50125 Firenze (Italy); Cimatti, A., E-mail: andrew.humphrey@astro.up.pt [Dipartimento di Astronomia, Universita di Bologna, Via Ranzani 1, I-40127 Bologna (Italy)

    2013-05-01

    We present spatially resolved spectropolarimetric measurements of the 100 kpc scale gaseous environment of the z = 2.34 radio galaxy TXS 0211-122. The polarization level of the narrow Ly{alpha} emission is low centrally (P < 5%), but rises to P = 16.4% {+-} 4.6% in the eastern part of the nebula, indicating that the nebula is at least partly powered by the scattering of Ly{alpha} photons by H I. Not only is this the first detection of polarized Ly{alpha} around a radio-loud active galaxy, it is also the second detection to date for any kind of Ly{alpha} nebula. We also detect a pair of diametrically opposed UV continuum sources along the slit, at the outer edges of the Ly{alpha} nebula, which we suggest may be the limb of a dusty shell, related to the large-scale H I absorbers often associated with high-z radio galaxies.

  15. MAPPING THE POLARIZATION OF THE RADIO-LOUD Ly α NEBULA B3 J2330+3927

    International Nuclear Information System (INIS)

    You, Chang; Zabludoff, Ann; Smith, Paul; Jannuzi, Buell; Yang, Yujin; Kim, Eunchong; Lee, Myung Gyoon; Prescott, Moire K. M.; Matsuda, Yuichi

    2017-01-01

    Ly α nebulae, or “Ly α blobs,” are extended (up to ∼100 kpc), bright (L Lyα  ≳ 10 43 erg s −1 ) clouds of Ly α emitting gas that tend to lie in overdense regions at z  ∼ 2–5. The origin of the Ly α emission remains unknown, but recent theoretical work suggests that measuring the polarization might discriminate among powering mechanisms. Here we present the first narrowband imaging polarimetry of a radio-loud Ly α nebula, B3 J2330+3927, at z = 3.09, with an embedded active galactic nucleus (AGN). The AGN lies near the blob’s Ly α emission peak, and its radio lobes align roughly with the blob’s major axis. With the SPOL polarimeter on the 6.5 m MMT telescope, we map the total (Ly α + continuum) polarization in a grid of circular apertures of a radius of 0.″6 (4.4 kpc), detecting a significant (>2 σ ) polarization fraction P % in nine apertures and achieving strong upper limits (as low as 2%) elsewhere. P % increases from <2% at ∼5 kpc from the blob center to 17% at ∼15–25 kpc. The detections are distributed asymmetrically, roughly along the nebula’s major axis. The polarization angles θ are mostly perpendicular to this axis. Comparing the Ly α flux to that of the continuum and conservatively assuming that the continuum is highly polarized (20%–100%) and aligned with the total polarization, we place lower limits on the polarization of the Ly α emission P %,Lyα ranging from no significant polarization at ∼5 kpc from the blob center to 3%–17% at 10–25 kpc. Like the total polarization, the Ly α polarization detections occur more often along the blob’s major axis.

  16. Pemetrexed single agent chemotherapy in previously treated patients with locally advanced or metastatic non-small cell lung cancer

    International Nuclear Information System (INIS)

    Russo, Francesca; Bearz, Alessandra; Pampaloni, Gianni; The investigators of the Italian Pemetrexed monotherapy of NSCLC group

    2008-01-01

    The main objective of this study was to evaluate the safety of second-line pemetrexed in Stage IIIB or IV NSCLC. Overall, 95 patients received pemetrexed 500 mg/m 2 i.v. over Day 1 of a 21-day cycle. Patients also received oral dexamethasone, oral folic acid and i.m. vitamin B12 supplementation to reduce toxicity. NCI CTC 2.0 was used to rate toxicity. All the adverse events were graded in terms of severity and relation to study treatment. Dose was reduced in case of toxicity and treatment was delayed for up to 42 days from Day 1 of any cycle to allow recovering from study drug-related toxicities. Tumor response was measured using the RECIST criteria. Patients received a median number of 4 cycles and 97.8% of the planned dose. Overall, 75 patients (78.9% of treated) reported at least one adverse event: 34 (35.8%) had grade 3 as worst grade and only 5 (5.2%) had grade 4. Drug-related events occurred in 57.9% of patients. Neutropenia (8.4%) and leukopenia (6.3 %) were the most common grade 3/4 hematological toxicities. Grade 3 anemia and thrombocytopenia were reported in 3.2% and 2.1% of patients, respectively. Diarrhea (6.3%), fatigue (3.2%) and dyspnea (3.2%) were the most common grade 3/4 non-hematological toxicities. The most common drug-related toxicities (any grade) were pyrexia (11.6%), vomiting, nausea, diarrhea and asthenia (9.5%) and fatigue (8.4%). Tumor Response Rate (CR/PR) in treated patients was 9.2%. The survival at 4.5 months (median follow-up) was 79% and the median PFS was 3.1 months. Twenty patients (21.1%) died mainly because of disease progression. Patients with locally advanced or metastatic NSCLC could benefit from second-line pemetrexed, with a low incidence of hematological and non-hematological toxicities

  17. 64Cu-Labeled LyP-1-Dendrimer for PET-CT Imaging of Atherosclerotic Plaque

    Science.gov (United States)

    2015-01-01

    The ability to detect and quantify macrophage accumulation can provide important diagnostic and prognostic information for atherosclerotic plaque. We have previously shown that LyP-1, a cyclic 9-amino acid peptide, binds to p32 proteins on activated macrophages, facilitating the visualization of atherosclerotic plaque with PET. Yet, the in vivo plaque accumulation of monomeric [18F]FBA-LyP-1 was low (0.31 ± 0.05%ID/g). To increase the avidity of LyP-1 constructs to p32, we synthesized a dendritic form of LyP-1 on solid phase using lysine as the core structural element. Imaging probes (FAM or 6-BAT) were conjugated to a lysine or cysteine on the dendrimer for optical and PET studies. The N-terminus of the dendrimer was further modified with an aminooxy group in order to conjugate LyP-1 and ARAL peptides bearing a ketone. Oxime ligation of peptides to both dendrimers resulted in (LyP-1)4- and (ARAL)4-dendrimers with optical (FAM) and PET probes (6-BAT). For PET-CT studies, (LyP-1)4- and (ARAL)4-dendrimer-6-BAT were labeled with 64Cu (t1/2 = 12.7 h) and intravenously injected into the atherosclerotic (ApoE–/–) mice. After two hours of circulation, PET-CT coregistered images demonstrated greater uptake of the (LyP-1)4-dendrimer-64Cu than the (ARAL)4-dendrimer-64Cu in the aortic root and descending aorta. Ex vivo images and the biodistribution acquired at three hours after injection also demonstrated a significantly higher uptake of the (LyP-1)4-dendrimer-64Cu (1.1 ± 0.26%ID/g) than the (ARAL)4-dendrimer-64Cu (0.22 ± 0.05%ID/g) in the aorta. Similarly, subcutaneous injection of the LyP-1-dendrimeric carriers resulted in preferential accumulation in plaque-containing regions over 24 h. In the same model system, ex vivo fluorescence images within aortic plaque depict an increased accumulation and penetration of the (LyP-1)4-dendrimer-FAM as compared to the (ARAL)4-dendrimer-FAM. Taken together, the results suggest that the (LyP-1)4-dendrimer can be applied for in

  18. Comparative study analyzing survival and safety of bevacizumab/carboplatin/paclitaxel and cisplatin/pemetrexed in chemotherapy-naïve patients with advanced non-squamous bronchogenic carcinoma not harboring EGFR mutation

    Directory of Open Access Journals (Sweden)

    Abdel Kader Y

    2013-07-01

    Full Text Available Yasser Abdel Kader,1 Thierry Le Chevalier,2 Tamer El-Nahas,1 Amr Sakr11Department of Clinical Oncology, Cairo University, Cairo, Egypt; 2Department of Medical Oncology, Institut Gustave Roussy, Villejuif, Paris, FrancePurpose: The majority of Egyptian patients with lung cancer present at a late stage of the disease. Bevacizumab/carboplatin/paclitaxel, as well as cisplatin plus pemetrexed, are both standard regimens for advanced non-squamous bronchogenic cancer. This study compares both regimens, in terms of efficacy and toxicity profile, in Egyptian patients.Patients and methods: This is a randomized Phase II study comparing toxicity profile and survival in 41 chemotherapy-naïve patients with stage IIIB or IV non-squamous NSCLC, with an ECOG performance status of 0 to 2. The epidermal growth factor receptor (EGFR mutation detection was performed prior to treatment of all patients. Patients in the first group received: bevacizumab 7.5 mg/m2 on Day 1 and Day 15; carboplatin area under the curve-5 on Day 1; and paclitaxel 60 mg/m2 on Day 1, Day 8, and Day 15 every 4 weeks. In the second group, patients received cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 every 3 weeks.Results: The combination of bevacizumab/carboplatin/paclitaxel demonstrated higher Grade III–IV toxicity than cisplatin/pemetrexed regarding sensory/motor neuropathy (P = 0.06, DVT (P = 0.23, proteinuria (P = 0.23, and hypertension (P = 0.11, as well as Grade II alopecia (P = 0.001; however, no significant difference in toxicities between both arms was recorded regarding nausea and vomiting (P = 0.66, hematological toxicity, febrile neutropenia (P = 1 and fatigue (P = 0.66. Progression-free survival was similar for both treatment arms with a median of 6 months (P = 0.978. Overall median survival was comparable in both arms, 16.07 months versus 16.01 months (P = 0.89.Conclusion: Bevacizumab/carboplatin/paclitaxel and cisplatin/pemetrexed provided meaningful and comparable efficacy

  19. Unlocking the Full Potential of Extragalactic Lyα through Its Polarization Properties

    Science.gov (United States)

    Eide, Marius B.; Gronke, Max; Dijkstra, Mark; Hayes, Matthew

    2018-04-01

    Lyα is a powerful astrophysical probe. Not only is it ubiquitous at high redshifts, it is also a resonant line, making Lyα photons scatter. This scattering process depends on the physical conditions of the gas through which Lyα propagates, and these conditions are imprinted on observables such as the Lyα spectrum and its surface brightness profile. In this work, we focus on a less-used observable capable of probing any scattering process: polarization. We implement the density matrix formalism of polarization into the Monte Carlo radiative transfer code tlac. This allows us to treat it as a quantum mechanical process where single photons develop and lose polarization from scatterings in arbitrary gas geometries. We explore static and expanding ellipsoids, biconical outflows, and clumpy multiphase media. We find that photons become increasingly polarized as they scatter and diffuse into the wings of the line profiles, making scattered Lyα polarized in general. The degree and orientation of Lyα polarization depends on the kinematics and distribution of the scattering H I gas. We find that it generally probes spatial or velocity space asymmetries and aligns itself tangentially to the emission source. We show that the mentioned observables, when studied separately, can leave similar signatures for different source models. We conclude by revealing how a joint analysis of the Lyα spectra, surface brightness profiles, and polarization can break these degeneracies and help us extract unique physical information on galaxies and their environments from their strongest, most prominent emission line.

  20. MAPPING THE POLARIZATION OF THE RADIO-LOUD Ly α NEBULA B3 J2330+3927

    Energy Technology Data Exchange (ETDEWEB)

    You, Chang; Zabludoff, Ann; Smith, Paul; Jannuzi, Buell [Steward Observatory, University of Arizona, 933 N Cherry Avenue, Tucson, AZ 85721 (United States); Yang, Yujin [Korea Astronomy and Space Science Institute, 776 Daedeokdae-ro, Yuseong-gu, Daejeon 34055 (Korea, Republic of); Kim, Eunchong; Lee, Myung Gyoon [Department of Physics and Astronomy, Seoul National University, Gwanak-gu, Seoul 88226 (Korea, Republic of); Prescott, Moire K. M. [Department of Astronomy, New Mexico State University, 1320 Frenger Mall, Las Cruces, NM 88003 (United States); Matsuda, Yuichi, E-mail: yyang@kasi.re.kr [National Astronomical Observatory of Japan, National Institutes of Natural Sciences, 2-21-1 Osawa, Mitaka, Tokyo 181-8588 (Japan)

    2017-01-10

    Ly α nebulae, or “Ly α blobs,” are extended (up to ∼100 kpc), bright (L{sub Lyα}  ≳ 10{sup 43} erg s{sup −1}) clouds of Ly α emitting gas that tend to lie in overdense regions at z  ∼ 2–5. The origin of the Ly α emission remains unknown, but recent theoretical work suggests that measuring the polarization might discriminate among powering mechanisms. Here we present the first narrowband imaging polarimetry of a radio-loud Ly α nebula, B3 J2330+3927, at z = 3.09, with an embedded active galactic nucleus (AGN). The AGN lies near the blob’s Ly α emission peak, and its radio lobes align roughly with the blob’s major axis. With the SPOL polarimeter on the 6.5 m MMT telescope, we map the total (Ly α + continuum) polarization in a grid of circular apertures of a radius of 0.″6 (4.4 kpc), detecting a significant (>2 σ ) polarization fraction P {sub %} in nine apertures and achieving strong upper limits (as low as 2%) elsewhere. P{sub %} increases from <2% at ∼5 kpc from the blob center to 17% at ∼15–25 kpc. The detections are distributed asymmetrically, roughly along the nebula’s major axis. The polarization angles θ are mostly perpendicular to this axis. Comparing the Ly α flux to that of the continuum and conservatively assuming that the continuum is highly polarized (20%–100%) and aligned with the total polarization, we place lower limits on the polarization of the Ly α emission P{sub %,Lyα} ranging from no significant polarization at ∼5 kpc from the blob center to 3%–17% at 10–25 kpc. Like the total polarization, the Ly α polarization detections occur more often along the blob’s major axis.

  1. Pharmacokinetics and pharmacodynamics of the cathepsin S inhibitor, LY3000328, in healthy subjects.

    Science.gov (United States)

    Payne, Christopher D; Deeg, Mark A; Chan, Melanie; Tan, Lai Hock; LaBell, Elizabeth Smith; Shen, Tong; DeBrota, David J

    2014-12-01

    The aim of this study was to assess the safety and tolerability, pharmacokinetics and pharmacodynamics of LY3000328 when administered as single escalating doses to healthy volunteers. This was a phase 1, placebo-controlled, dose escalation study with LY3000328 in 21 healthy male volunteers. Subjects were administered escalating LY3000328 doses up to 300 mg with food in this single dose study. Blood samples were collected at set times post-dose for the assessment of LY3000328 pharmacokinetics and the measurement of cathepsin S (CatS) activity, CatS mass and calculated CatS specific activity. All doses of LY3000328 were well tolerated, with linear pharmacokinetics up to the 300 mg dose. The pharmacodynamic activity of LY3000328 was measured ex vivo showing a biphasic response to LY3000328, where CatS activity declines, then returns to baseline, and then increases to a level above baseline. CatS mass was also assessed post-dose which increased in a dose-dependent manner, and continued to increase after LY3000328 had been cleared from the body. CatS specific activity was additionally calculated to normalize CatS activity for changes in CatS mass. This demonstrated the increase in CatS activity was attributable to the increase in CatS mass detected in plasma. A specific inhibitor of CatS which is cleared quickly from plasma may produce a transient decrease in plasma CatS activity which is followed by a more prolonged increase in plasma CatS mass which may have implications for the future clinical development of inhibitors of CatS. © 2014 The British Pharmacological Society.

  2. A Faint Flux-limited Lyα Emitter Sample at z ˜ 0.3

    Science.gov (United States)

    Wold, Isak G. B.; Finkelstein, Steven L.; Barger, Amy J.; Cowie, Lennox L.; Rosenwasser, Benjamin

    2017-10-01

    We present a flux-limited sample of z ˜ 0.3 Lyα emitters (LAEs) from Galaxy Evolution Explorer (GALEX) grism spectroscopic data. The published GALEX z ˜ 0.3 LAE sample is pre-selected from continuum-bright objects and thus is biased against high equivalent width (EW) LAEs. We remove this continuum pre-selection and compute the EW distribution and the luminosity function of the Lyα emission line directly from our sample. We examine the evolution of these quantities from z ˜ 0.3 to 2.2 and find that the EW distribution shows little evidence for evolution over this redshift range. As shown by previous studies, the Lyα luminosity density from star-forming (SF) galaxies declines rapidly with declining redshift. However, we find that the decline in Lyα luminosity density from z = 2.2 to z = 0.3 may simply mirror the decline seen in the Hα luminosity density from z = 2.2 to z = 0.4, implying little change in the volumetric Lyα escape fraction. Finally, we show that the observed Lyα luminosity density from AGNs is comparable to the observed Lyα luminosity density from SF galaxies at z = 0.3. We suggest that this significant contribution from AGNs to the total observed Lyα luminosity density persists out to z ˜ 2.2. Some of the data presented herein were obtained at the W.M. Keck Observatory, which is operated as a scientific partnership among the California Institute of Technology, the University of California, and the National Aeronautics and Space Administration. The Observatory was made possible by the generous financial support of the W.M. Keck Foundation.

  3. THE REST-FRAME OPTICAL SPECTROSCOPIC PROPERTIES OF LY α -EMITTERS AT z  ∼ 2.5: THE PHYSICAL ORIGINS OF STRONG LY α EMISSION

    Energy Technology Data Exchange (ETDEWEB)

    Trainor, Ryan F. [Department of Astronomy, University of California, Berkeley, 501 Campbell Hall, Berkeley, CA 94720 (United States); Strom, Allison L.; Steidel, Charles C. [Cahill Center for Astrophysics, MC 249-17, 1200 E California Boulevard, Pasadena, CA 91125 (United States); Rudie, Gwen C., E-mail: trainor@berkeley.edu [Carnegie Observatories, 813 Santa Barbara Street, Pasadena, CA 91101 (United States)

    2016-12-01

    We present the rest-frame optical spectroscopic properties of 60 faint ( R {sub AB} ∼ 27; L ∼ 0.1 L {sub *}) Ly α -selected galaxies (LAEs) at z  ≈ 2.56. These LAEs also have rest-UV spectra of their Ly α emission line morphologies, which trace the effects of interstellar and circumgalactic gas on the escape of Ly α photons. We find that the LAEs have diverse rest-optical spectra, but their average spectroscopic properties are broadly consistent with the extreme low-metallicity end of the populations of continuum-selected galaxies selected at z  ≈ 2–3. In particular, the LAEs have extremely high [O iii] λ 5008/H β ratios (log([O iii]/H β ) ∼ 0.8) and low [N ii] λ 6585/H α ratios (log([N ii]/H α ) < 1.15). Coupled with a detection of the [O iii] λ 4364 auroral line, these measurements indicate that the star-forming regions in faint LAEs are characterized by high electron temperatures (T{sub e} ≈ 1.8 × 10{sup 4} K), low oxygen abundances (12 + log(O/H) ≈ 8.04, Z{sub neb} ≈ 0.22 Z {sub ⊙}), and high excitations with respect to their more luminous continuum-selected analogs. Several of our faintest LAEs have line ratios consistent with even lower metallicities, including six with 12 + log(O/H) ≈ 6.9–7.4 (Z {sub neb} ≈ 0.02–0.05 Z{sub ⊙}). We interpret these observations in light of new models of stellar evolution (including binary interactions) that have been shown to produce long-lived populations of hot, massive stars at low metallicities. We find that strong, hard ionizing continua are required to reproduce our observed line ratios, suggesting that faint galaxies are efficient producers of ionizing photons and important analogs of reionization-era galaxies. Furthermore, we investigate the physical trends accompanying Ly α emission across the largest current sample of combined Ly α and rest-optical galaxy spectroscopy, including both the 60 KBSS-Ly α LAEs and 368 more luminous galaxies at similar redshifts. We

  4. Human IgG1 Responses to Surface Localised Schistosoma mansoni Ly6 Family Members Drop following Praziquantel Treatment.

    Directory of Open Access Journals (Sweden)

    Iain W Chalmers

    Full Text Available The heptalaminate-covered, syncytial tegument is an important anatomical adaptation that enables schistosome parasites to maintain long-term, intravascular residence in definitive hosts. Investigation of the proteins present in this surface layer and the immune responses elicited by them during infection is crucial to our understanding of host/parasite interactions. Recent studies have revealed a number of novel tegumental surface proteins including three (SmCD59a, SmCD59b and Sm29 containing uPAR/Ly6 domains (renamed SmLy6A SmLy6B and SmLy6D in this study. While vaccination with SmLy6A (SmCD59a and SmLy6D (Sm29 induces protective immunity in experimental models, human immunoglobulin responses to representative SmLy6 family members have yet to be thoroughly explored.Using a PSI-BLAST-based search, we present a comprehensive reanalysis of the Schistosoma mansoni Ly6 family (SmLy6A-K. Our examination extends the number of members to eleven (including three novel proteins and provides strong evidence that the previously identified vaccine candidate Sm29 (renamed SmLy6D is a unique double uPAR/Ly6 domain-containing representative. Presence of canonical cysteine residues, signal peptides and GPI-anchor sites strongly suggest that all SmLy6 proteins are cell surface-bound. To provide evidence that SmLy6 members are immunogenic in human populations, we report IgG1 (as well as IgG4 and IgE responses against two surface-bound representatives (SmLy6A and SmLy6B within a cohort of S. mansoni-infected Ugandan males before and after praziquantel treatment. While pre-treatment IgG1 prevalence for SmLy6A and SmLy6B differs amongst the studied population (7.4% and 25.3% of the cohort, respectively, these values are both higher than IgG1 prevalence (2.7% for a sub-surface tegumental antigen, SmTAL1. Further, post-treatment IgG1 levels against surface-associated SmLy6A and SmLy6B significantly drop (p = 0.020 and p < 0.001, respectively when compared to rising Ig

  5. Home administration of maintenance pemetrexed for patients with advanced non-squamous non-small cell lung cancer: rationale, practicalities and phase II feasibility study design.

    Science.gov (United States)

    Lal, Rohit; Bourayou, Nawel; Hillerdal, Gunnar; Nicolson, Marianne; Vikstrom, Anders; Lorenzo, Maria; D'yachkova, Yulia; Barriga, Susana; Visseren-Grul, Carla

    2013-10-03

    Home-based care in oncology is mainly reserved for patients at the end of life. Regulations regarding home delivery of cytotoxics differ across Europe, with a notable lack of practice guidelines in most countries. This has led to a lack of data addressing the feasibility of home-based administration of cytotoxic chemotherapy. In advanced non-squamous non-small cell lung cancer, pemetrexed is approved as maintenance therapy after first-line chemotherapy. In this setting, patients have the potential to be treated long-term with maintenance therapy, which, in the absence of unacceptable toxicity, is continued until disease progression. The favourable safety profile of pemetrexed and the ease of its administration by 10-minute intravenous infusion every 3 weeks make this drug a suitable candidate for administration in a home setting. Literature and regulations relevant to the home-based delivery of cytotoxic therapy were reviewed, and a phase II feasibility study of home administration of pemetrexed maintenance therapy was designed. At least 50 patients with advanced non-squamous non-small cell lung cancer, Eastern Cooperative Oncology Group performance status 0-1 and no progressive disease after four cycles of platinum-based first-line therapy are required to allow investigation of the feasibility of home-based administration of pemetrexed maintenance therapy (500 mg/m(2) every 3 weeks until progressive disease or unacceptable toxicity). Feasibility is being assessed as adherence to the home-based administration process (primary endpoint), patient safety, impact on patients' quality of life, patient and physician satisfaction with home care, and healthcare resource use and costs. Enrolment of patients from the UK and Sweden, where home-based care is relatively well developed, commenced in December 2011. This feasibility study addresses an important aspect of maintenance therapy, that is, patient comfort during protracted home-based chemotherapy. The study design

  6. The Diversity of Diffuse Ly α Nebulae around Star-forming Galaxies at High Redshift

    Energy Technology Data Exchange (ETDEWEB)

    Xue, Rui; Lee, Kyoung-Soo [Department of Physics and Astronomy, Purdue University, 525 Northwestern Avenue, West Lafayette, IN 47907 (United States); Dey, Arjun; Inami, Hanae [National Optical Astronomy Observatory, 950 N. Cherry Avenue, Tucson, AZ 85719 (United States); Reddy, Naveen [Department of Physics and Astronomy, University of California, Riverside, 900 University Avenue, Riverside, CA 92521 (United States); Hong, Sungryong [Department of Astronomy, University of Texas at Austin, 2515 Speedway, Stop C1400, Austin, TX 78712 (United States); Prescott, Moire K. M. [Department of Astronomy, New Mexico State University, P.O. Box 30001, Las Cruces, NM 88001 (United States); Jannuzi, Buell T. [Steward Observatory, University of Arizona, 933 N Cherry Avenue, Tucson, AZ 85721 (United States); Gonzalez, Anthony H. [Department of Astronomy, University of Florida, 211 Bryant Space Science Center, Gainesville, FL 32611 (United States)

    2017-03-10

    We report the detection of diffuse Ly α emission, or Ly α halos (LAHs), around star-forming galaxies at z ≈ 3.78 and 2.66 in the NOAO Deep Wide-Field Survey Boötes field. Our samples consist of a total of ∼1400 galaxies, within two separate regions containing spectroscopically confirmed galaxy overdensities. They provide a unique opportunity to investigate how the LAH characteristics vary with host galaxy large-scale environment and physical properties. We stack Ly α images of different samples defined by these properties and measure their median LAH sizes by decomposing the stacked Ly α radial profile into a compact galaxy-like and an extended halo-like component. We find that the exponential scale-length of LAHs depends on UV continuum and Ly α luminosities, but not on Ly α equivalent widths or galaxy overdensity parameters. The full samples, which are dominated by low UV-continuum luminosity Ly α emitters ( M {sub UV} ≳ −21), exhibit LAH sizes of 5–6 kpc. However, the most UV- or Ly α- luminous galaxies have more extended halos with scale-lengths of 7–9 kpc. The stacked Ly α radial profiles decline more steeply than recent theoretical predictions that include the contributions from gravitational cooling of infalling gas and from low-level star formation in satellites. However, the LAH extent matches what one would expect for photons produced in the galaxy and then resonantly scattered by gas in an outflowing envelope. The observed trends of LAH sizes with host galaxy properties suggest that the physical conditions of the circumgalactic medium (covering fraction, H i column density, and outflow velocity) change with halo mass and/or star formation rates.

  7. Observation of solar hydrogen Ly-αline with the K-10-12 rocket

    International Nuclear Information System (INIS)

    Koshio, Takafumi; Masuoka, Toshio; Tono, Ichiro; Watanabe, Norihiko.

    1976-01-01

    The purpose of the observation is to perform the absolute irradiance measurement of the solar hydrogen Ly-α line (1216 A 0 ) in the exosphere. The solar hydrogen Ly-α line is emitted from the chromosphere, and contributes to the ionization in the lower ionosphere. The ionization chamber was used for the detection of the solar hydrogen Ly-α line. The K-10-9 rocket was launched on Jan. 18, 1976. The irradiance of the solar hydrogen Ly-α line was measured in the exosphere, and the height distribution of O 2 density was studied on the basis of the absorbancy of the HLy-α line. The result was in good agreement with the previously observed results. (Yoshimori, M.)

  8. Anne-Ly Võlli: Iga inimene ja asutus vajab omamoodi lähenemist / Anne-Ly Võlli ; intervjueerinud Jaanika Kressa

    Index Scriptorium Estoniae

    Võlli, Anne-Ly, 1976-

    2009-01-01

    MTÜ Jõgevamaa Omavalitsuste Aktiviseerimiskeskus kinnitas avaliku konkursi tulemusel juhatuse liikmeks Anne-Ly Võlli, kelle ülesandeks on keskuse tegevuse juhtimine ja koostöö arendamine partneromavalitsuste ja teiste koostööpartnerite vahel

  9. Regulation of expression of two LY-6 family genes by intron retention and transcription induced chimerism

    Directory of Open Access Journals (Sweden)

    Mallya Meera

    2008-09-01

    Full Text Available Abstract Background Regulation of the expression of particular genes can rely on mechanisms that are different from classical transcriptional and translational control. The LY6G5B and LY6G6D genes encode LY-6 domain proteins, whose expression seems to be regulated in an original fashion, consisting of an intron retention event which generates, through an early premature stop codon, a non-coding transcript, preventing expression in most cell lines and tissues. Results The MHC LY-6 non-coding transcripts have shown to be stable and very abundant in the cell, and not subject to Nonsense Mediated Decay (NMD. This retention event appears not to be solely dependent on intron features, because in the case of LY6G5B, when the intron is inserted in the artificial context of a luciferase expression plasmid, it is fully spliced but strongly stabilises the resulting luciferase transcript. In addition, by quantitative PCR we found that the retained and spliced forms are differentially expressed in tissues indicating an active regulation of the non-coding transcript. EST database analysis revealed that these genes have an alternative expression pathway with the formation of Transcription Induced Chimeras (TIC. This data was confirmed by RT-PCR, revealing the presence of different transcripts that would encode the chimeric proteins CSNKβ-LY6G5B and G6F-LY6G6D, in which the LY-6 domain would join to a kinase domain and an Ig-like domain, respectively. Conclusion In conclusion, the LY6G5B and LY6G6D intron-retained transcripts are not subjected to NMD and are more abundant than the properly spliced forms. In addition, these genes form chimeric transcripts with their neighbouring same orientation 5' genes. Of interest is the fact that the 5' genes (CSNKβ or G6F undergo differential splicing only in the context of the chimera (CSNKβ-LY6G5B or G6F-LY6G6C and not on their own.

  10. Specific Depletion of Ly6Chi Inflammatory Monocytes Prevents Immunopathology in Experimental Cerebral Malaria

    Science.gov (United States)

    Kuepper, Janina M.; Biswas, Aindrila; Djie-Maletz, Andrea; Limmer, Andreas; van Rooijen, Nico; Mack, Matthias; Hoerauf, Achim; Dunay, Ildiko Rita

    2015-01-01

    Plasmodium berghei ANKA (PbA) infection of C57BL/6 mice leads to experimental cerebral malaria (ECM) that is commonly associated with serious T cell mediated damage. In other parasitic infection models, inflammatory monocytes have been shown to regulate Th1 responses but their role in ECM remains poorly defined, whereas neutrophils are reported to contribute to ECM immune pathology. Making use of the recent development of specific monoclonal antibodies (mAb), we depleted in vivo Ly6Chi inflammatory monocytes (by anti-CCR2), Ly6G+ neutrophils (by anti-Ly6G) or both cell types (by anti-Gr1) during infection with Ovalbumin-transgenic PbA parasites (PbTg). Notably, the application of anti-Gr1 or anti-CCR2 but not anti-Ly6G antibodies into PbTg-infected mice prevented ECM development. In addition, depletion of Ly6Chi inflammatory monocytes but not neutrophils led to decreased IFNγ levels and IFNγ+CD8+ T effector cells in the brain. Importantly, anti-CCR2 mAb injection did not prevent the generation of PbTg-specific T cell responses in the periphery, whereas anti-Gr1 mAb injection strongly diminished T cell frequencies and CTL responses. In conclusion, the specific depletion of Ly6Chi inflammatory monocytes attenuated brain inflammation and immune cell recruitment to the CNS, which prevented ECM following Plasmodium infection, pointing out a substantial role of Ly6C+ monocytes in ECM inflammatory processes. PMID:25884830

  11. SPATIALLY RESOLVED GAS KINEMATICS WITHIN A Lyα NEBULA: EVIDENCE FOR LARGE-SCALE ROTATION

    Energy Technology Data Exchange (ETDEWEB)

    Prescott, Moire K. M. [Dark Cosmology Centre, Niels Bohr Institute, University of Copenhagen, Juliane Maries Vej 30, DK-2100 Copenhagen (Denmark); Martin, Crystal L. [Department of Physics, Broida Hall, Mail Code 9530, University of California, Santa Barbara, CA 93106 (United States); Dey, Arjun, E-mail: mkmprescott@dark-cosmology.dk [National Optical Astronomy Observatory, 950 North Cherry Avenue, Tucson, AZ 85719 (United States)

    2015-01-20

    We use spatially extended measurements of Lyα as well as less optically thick emission lines from an ≈80 kpc Lyα nebula at z ≈ 1.67 to assess the role of resonant scattering and to disentangle kinematic signatures from Lyα radiative transfer effects. We find that the Lyα, C IV, He II, and C III] emission lines all tell a similar story in this system, and that the kinematics are broadly consistent with large-scale rotation. First, the observed surface brightness profiles are similar in extent in all four lines, strongly favoring a picture in which the Lyα photons are produced in situ instead of being resonantly scattered from a central source. Second, we see low kinematic offsets between Lyα and the less optically thick He II line (∼100-200 km s{sup –1}), providing further support for the argument that the Lyα and other emission lines are all being produced within the spatially extended gas. Finally, the full velocity field of the system shows coherent velocity shear in all emission lines: ≈500 km s{sup –1} over the central ≈50 kpc of the nebula. The kinematic profiles are broadly consistent with large-scale rotation in a gas disk that is at least partially stable against collapse. These observations suggest that the Lyα nebula represents accreting material that is illuminated by an offset, hidden active galactic nucleus or distributed star formation, and that is undergoing rotation in a clumpy and turbulent gas disk. With an implied mass of M(

  12. A SUCCESSFUL BROADBAND SURVEY FOR GIANT Lyα NEBULAE. I. SURVEY DESIGN AND CANDIDATE SELECTION

    International Nuclear Information System (INIS)

    Prescott, Moire K. M.; Dey, Arjun; Jannuzi, Buell T.

    2012-01-01

    Giant Lyα nebulae (or Lyα 'blobs') are likely sites of ongoing massive galaxy formation, but the rarity of these powerful sources has made it difficult to form a coherent picture of their properties, ionization mechanisms, and space density. Systematic narrowband Lyα nebula surveys are ongoing, but the small redshift range covered and the observational expense limit the comoving volume that can be probed by even the largest of these surveys and pose a significant problem when searching for such rare sources. We have developed a systematic search technique designed to find large Lyα nebulae at 2 ∼ 2 NOAO Deep Wide-Field Survey Boötes field. With a total survey comoving volume of ≈10 8 h –3 70 Mpc 3 , this is the largest volume survey for Lyα nebulae ever undertaken. In this first paper in the series, we present the details of the survey design and a systematically selected sample of 79 candidates, which includes one previously discovered Lyα nebula.

  13. Combined treatment with pemetrexed and vinflunine in patients with metastatic urothelial cell carcinoma after prior platinum-containing chemotherapy - results of an exploratory phase I study

    DEFF Research Database (Denmark)

    Pappot, H; von der Maase, H; Ullén, A

    2017-01-01

    experienced grade 4 thrombocytopenia and a second demonstrated hepatobiliary toxicity grade 3 with an increase in alanine aminotransaminase. Most common grade 3 and 4 adverse events were anemia, thrombocytopenia and neutropenia. Three out of four patients received 3 cycles of pemetrexed and vinflunine, all...

  14. Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition.

    Science.gov (United States)

    Wibowo, Ardian S; Singh, Mirage; Reeder, Kristen M; Carter, Joshua J; Kovach, Alexander R; Meng, Wuyi; Ratnam, Manohar; Zhang, Faming; Dann, Charles E

    2013-09-17

    Antifolates, folate analogs that inhibit vitamin B9 (folic acid)-using cellular enzymes, have been used over several decades for the treatment of cancer and inflammatory diseases. Cellular uptake of the antifolates in clinical use occurs primarily via widely expressed facilitative membrane transporters. More recently, human folate receptors (FRs), high affinity receptors that transport folate via endocytosis, have been proposed as targets for the specific delivery of new classes of antifolates or folate conjugates to tumors or sites of inflammation. The development of specific, FR-targeted antifolates would be accelerated if additional biophysical data, particularly structural models of the receptors, were available. Here we describe six distinct crystallographic models that provide insight into biological trafficking of FRs and distinct binding modes of folate and antifolates to these receptors. From comparison of the structures, we delineate discrete structural conformations representative of key stages in the endocytic trafficking of FRs and propose models for pH-dependent conformational changes. Additionally, we describe the molecular details of human FR in complex with three clinically prevalent antifolates, pemetrexed (also Alimta), aminopterin, and methotrexate. On the whole, our data form the basis for rapid design and implementation of unique, FR-targeted, folate-based drugs for the treatment of cancer and inflammatory diseases.

  15. STACKED REST-FRAME ULTRAVIOLET SPECTRA OF Lyα-EMITTING AND CONTINUUM-SELECTED GALAXIES AT 2 < z < 3.5

    International Nuclear Information System (INIS)

    Berry, Michael; Gawiser, Eric; Guaita, Lucia; Padilla, Nelson; Francke, Harold; Treister, Ezequiel; Blanc, Guillermo A.; Ciardullo, Robin; Gronwall, Caryl

    2012-01-01

    We present properties of individual and composite rest-UV spectra of continuum- and narrowband-selected star-forming galaxies (SFGs) at a redshift of 2 Lyα > 20 Å, the canonical limit to be classified as an Lyα-emitting galaxy. We divide our data set into subsamples based on properties that we are able to measure for each individual galaxy: Lyα equivalent width, rest-frame UV colors, and redshift. Among our subsample of galaxies with R Lyα > 20 Å have bluer UV continua, weaker low-ionization interstellar absorption lines, weaker C IV absorption, and stronger Si II* nebular emission than those with W Lyα –1 between Lyα emission and low-ionization absorption, which does not vary substantially among any of our subsamples. We find that the interstellar component, as opposed to the stellar component, dominates the high-ionization absorption line profiles. We find that the low- and high-ionization Si ionization states have similar kinematic properties, yet the low-ionization absorption is correlated with Lyα emission and the high-ionization absorption is not. These trends are consistent with outflowing neutral gas being in the form of neutral clouds embedded in ionized gas as previously suggested by Steidel et al. Moreover, our galaxies with bluer UV colors have stronger Lyα emission, weaker low-ionization absorption, and more prominent nebular emission line profiles. From a redshift of 2.7 Lyα Lyα > 20 Å exhibit weaker Lyα emission at lower redshifts, although we caution that this could be caused by spectroscopic confirmation of low Lyα equivalent width galaxies being harder at z ∼ 3 than z ∼ 2.

  16. Ly-alpha polarimeter design for CLASP rocket experiment

    Science.gov (United States)

    Kubo, M.; Watanabe, H.; Narukage, N.; Ishikawa, R.; Bando, T.; Kano, R.; Tsuneta, S.; Kobayashi, K.; Ichimoto, K.; Trujillo Bueno, J.; Song, D.

    2011-12-01

    A sounding-rocket program called the Chromospheric Lyman-Alpha Spectro-Polarimeter (CLASP) is proposed to be launched in the Summer of 2014. CLASP will observe the upper solar chromosphere in Ly-alpha (121.567 nm), aiming to detect the linear polarization signal produced by scattering processes and the Hanle effect for the first time. The CLASP needs a rotating half-waveplate and a polarization analyzer working at the Ly-alpha wavelength to measure the linear polarization signal. We select Magnesium Fluoride (MgF2) as a material of the optical components because of its birefringent property and high transparency at UV wavelength. We have confirmed that the reflection at the Brewster's Angle of MgF2 plate is a good polarization analyzer for the Ly-alpha line by deriving its ordinary refractive index and extinction coefficient along the ordinary and extraordinary axes. These optical parameters are calculated with a least-square fitting in such a way that the reflectance and transmittance satisfy the Kramers-Kronig relation. The reflectance and transmittance against oblique incident angles for the s-polarized and the p-polarized light are measured using the synchrotron beamline at the Ultraviolet Synchrotron Orbital Radiation Facility (UVSOR). We have also measured a retardation of a zeroth-order waveplate made of MgF2. The thickness difference of the waveplate is 14.57 um.This waveplate works as a half-waveplate at 121.74 nm. From this measurement, we estimate that a waveplate with the thickness difference of 15.71 um will work as a half-waveplate at the Ly-alpha wavelength. We have developed a rotating waveplate - polarization analyzer system called a prototype of CLASP polarimeter, and input the perfect Stokes Q and U signals. The modulation patterns that are consistent with the theoretical prediction are successfully obtained in both cases.

  17. Myostatin antibody (LY2495655) in older weak fallers: a proof-of-concept, randomised, phase 2 trial

    Science.gov (United States)

    BACKGROUND: Myostatin inhibits skeletal muscle growth. The humanised monoclonal antibody LY2495655 (LY) binds and neutralises myostatin. We aimed to test whether LY increases appendicular lean body mass (aLBM) and improves physical performance in older individuals who have had recent falls and low m...

  18. Constraint on neutrino masses from SDSS-III/BOSS Ly$\\alpha$ forest and other cosmological probes

    CERN Document Server

    Palanque-Delabrouille, Nathalie; Lesgourgues, Julien; Rossi, Graziano; Borde, Arnaud; Viel, Matteo; Aubourg, Eric; Kirkby, David; LeGoff, Jean-Marc; Rich, James; Roe, Natalie; Ross, Nicholas P.; Schneider, Donald P.; Weinberg, David

    2015-02-27

    We present constraints on the parameters of the $\\Lambda$CDM cosmological model in the presence of massive neutrinos, using the one-dimensional Ly$\\alpha$ forest power spectrum obtained with the Baryon Oscillation Spectroscopic Survey (BOSS) of the Sloan Digital Sky Survey (SDSS) by Palanque-Delabrouille et al. (2013), complemented by additional cosmological probes. The interpretation of the measured Ly$\\alpha$ spectrum is done using a second-order Taylor expansion of the simulated power spectrum. BOSS Ly$\\alpha$ data alone provide better bounds than previous Ly$\\alpha$ results, but are still poorly constraining, especially for the sum of neutrino masses $\\sum m_\

  19. A new ultrafast and high-throughput mass spectrometric approach for the therapeutic drug monitoring of the multi-targeted anti-folate pemetrexed in plasma from lung cancer patients

    NARCIS (Netherlands)

    R.J.W. Meesters (Roland); R. Cornelissen (Robin); R.J. van Klaveren (Rob); R. de Jonge (Robert); E. den Boer (Ethan); J. Lindemans (Jan); T.M. Luider (Theo)

    2010-01-01

    textabstractAn analytical assay has been developed and validated for ultrafast and high-throughput mass spectrometric determination of pemetrexed concentrations in plasma using matrix assisted laser desorption/ionization-triple quadrupole-tandem mass spectrometry. Patient plasma samples spiked with

  20. GAS MOTION STUDY OF Lyα EMITTERS AT z ∼ 2 USING FUV AND OPTICAL SPECTRAL LINES ,

    International Nuclear Information System (INIS)

    Hashimoto, Takuya; Shimasaku, Kazuhiro; Nakajima, Kimihiko; Ouchi, Masami; Ono, Yoshiaki; Rauch, Michael; Janice Lee; Okamura, Sadanori

    2013-01-01

    We present the results of Magellan/MMIRS and Keck/NIRSPEC spectroscopy for five Lyα emitters (LAEs) at z ≅ 2.2 for which high-resolution FUV spectra from Magellan/MagE are available. We detect nebular emission lines including Hα on the individual basis and low-ionization interstellar (LIS) absorption lines in a stacked FUV spectrum, and measure average offset velocities of the Lyα line, Δv Lyα , and LIS absorption lines, Δv abs , with respect to the systemic velocity defined by the nebular lines. For a sample of eight z ∼ 2-3 LAEs without active galactic nucleus from our study and the literature, we obtain Δv Lyα = 175 ± 35 km s –1 , which is significantly smaller than that of Lyman-break Galaxies (LBGs), Δv Lyα ≅ 400 km s –1 . The stacked FUV spectrum gives Δv abs = –179 ± 73 km s –1 , comparable to that of LBGs. These positive Δv Lyα and negative Δv abs suggest that LAEs also have outflows. In contrast to LBGs, however, the LAEs' Δv Lyα is as small as |Δv abs |, suggesting low neutral hydrogen column densities. Such a low column density with a small number of resonant scattering may cause the observed strong Lyα emission of LAEs. We find an anti-correlation between Lyα equivalent width (EW) and Δv Lyα in a compilation of LAE and LBG samples. Although its physical origin is not clear, this anti-correlation result appears to challenge the hypothesis that a strong outflow, by means of a reduced number of resonant scattering, produces a large EW. If LAEs at z > 6 have similarly small Δv Lyα values, constraints on the reionization history derived from the Lyα transmissivity may need to be revised.

  1. Anomalous Temporal Behaviour of Broadband Ly Alpha Observations During Solar Flares from SDO/EVE

    Science.gov (United States)

    Milligan, Ryan O.; Chamberlin, Phillip C.

    2016-01-01

    Although it is the most prominent emission line in the solar spectrum, there has been a notable lack of studies devoted to variations in Lyman-alpha (Ly-alpha) emission during solar flares in recent years. However, the few examples that do exist have shown Ly-alpha emission to be a substantial radiator of the total energy budget of solar flares (of the order of 10 percent). It is also a known driver of fluctuations in the Earth's ionosphere. The EUV (Extreme Ultra-Violet) Variability Experiment (EVE) on board the Solar Dynamics Observatory (SDO) now provides broadband, photometric Ly-alpha data at 10-second cadence with its Multiple EUV Grating Spectrograph-Photometer (MEGS-P) component, and has observed scores of solar flares in the 5 years since it was launched. However, the MEGS-P time profiles appear to display a rise time of tens of minutes around the time of the flare onset. This is in stark contrast to the rapid, impulsive increase observed in other intrinsically chromospheric features (H-alpha, Ly-beta, LyC, C III, etc.). Furthermore, the emission detected by MEGS-P peaks around the time of the peak of thermal soft X-ray emission and not during the impulsive phase when energy deposition in the chromosphere (often assumed to be in the form of non-thermal electrons) is greatest. The time derivative of Ly-alpha lightcurves also appears to resemble that of the time derivative of soft X-rays, reminiscent of the Neupert effect. Given that spectrally-resolved Ly-alpha observations during flares from SORCE / SOLSTICE (Solar Radiation and Climate Experiment / Solar Stellar Irradiance Comparison Experiment) peak during the impulsive phase as expected, this suggests that the atypical behaviour of MEGS-P data is a manifestation of the broadband nature of the observations. This could imply that other lines andor continuum emission that becomes enhanced during flares could be contributing to the passband. Users are hereby urged to exercise caution when interpreting

  2. A SUCCESSFUL BROADBAND SURVEY FOR GIANT Ly{alpha} NEBULAE. I. SURVEY DESIGN AND CANDIDATE SELECTION

    Energy Technology Data Exchange (ETDEWEB)

    Prescott, Moire K. M. [Department of Physics, Broida Hall, Mail Code 9530, University of California, Santa Barbara, CA 93106 (United States); Dey, Arjun; Jannuzi, Buell T., E-mail: mkpresco@physics.ucsb.edu [National Optical Astronomy Observatory, 950 North Cherry Avenue, Tucson, AZ 85719 (United States)

    2012-04-01

    Giant Ly{alpha} nebulae (or Ly{alpha} 'blobs') are likely sites of ongoing massive galaxy formation, but the rarity of these powerful sources has made it difficult to form a coherent picture of their properties, ionization mechanisms, and space density. Systematic narrowband Ly{alpha} nebula surveys are ongoing, but the small redshift range covered and the observational expense limit the comoving volume that can be probed by even the largest of these surveys and pose a significant problem when searching for such rare sources. We have developed a systematic search technique designed to find large Ly{alpha} nebulae at 2 {approx}< z {approx}< 3 within deep broadband imaging and have carried out a survey of the 9.4 deg{sup 2} NOAO Deep Wide-Field Survey Booetes field. With a total survey comoving volume of Almost-Equal-To 10{sup 8} h{sup -3}{sub 70} Mpc{sup 3}, this is the largest volume survey for Ly{alpha} nebulae ever undertaken. In this first paper in the series, we present the details of the survey design and a systematically selected sample of 79 candidates, which includes one previously discovered Ly{alpha} nebula.

  3. Positive regulation of plasmacytoid dendritic cell function via Ly49Q recognition of class I MHC

    Science.gov (United States)

    Tai, Lee-Hwa; Goulet, Marie-Line; Belanger, Simon; Toyama-Sorimachi, Noriko; Fodil-Cornu, Nassima; Vidal, Silvia M.; Troke, Angela D.; McVicar, Daniel W.; Makrigiannis, Andrew P.

    2008-01-01

    Plasmacytoid dendritic cells (pDCs) are an important source of type I interferon (IFN) during initial immune responses to viral infections. In mice, pDCs are uniquely characterized by high-level expression of Ly49Q, a C-type lectin-like receptor specific for class I major histocompatibility complex (MHC) molecules. Despite having a cytoplasmic immunoreceptor tyrosine-based inhibitory motif, Ly49Q was found to enhance pDC function in vitro, as pDC cytokine production in response to the Toll-like receptor (TLR) 9 agonist CpG-oligonucleotide (ODN) could be blocked using soluble monoclonal antibody (mAb) to Ly49Q or H-2Kb. Conversely, CpG-ODN–dependent IFN-α production by pDCs was greatly augmented upon receptor cross-linking using immobilized anti-Ly49Q mAb or recombinant H-2Kb ligand. Accordingly, Ly49Q-deficient pDCs displayed a severely reduced capacity to produce cytokines in response to TLR7 and TLR9 stimulation both in vitro and in vivo. Finally, TLR9-dependent antiviral responses were compromised in Ly49Q-null mice infected with mouse cytomegalovirus. Thus, class I MHC recognition by Ly49Q on pDCs is necessary for optimal activation of innate immune responses in vivo. PMID:19075287

  4. Specific depletion of Ly6C(hi) inflammatory monocytes prevents immunopathology in experimental cerebral malaria.

    Science.gov (United States)

    Schumak, Beatrix; Klocke, Katrin; Kuepper, Janina M; Biswas, Aindrila; Djie-Maletz, Andrea; Limmer, Andreas; van Rooijen, Nico; Mack, Matthias; Hoerauf, Achim; Dunay, Ildiko Rita

    2015-01-01

    Plasmodium berghei ANKA (PbA) infection of C57BL/6 mice leads to experimental cerebral malaria (ECM) that is commonly associated with serious T cell mediated damage. In other parasitic infection models, inflammatory monocytes have been shown to regulate Th1 responses but their role in ECM remains poorly defined, whereas neutrophils are reported to contribute to ECM immune pathology. Making use of the recent development of specific monoclonal antibodies (mAb), we depleted in vivo Ly6C(hi) inflammatory monocytes (by anti-CCR2), Ly6G+ neutrophils (by anti-Ly6G) or both cell types (by anti-Gr1) during infection with Ovalbumin-transgenic PbA parasites (PbTg). Notably, the application of anti-Gr1 or anti-CCR2 but not anti-Ly6G antibodies into PbTg-infected mice prevented ECM development. In addition, depletion of Ly6C(hi) inflammatory monocytes but not neutrophils led to decreased IFNγ levels and IFNγ+CD8+ T effector cells in the brain. Importantly, anti-CCR2 mAb injection did not prevent the generation of PbTg-specific T cell responses in the periphery, whereas anti-Gr1 mAb injection strongly diminished T cell frequencies and CTL responses. In conclusion, the specific depletion of Ly6C(hi) inflammatory monocytes attenuated brain inflammation and immune cell recruitment to the CNS, which prevented ECM following Plasmodium infection, pointing out a substantial role of Ly6C+ monocytes in ECM inflammatory processes.

  5. The Abundance of Low-Luminosity Lyα Emitters at High Redshift

    Science.gov (United States)

    Santos, Michael R.; Ellis, Richard S.; Kneib, Jean-Paul; Richard, Johan; Kuijken, Konrad

    2004-05-01

    We derive the luminosity function of high-redshift Lyα-emitting sources from a deep, blind, spectroscopic survey that utilized strong-lensing magnification by intermediate-redshift clusters of galaxies. We observed carefully selected regions near nine clusters, consistent with magnification factors generally greater than 10 for the redshift range 4.5account our varying intrinsic Lyα line sensitivity as a function of wavelength and sky position. By virtue of the strong magnification factor, we provide constraints on the Lyα luminosity function to unprecedented limits of 1040 ergs s -1, corresponding to a star formation rate of 0.01 Msolar yr-1. Our cumulative z~=5 Lyα luminosity function is consistent with a power-law form n(>L)~L-1 over 1041-1042.5 ergs s-1. When combined with the results of other surveys, limited at higher luminosities, our results suggest evidence for the suppression of star formation in low-mass halos, as predicted in popular models of galaxy formation. Data presented herein were obtained at the W. M. Keck Observatory, which is operated as a scientific partnership among the California Institute of Technology, the University of California, and the National Aeronautics and Space Administration. The Observatory was made possible by the generous financial support of the W. M. Keck Foundation.

  6. WARM GAS IN THE VIRGO CLUSTER. I. DISTRIBUTION OF Lyα ABSORBERS

    International Nuclear Information System (INIS)

    Yoon, Joo Heon; Putman, Mary E.; Bryan, Greg L.; Thom, Christopher; Chen, Hsiao-Wen

    2012-01-01

    The first systematic study of the warm gas (T = 10 4–5 K) distribution across a galaxy cluster is presented using multiple background QSOs in and around the Virgo Cluster. We detect 25 Lyα absorbers (N HI = 10 13.1–15.4 cm –2 ) in the Virgo velocity range toward 9 of 12 QSO sightlines observed with the Cosmic Origin Spectrograph, with a cluster impact parameter range of 0.36-1.65 Mpc (0.23-1.05 R vir ). Including 18 Lyα absorbers previously detected by STIS or GHRS toward 7 of 11 background QSOs in and around the Virgo Cluster, we establish a sample of 43 absorbers toward a total of 23 background probes for studying the incidence of Lyα absorbers in and around the Virgo Cluster. With these absorbers, we find (1) warm gas is predominantly in the outskirts of the cluster and avoids the X-ray-detected hot intracluster medium (ICM). Also, Lyα absorption strength increases with cluster impact parameter. (2) Lyα-absorbing warm gas traces cold H I-emitting gas in the substructures of the Virgo Cluster. (3) Including the absorbers associated with the surrounding substructures, the warm gas covering fraction (100% for N HI > 10 13.1 cm –2 ) is in agreement with cosmological simulations. We speculate that the observed warm gas is part of large-scale gas flows feeding the cluster both in the ICM and galaxies.

  7. Materiály pro superkondenzátory

    OpenAIRE

    Dvořák, Petr

    2014-01-01

    Tato dizertační práce se zabývá elektrodovými materiály, kapalnými a gelovými elektrolyty vhodnými pro superkondenzátory. V oblasti elektrodových materiálů byly zkoumány uhlíkové materiály na bázi uhlíkových sazí, expandovaného a mikromletého grafitu vhodné pro superkondenzátory pracující na principu dvojvrstvy. Další oblastí, které se tato práce věnuje, jsou kapalné aprotické elektrolyty připravené z vhodných typů solí a bezvodných organických rozpouštědel. Poslední část této práce je zaměře...

  8. High-Velocity Ly(Alpha) Emission from SMR 1987A

    Science.gov (United States)

    Michael, Eli; McCray, Richard; Borkowski, Kazimierz J.; Pun, Chu S. J.; Sonneborn, George

    1998-01-01

    The high-velocity Ly(Alpha) emission from SN 1987A observed with the Space Telescope Imaging Spectrograph (STIS) evidently comes from a reverse shock formed where the outer envelope of SN 1987A strikes ionized gas inside the inner circumstellar ring. The observations can be explained by a simple kinematic model, in which the Ly(Alpha) emission comes from hydrogen atoms with radial velocity approximately 15,000 km s(exp -1) crossing a reverse shock in the shape of a slightly prolate ellipsoid with equatorial radius 4.8 x 10(exp 17) cm or approximately 80% of the distance to the inner surface of the inner ring. N v double Lambda 1239, 1243 emission, if present, has a net luminosity approximately less than 30% times that of the Ly(Alpha) emission. Future STIS observations should enable us to predict the time of impact with the inner ring and to determine unambiguously whether or not N v emission is present. These observations will offer a unique opportunity to probe the structure of SN 1987A's circumstellar environment and the hydrodynamics and kinetics of very fast shocks.

  9. Nonclassical Ly6C− Monocytes Drive the Development of Inflammatory Arthritis in Mice

    Directory of Open Access Journals (Sweden)

    Alexander V. Misharin

    2014-10-01

    Full Text Available Different subsets and/or polarized phenotypes of monocytes and macrophages may play distinct roles during the development and resolution of inflammation. Here, we demonstrate in a murine model of rheumatoid arthritis that nonclassical Ly6C− monocytes are required for the initiation and progression of sterile joint inflammation. Moreover, nonclassical Ly6C− monocytes differentiate into inflammatory macrophages (M1, which drive disease pathogenesis and display plasticity during the resolution phase. During the development of arthritis, these cells polarize toward an alternatively activated phenotype (M2, promoting the resolution of joint inflammation. The influx of Ly6C− monocytes and their subsequent classical and then alternative activation occurs without changes in synovial tissue-resident macrophages, which express markers of M2 polarization throughout the course of the arthritis and attenuate joint inflammation during the initiation phase. These data suggest that circulating Ly6C− monocytes recruited to the joint upon injury orchestrate the development and resolution of autoimmune joint inflammation.

  10. GAS MOTION STUDY OF Ly{alpha} EMITTERS AT z {approx} 2 USING FUV AND OPTICAL SPECTRAL LINES {sup ,}

    Energy Technology Data Exchange (ETDEWEB)

    Hashimoto, Takuya; Shimasaku, Kazuhiro; Nakajima, Kimihiko [Department of Astronomy, Graduate School of Science, The University of Tokyo, Tokyo 113-0033 (Japan); Ouchi, Masami; Ono, Yoshiaki [Institute for Cosmic Ray Research, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8582 (Japan); Rauch, Michael; Janice Lee [Observatories of the Carnegie Institution of Washington, 813 Santa Barbara Street, Pasadena, CA 91101 (United States); Okamura, Sadanori, E-mail: thashimoto@astron.s.u-tokyo.ac.jp [Department of Advanced Sciences, Faculty of Science and Engineering, Hosei University, 3-7-2 Kajino-cho, Koganei-shi, Tokyo 184-8584 (Japan)

    2013-03-01

    We present the results of Magellan/MMIRS and Keck/NIRSPEC spectroscopy for five Ly{alpha} emitters (LAEs) at z {approx_equal} 2.2 for which high-resolution FUV spectra from Magellan/MagE are available. We detect nebular emission lines including H{alpha} on the individual basis and low-ionization interstellar (LIS) absorption lines in a stacked FUV spectrum, and measure average offset velocities of the Ly{alpha} line, {Delta}v {sub Ly{alpha}}, and LIS absorption lines, {Delta}v {sub abs}, with respect to the systemic velocity defined by the nebular lines. For a sample of eight z {approx} 2-3 LAEs without active galactic nucleus from our study and the literature, we obtain {Delta}v {sub Ly{alpha}} = 175 {+-} 35 km s{sup -1}, which is significantly smaller than that of Lyman-break Galaxies (LBGs), {Delta}v {sub Ly{alpha}} {approx_equal} 400 km s{sup -1}. The stacked FUV spectrum gives {Delta}v {sub abs} = -179 {+-} 73 km s{sup -1}, comparable to that of LBGs. These positive {Delta}v {sub Ly{alpha}} and negative {Delta}v {sub abs} suggest that LAEs also have outflows. In contrast to LBGs, however, the LAEs' {Delta}v {sub Ly{alpha}} is as small as |{Delta}v {sub abs}|, suggesting low neutral hydrogen column densities. Such a low column density with a small number of resonant scattering may cause the observed strong Ly{alpha} emission of LAEs. We find an anti-correlation between Ly{alpha} equivalent width (EW) and {Delta}v {sub Ly{alpha}} in a compilation of LAE and LBG samples. Although its physical origin is not clear, this anti-correlation result appears to challenge the hypothesis that a strong outflow, by means of a reduced number of resonant scattering, produces a large EW. If LAEs at z > 6 have similarly small {Delta}v {sub Ly{alpha}} values, constraints on the reionization history derived from the Ly{alpha} transmissivity may need to be revised.

  11. Effect of Pemetrexed combined with cis-platinum chemotherapy on matrix metalloproteinase VEGF, NK cells and immune function in patients with non-squamous non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Feng Wen

    2017-07-01

    Full Text Available Objective: To explore effect of Pemetrexed combined with cis-platinum chemotherapy on matrix metalloproteinase (MMPs, vascular esandothelial growth factor (VEGF, NK cells and immune function in patients with non-squamous non-small cell lung cancer. Method: A total of 86 cases of non-squamous non-small cell lung cancer patients were divided into control group (n=44 and observation group (n=42, control group was given docetaxel combined cisplatinum chemotherapy, pemetrexed combined cis-platinum chemotherapy, was applied for observation group. Compared MMP-2, MMP-9, VEGF, NK cells and immune function level before and after treatment in both groups. Results: MMP-2, MMP-9, VEGF, NK cells, CD3+, CD4+, CD8+, CD4+/CD8+ level in both groups before treatment was no significant difference. After treatment, MMP-2, MMP-9, VEGF, CD8+level in both groups was significant lower than before treatment intra-group, and observation was lower than control group, there was significant difference. After treatment, NK cells, CD3+, CD4+, CD8+, CD4+/CD8+ level in both groups was increased dramatically than before treatment of intra-group, moreover, NK cells, CD3+, CD4+, CD8+, CD4+/CD8+level in observation group after treatment was obvious higher than in control group after treatment, there was significant difference. Conclusion: Pemetrexed combined with cis-platinum chemotherapy for non-squamous non-small cell lung cancer could effectively decrease serum MMPs, VEGF level and increase NK cell level, regulate immune function, with definite clinical significance.

  12. Lyα-Lyman continuum connection in 3.5 ≤ z ≤ 4.3 star-forming galaxies from the VUDS survey

    Science.gov (United States)

    Marchi, F.; Pentericci, L.; Guaita, L.; Schaerer, D.; Verhamme, A.; Castellano, M.; Ribeiro, B.; Garilli, B.; Fèvre, O. Le; Amorin, R.; Bardelli, S.; Cassata, P.; Durkalec, A.; Grazian, A.; Hathi, N. P.; Lemaux, B. C.; Maccagni, D.; Vanzella, E.; Zucca, E.

    2018-06-01

    Context. To identify the galaxies responsible for the reionization of the Universe, we must rely on the investigation of the Lyman continuum (LyC) properties of z ≲ 5 star-forming galaxies, where we can still directly observe their ionizing radiation. Aims: The aim of this work is to explore the correlation between the LyC emission and some of the proposed indirect indicators of LyC radiation at z 4 such as a bright Lyα emission and a compact UV continuum size. Methods: We selected a sample of 201 star-forming galaxies from the Vimos Ultra Deep Survey (VUDS) at 3.5 ≤ z ≤ 4.3 in the COSMOS, ECDFS, and VVDS-2h fields, including only those with reliable spectroscopic redshifts, a clean spectrum in the LyC range and clearly not contaminated by bright nearby sources in the same slit. For all galaxies we measured the Lyα EW, the Lyα velocity shift with respect to the systemic redshift, the Lyα spatial extension and the UV continuum effective radius. We then selected different sub-samples according to the properties predicted to be good LyC emission indicators: in particular we created sub-samples of galaxies with EW(Lyα) ≥ 70 Å, Lyαext ≤ 5.7 kpc, rUV ≤ 0.30 kpc and |ΔvLyα|≤ 200 km s-1. We stacked all the galaxies in each sub-sample and measured the flux density ratio (fλ(895)/fλ(1470)), that we considered to be a proxy for LyC emission. We then compared these ratios to those obtained for the complementary samples. Finally, to estimate the statistical contamination from lower redshift inter-lopers in our samples, we performed dedicated Monte Carlo simulations using an ultradeep U-band image of the ECDFS field. Results: We find that the stacks of galaxies which are UV compact (rUV ≤ 0.30 kpc) and have bright Lyα emission (EW(Lyα) ≥ 70 Å), have much higher LyC fluxes compared to the rest of the galaxy population. These parameters appear to be good indicators of LyC radiation in agreement with theoretical studies and previous observational

  13. The Ly49E receptor inhibits the immune control of acute Trypanosoma cruzi infection

    Directory of Open Access Journals (Sweden)

    Jessica Filtjens

    2016-11-01

    Full Text Available The protozoan parasite Trypanosoma cruzi (T. cruzi circulates in the blood upon infection and invades a variety of cells. Parasites intensively multiply during the acute phase of infection and persist lifelong at low levels in tissues and blood during the chronic phase. Natural killer (NK and NKT cells play an important role in the immune control of T. cruzi infection, mainly by releasing the cytokine IFN-γ that activates the microbicidal action of macrophages and other cells and shapes a protective type 1 immune response. The mechanisms by which immune cells are regulated to produce IFN-γ during T. cruzi infection are still incompletely understood. Here, we show that urokinase plasminogen activator (uPA is induced early upon T. cruzi infection, and remains elevated until day 20 post inoculation. We previously demonstrated that the inhibitory receptor Ly49E, which is expressed, among others, on NK and NKT cells, is triggered by uPA. Therefore, we compared wild type (WT to Ly49E knockout (KO mice for their control of experimental T. cruzi infection. Our results show that young, i.e. 4- and 6-week-old, Ly49E KO mice control the infection better than WT mice, indicated by a lower parasite load and less cachexia. The beneficial effect of Ly49E depletion is more obvious in 4-week-old male than in female mice and weakens in 8-week-old mice. In young mice, the lower T. cruzi parasitemia in Ly49E KO mice is paralleled by higher IFN-γ production compared to their WT controls. Our data indicate that Ly49E receptor expression inhibits the immune control of T. cruzi infection. This is the first demonstration that the inhibitory Ly49E receptor can interfere with the immune response to a pathogen in vivo.

  14. Neutral ISM, Ly α , and Lyman-continuum in the Nearby Starburst Haro 11

    Energy Technology Data Exchange (ETDEWEB)

    Rivera-Thorsen, T. Emil; Östlin, Göran; Hayes, Matthew; Puschnig, Johannes, E-mail: trive@astro.su.se [Department of Astronomy, Stockholm University, AlbaNova University Centre, SE-106 91 Stockholm (Sweden)

    2017-03-01

    Star-forming galaxies are believed to be a major source of Lyman continuum (LyC) radiation responsible for reionizing the early universe. Direct observations of escaping ionizing radiation have however been sparse and with low escape fractions. In the local universe, only 10 emitters have been observed, with typical escape fractions of a few percent. The mechanisms regulating this escape need to be strongly evolving with redshift in order to account for the epoch of reionization. Gas content and star formation feedback are among the main suspects, known to both regulate neutral gas coverage and evolve with cosmic time. In this paper, we reanalyze Hubble Space Telescope ( HST )-Cosmic Origins Spectrograph (COS) spectrocopy of the first detected local LyC leaker, Haro 11. We examine the connection between LyC leakage and Ly α line shape, and feedback-influenced neutral interstellar medium (ISM) properties like kinematics and gas distribution. We discuss the two extremes of an optically thin, density bounded ISM and a riddled, optically thick, ionization bounded ISM, and how Haro 11 fits into theoretical predictions. We find that the most likely ISM model is a clumpy neutral medium embedded in a highly ionized medium with a combined covering fraction of unity and a residual neutral gas column density in the ionized medium high enough to be optically thick to Ly α , but low enough to be at least partly transparent to LyC and undetected in Si ii. This suggests that star formation feedback and galaxy-scale interaction events play a major role in opening passageways for ionizing radiation through the neutral medium.

  15. Neutral ISM, Ly α , and Lyman-continuum in the Nearby Starburst Haro 11

    International Nuclear Information System (INIS)

    Rivera-Thorsen, T. Emil; Östlin, Göran; Hayes, Matthew; Puschnig, Johannes

    2017-01-01

    Star-forming galaxies are believed to be a major source of Lyman continuum (LyC) radiation responsible for reionizing the early universe. Direct observations of escaping ionizing radiation have however been sparse and with low escape fractions. In the local universe, only 10 emitters have been observed, with typical escape fractions of a few percent. The mechanisms regulating this escape need to be strongly evolving with redshift in order to account for the epoch of reionization. Gas content and star formation feedback are among the main suspects, known to both regulate neutral gas coverage and evolve with cosmic time. In this paper, we reanalyze Hubble Space Telescope ( HST )-Cosmic Origins Spectrograph (COS) spectrocopy of the first detected local LyC leaker, Haro 11. We examine the connection between LyC leakage and Ly α line shape, and feedback-influenced neutral interstellar medium (ISM) properties like kinematics and gas distribution. We discuss the two extremes of an optically thin, density bounded ISM and a riddled, optically thick, ionization bounded ISM, and how Haro 11 fits into theoretical predictions. We find that the most likely ISM model is a clumpy neutral medium embedded in a highly ionized medium with a combined covering fraction of unity and a residual neutral gas column density in the ionized medium high enough to be optically thick to Ly α , but low enough to be at least partly transparent to LyC and undetected in Si ii. This suggests that star formation feedback and galaxy-scale interaction events play a major role in opening passageways for ionizing radiation through the neutral medium.

  16. Physical properties of z ~ 4 LBGs: differences between galaxies with and without Lyα emission

    Science.gov (United States)

    Pentericci, L.; Grazian, A.; Fontana, A.; Salimbeni, S.; Santini, P.; de Santis, C.; Gallozzi, S.; Giallongo, E.

    2007-08-01

    Aims:We analysed the physical properties of z ˜4 Lyman Break Galaxies observed in the GOODS-S survey, in order to investigate possible differences between galaxies where the Lyα is present in emission, and those where the line is absent or in absorption. Methods: The objects were selected from their optical color and then spectroscopically confirmed by Vanzella et al. (2005). From the public spectra we assessed the nature of the Lyα emission and divided the sample into galaxies with Lyα in emission and objects without a Lyα line (i.e. either absent or in absorption). We then used complete photometry, from U band to mid-infrared from the GOODS-MUSIC database, to study the observational properties of the galaxies, such as UV spectral slopes and optical to mid-infrared colors, and the possible differences between the two samples. Lastly, we used standard spectral fitting techniques to determine the physical properties of the galaxies, such as total stellar mass, stellar ages and so on, and again we looked at the possible differences between the two samples. Results: Our results indicate that LBG with Lyα in emission are on average a much younger and less massive population than the LBGs without Lyα emission. Both populations are forming stars very actively and are relatively dust free, although those with line emission seem to be even less dusty on average. We briefly discuss these results in the context of recent models for the evolution of Lyman break galaxies and Lyα emitters.

  17. Specific depletion of Ly6C(hi inflammatory monocytes prevents immunopathology in experimental cerebral malaria.

    Directory of Open Access Journals (Sweden)

    Beatrix Schumak

    Full Text Available Plasmodium berghei ANKA (PbA infection of C57BL/6 mice leads to experimental cerebral malaria (ECM that is commonly associated with serious T cell mediated damage. In other parasitic infection models, inflammatory monocytes have been shown to regulate Th1 responses but their role in ECM remains poorly defined, whereas neutrophils are reported to contribute to ECM immune pathology. Making use of the recent development of specific monoclonal antibodies (mAb, we depleted in vivo Ly6C(hi inflammatory monocytes (by anti-CCR2, Ly6G+ neutrophils (by anti-Ly6G or both cell types (by anti-Gr1 during infection with Ovalbumin-transgenic PbA parasites (PbTg. Notably, the application of anti-Gr1 or anti-CCR2 but not anti-Ly6G antibodies into PbTg-infected mice prevented ECM development. In addition, depletion of Ly6C(hi inflammatory monocytes but not neutrophils led to decreased IFNγ levels and IFNγ+CD8+ T effector cells in the brain. Importantly, anti-CCR2 mAb injection did not prevent the generation of PbTg-specific T cell responses in the periphery, whereas anti-Gr1 mAb injection strongly diminished T cell frequencies and CTL responses. In conclusion, the specific depletion of Ly6C(hi inflammatory monocytes attenuated brain inflammation and immune cell recruitment to the CNS, which prevented ECM following Plasmodium infection, pointing out a substantial role of Ly6C+ monocytes in ECM inflammatory processes.

  18. Carboplatin-pemetrexed in treatment of patients with recurrent/metastatic cancers of the head and neck; superior outcomes in oropharyngeal primaries.

    Directory of Open Access Journals (Sweden)

    Binu eMalhotra

    2015-01-01

    Full Text Available Background – Platinum based therapy in combination with 5-fluorouracil with cetuximab has shown the best survival in pts with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN. The purpose of this study is to evaluate the efficacy and tolerability of carboplatin, pemetrexed and to assess differential outcomes in patients with oropharyngeal primary and HPV related disease.Patients and Methods –The charts of consecutive patients with R/M SCCHN were reviewed. All patients receiving at least 1 cycle of the 2-drug regimen (pemetrexed 500 mg/m2, carboplatin area under the curve of 5 intravenously, were included for assessment of response, safety, toxicity and survival.Results - A total of 86 patients received this regimen between January 2008 and December 2012, of which, 63 were included in this analysis. Forty one percent (26 of the patients had cancers of the oropharynx, and of those, 50% had HPV positive disease, 32% (20 had cancers of the larynx and 24% (15 of the oral cavity. Median number of cycles administered was 4 (range 1-14 cycles with 50% of the patients receiving 4 or more cycles. Half the patients achieved stable disease as their best response, 8% (5 attained a partial response, 24% progressed on therapy and the remaining patients (12 could not have their response assessed.On the basis of Kaplan Meier analysis, median progression free survival (PFS was 5.1 months (95% CI 3.2, 6.2 and median overall survival (OS was 9.4 months (95% CI 4.3, 13.1. Among pts with oropharyngeal primary (n=26, median PFS was 6.4 months (95% CI 2.8, 7.9 and median OS was 16.6 months (95% CI 9.6, 19.5. Among HPV+ pts (n=13, median PFS was 7.0 months (95% CI 4.8, ne and median OS was 17.1 months (95% CI 11.2, 21.7. Conclusion: Combination carboplatin-pemetrexed is an effective and well tolerated treatment, associated with a median PFS of 5.1 months and a clinical benefit in at least 57% of the patients treated.

  19. CHEMISTRY OF A PROTOPLANETARY DISK WITH GRAIN SETTLING AND Lyα RADIATION

    International Nuclear Information System (INIS)

    Fogel, Jeffrey K. J.; Bethell, Thomas J.; Bergin, Edwin A.; Calvet, Nuria; Semenov, Dmitry

    2011-01-01

    We present results from a model of the chemical evolution of protoplanetary disks. In our models, we directly calculate the changing propagation and penetration of a high energy radiation field with Lyα radiation included. We also explore the effect on our models of including dust grain settling. We find that, in agreement with earlier studies, the evolution of dust grains plays a large role in determining how deep the UV radiation penetrates into the disk. Significant grain settling at the midplane leads to much smaller freeze-out regions and a correspondingly larger molecular layer, which leads to an increase in column density for molecular species such as CO, CN, and SO. The inclusion of Lyα radiation impacts the disk chemistry through specific species that have large photodissociation cross sections at 1216 A. These include HCN, NH 3 , and CH 4 , for which the column densities are decreased by an order of magnitude or more due to the presence of Lyα radiation in the UV spectrum. A few species, such as CO 2 and SO, are enhanced by the presence of Lyα radiation, but rarely by more than a factor of a few.

  20. LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism

    International Nuclear Information System (INIS)

    Sun Haipeng; Xu Beibei; Sheveleva, Elena; Chen, Qin M.

    2008-01-01

    Glucocorticoids induce COX-2 expression in rat cardiomyocytes. While investigating whether phosphatidylinositol 3 kinase (PI3K) plays a role in corticosterone (CT)-induced COX-2, we found that LY294002 (LY29) but not wortmannin (WM) attenuates CT from inducing COX-2 gene expression. Expression of a dominant-negative mutant of p85 subunit of PI3K failed to inhibit CT from inducing COX-2 expression. CT did not activate PI3K/AKT signaling pathway whereas LY29 and WM decreased the activity of PI3K. LY303511 (LY30), a structural analogue and a negative control for PI3K inhibitory activity of LY29, also suppressed COX-2 induction. These data suggest PI3K-independent mechanisms in regulating CT-induced COX-2 expression. LY29 and LY30 do not inhibit glucocorticoid receptor transactivity. Both compounds have been reported to inhibit Casein Kinase 2 activity and modulate potassium and calcium levels independent of PI3K, while LY29 has been reported to inhibit mammalian Target of Rapamycin (mTOR), and DNA-dependent Protein Kinase (DNA-PK). Inhibitor of Casein Kinase 2 (CK2), mTOR or DNA-PK failed to prevent CT from inducing COX-2 expression. Tetraethylammonium (TEA), a potassium channel blocker, and nimodipine, a calcium channel blocker, both attenuated CT from inducing COX-2 gene expression. CT was found to increase intracellular Ca 2+ concentration, which can be inhibited by LY29, TEA or nimodipine. These data suggest a possible role of calcium instead of PI3K in CT-induced COX-2 expression in cardiomyocytes

  1. Interaction of LY171883 and other peroxisome proliferators with fatty-acid-binding protein isolated from rat liver.

    Science.gov (United States)

    Cannon, J R; Eacho, P I

    1991-01-01

    Fatty-acid-binding protein (FABP) is a 14 kDa protein found in hepatic cytosol which binds and transports fatty acids and other hydrophobic ligands throughout the cell. The purpose of this investigation was to determine whether LY171883, a leukotriene D4 antagonist, and other peroxisome proliferators bind to FABP and displace an endogenous fatty acid. [3H]Oleic acid was used to monitor the elution of FABP during chromatographic purification. [14C]LY171883 had a similar elution profile when substituted in the purification, indicating a common interaction with FABP. LY171883 and its structural analogue, LY189585, as well as the hypolipidaemic peroxisome proliferators clofibric acid, ciprofibrate, bezafibrate and WY14,643, displaced [3H]oleic acid binding to FABP. Analogues of LY171883 that do not induce peroxisome proliferation only weakly displaced oleate binding. [3H]Ly171883 bound directly to FABP with a Kd of 10.8 microM, compared with a Kd of 0.96 microM for [3H]oleate. LY171883 binding was inhibited by LY189585, clofibric acid, ciprofibrate and bezafibrate. These findings demonstrate that peroxisome proliferators, presumably due to their structural similarity to fatty acids, are able to bind to FABP and displace an endogenous ligand from its binding site. Interaction of peroxisome proliferators with FABP may be involved in perturbations of fatty acid metabolism caused by these agents as well as in the development of the pleiotropic response of peroxisome proliferation. Images Fig. 2. PMID:1747111

  2. The matter power spectrum from the Ly alpha forest : an optical depth estimate

    NARCIS (Netherlands)

    Zaroubi, S; Nusser, A; Haehnelt, M; Kim, TS; Viel, M.

    2006-01-01

    We measure the matter power spectrum from 31 Ly alpha spectra spanning the redshift range of 1.6-3.6. The optical depth, tau, for Ly alpha absorption of the intergalactic medium is obtained from the flux using the inversion method of Nusser & Haehnelt. The optical depth is converted to density by

  3. An economic analysis of erlotinib, docetaxel, pemetrexed and best supportive care as second or third line treatment of non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    A. Araújo

    2008-11-01

    Full Text Available Aim: Evaluate costs and benefits of erlotinib as 2nd or 3rd line treatment of advanced or metastatic nonsmall cell lung cancer (NSCLC versus docetaxel, pemetrexed and best supportive care. Materials and methods: Cost-minimisation and cost-utility analysis were performed. Time horizon of two years. Portuguese National Health System (NHS perspective was applied. Survival and time to progression were obtained from three clinical trials. Base-case analysis: 2nd or 3rd line patients with advanced or metastatic NSCLC. Quality Adjusted Life Years (QALYs were obtained from a UK study. Resource consumption was estimated by a Portuguese panel of experts. Costs were calculated according to official Portuguese databases (updated to 2008. Only direct health costs were applied. Annual discount rate: 5%. Sensitivity analysis included different subpopulations, a three year time horizon and a probabilistic analysis. Results: The cost per patient was lower with erlotinib (€26 478 than docetaxel (€29 262 or pemetrexed (€32 762 and higher than best supportive care (€16 112. QALYs per patient were higher with erlotinib (0.250 than docetaxel (0.225, pemetrexed (0.241 or best supportive care (0.186. Erlotinib was dominant in the cost-utility analysis, with a lower cost and a higher efficacy than docetaxel and pemetrexed. The sensitivity analysis confirmed the robustness of the base-case analysis results. Conclusions: The use of erlotinib instead of docetaxel or pemetrexed could contribute to annual savings for the NHS (substitution rates: 5%–65% ranging from €135 046-€1 755 602 (docetaxel replacement and €291 801-€3 793 409 (pemetrexed replacement, with a gain in terms of QALYs. Resumo: Objectivo: Avaliar o custo-efectividade de erlotinib na segunda ou terceira linha do tratamento do cancro do pulmão de não pequenas células (CPNPC avançado ou metastizado versus docetaxel, pemetrexedo ou tratamento de suporte

  4. [Development and validation of event-specific quantitative PCR method for genetically modified maize LY038].

    Science.gov (United States)

    Mano, Junichi; Masubuchi, Tomoko; Hatano, Shuko; Futo, Satoshi; Koiwa, Tomohiro; Minegishi, Yasutaka; Noguchi, Akio; Kondo, Kazunari; Akiyama, Hiroshi; Teshima, Reiko; Kurashima, Takeyo; Takabatake, Reona; Kitta, Kazumi

    2013-01-01

    In this article, we report a novel real-time PCR-based analytical method for quantitation of the GM maize event LY038. We designed LY038-specific and maize endogenous reference DNA-specific PCR amplifications. After confirming the specificity and linearity of the LY038-specific PCR amplification, we determined the conversion factor required to calculate the weight-based content of GM organism (GMO) in a multilaboratory evaluation. Finally, in order to validate the developed method, an interlaboratory collaborative trial according to the internationally harmonized guidelines was performed with blind DNA samples containing LY038 at the mixing levels of 0, 0.5, 1.0, 5.0 and 10.0%. The precision of the method was evaluated as the RSD of reproducibility (RSDR), and the values obtained were all less than 25%. The limit of quantitation of the method was judged to be 0.5% based on the definition of ISO 24276 guideline. The results from the collaborative trial suggested that the developed quantitative method would be suitable for practical testing of LY038 maize.

  5. THE Lyα LINE PROFILES OF ULTRALUMINOUS INFRARED GALAXIES: FAST WINDS AND LYMAN CONTINUUM LEAKAGE

    Energy Technology Data Exchange (ETDEWEB)

    Martin, Crystal L.; Wong, Joseph [Department of Physics, University of California, Santa Barbara, CA, 93106 (United States); Dijkstra, Mark [Institute of Theoretical Astrophysics, University of Oslo, Postboks 1029, 0858 Oslo (Norway); Henry, Alaina [Astrophysics Science Division, Goddard Space Flight Center, Code 665, Greenbelt, MD 20771 (United States); Soto, Kurt T. [Institute for Astronomy, Department of Physics, ETH Zurich, CH-8093 Zurich (Switzerland); Danforth, Charles W., E-mail: cmartin@physics.ucsb.edu [CASA, Department of Astrophysical and Planetary Sciences, University of Colorado, 389-UCB, Boulder, CO, 80309 (United States)

    2015-04-10

    We present new Hubble Space Telescope Cosmic Origins Spectrograph far-ultraviolet (far-UV) spectroscopy and Keck Echellete optical spectroscopy of 11 ultraluminous infrared galaxies (ULIRGs), a rare population of local galaxies experiencing massive gas inflows, extreme starbursts, and prominent outflows. We detect Lyα emission from eight ULIRGs and the companion to IRAS09583+4714. In contrast to the P Cygni profiles often seen in galaxy spectra, the Lyα profiles exhibit prominent, blueshifted emission out to Doppler shifts exceeding −1000 km s{sup −1} in three H ii-dominated and two AGN-dominated ULIRGs. To better understand the role of resonance scattering in shaping the Lyα line profiles, we directly compare them to non-resonant emission lines in optical spectra. We find that the line wings are already present in the intrinsic nebular spectra, and scattering merely enhances the wings relative to the line core. The Lyα attenuation (as measured in the COS aperture) ranges from that of the far-UV continuum to over 100 times more. A simple radiative transfer model suggests the Lyα photons escape through cavities which have low column densities of neutral hydrogen and become optically thin to the Lyman continuum in the most advanced mergers. We show that the properties of the highly blueshifted line wings on the Lyα and optical emission-line profiles are consistent with emission from clumps of gas condensing out of a fast, hot wind. The luminosity of the Lyα emission increases nonlinearly with the ULIRG bolometric luminosity and represents about 0.1–1% of the radiative cooling from the hot winds in the H ii-dominated ULIRGs.

  6. CLASP/SJ Observations of Rapid Time Variations in the Ly α Emission in a Solar Active Region

    Energy Technology Data Exchange (ETDEWEB)

    Ishikawa, Shin-nosuke [Institute of Space and Astronautical Science, Japan Aerospace Exploration Agency, 3-1-1 Yoshinodai, Chuo-ku, Sagamihara, Kanagawa 252–5210 (Japan); Kubo, Masahito; Katsukawa, Yukio; Kano, Ryouhei; Narukage, Noriyuki; Ishikawa, Ryohko; Bando, Takamasa [National Astronomical Observatory of Japan, 2-21-1 Osawa, Mitaka, Tokyo 181-8588 (Japan); Winebarger, Amy; Kobayashi, Ken [NASA Marshall Space Flight Center, Huntsville, AL 35812 (United States); Trujillo Bueno, Javier [Instituto de Astrofísica de Canarias, E-38205 La Laguna, Tenerife (Spain); Auchère, Frédéric, E-mail: s.ishikawa@solar.isas.jaxa.jp [Institut d’Astrophysique Spatiale, CNRS/Univ. Paris-Sud 11, Bätiment 121, F-91405 Orsay (France)

    2017-09-10

    The Chromospheric Ly α SpectroPolarimeter (CLASP) is a sounding rocket experiment launched on 2015 September 3 to investigate the solar chromosphere and transition region. The slit-jaw (SJ) optical system captured Ly α images with a high time cadence of 0.6 s. From the CLASP/SJ observations, many variations in the solar chromosphere and transition region emission with a timescale of <1 minute were discovered. In this paper, we focus on the active region within the SJ field of view and investigate the relationship between short (<30 s) temporal variations in the Ly α emission and the coronal structures observed by Solar Dynamics Observatory/Atmospheric Imaging Assembly (AIA). We compare the Ly α temporal variations at the coronal loop footpoints observed in the AIA 211 Å (≈2 MK) and AIA 171 Å (≈0.6 MK) channels with those in the regions with bright Ly α features without a clear association with the coronal loop footpoints. We find more short (<30 s) temporal variations in the Ly α intensity in the footpoint regions. Those variations did not depend on the temperature of the coronal loops. Therefore, the temporal variations in the Ly α intensity at this timescale range could be related to the heating of the coronal structures up to temperatures around the sensitivity peak of 171 Å. No signature was found to support the scenario that these Ly α intensity variations were related to the nanoflares. Waves or jets from the lower layers (lower chromosphere or photosphere) are possible causes for this phenomenon.

  7. Studies on Inhibition of Proliferation of Enterovirus-71 by Compound YZ-LY-0.

    Science.gov (United States)

    Yang, Qingzhan; Jie, Qing; Shaw, Neil; Li, Lei; Rao, Zihe; Yin, Zheng; Lou, Zhiyong

    2015-01-01

    In recent years, hand-foot-and-mouth disease (HFMD), which is caused by Enteroviruses, has emerged as a serious illness. It affects mainly children under the age of five and results in high fatality rates. Enterovirus 71 (EV71) is the main causative agent of HFMD in China and currently there are no effective anti-viral drugs available to treat HFMD. In the present study, we screened compounds for inhibition of proliferation of EV71. Compound YZ-LY-0 stalled the life cycle of EV71. The inhibitor exhibited EC50 value of 0.29 μm against SK-EV006 strain of EV71. Notably, YZ-LY-0 had low cytotoxicity (CC50 > 100 μM) and a high selectivity index (over 300) in Vero and RD cells. YZ-LY-0 in combination with an EV71 RdRp inhibitor or an entry inhibitor showed an antagonistic effect at very low concentrations. However, at higher concentrations the inhibitors exhibited a synergistic effect in inhibiting viral replication. Preliminary results on investigation of the mechanism of inhibition indicate that YZ-LY-0 does not block the entry of the virus in the host cell, but instead inhibits an early stage of EV71 replication. Our studies provide a potential clinical therapeutic option against EV71 infections and suggest that a combined application of YZ-LY-0 with other inhibitors could be more effective in the treatment of HFMD.

  8. Polymeric Nano-Micelles as Novel Cargo-Carriers for LY2157299 Liver Cancer Cells Delivery

    Directory of Open Access Journals (Sweden)

    Nemany Abdelhamid Nemany Hanafy

    2018-03-01

    Full Text Available LY2157299 (LY, which is very small molecule bringing high cancer diffusion, is a pathway antagonist against TGFβ. LY dosage can be diluted by blood plasma, can be captured by immune system or it might be dissolved during digestion in gastrointestinal tract. The aim of our study is to optimize a “nano-elastic” carrier to avoid acidic pH of gastrointestinal tract, colon alkaline pH, and anti-immune recognition. Polygalacturonic acid (PgA is not degradable in the gastrointestinal tract due to its insolubility at acidic pH. To avoid PgA solubility in the colon, we have designed its conjugation with Polyacrylic acid (PAA. PgA-PAA conjugation has enhanced their potential use for oral and injected dosage. Following these pre-requisites, novel polymeric nano-micelles derived from PgA-PAA conjugation and loading LY2157299 are developed and characterized. Efficacy, uptake and targeting against a hepatocellular carcinoma cell line (HLF have also been demonstrated.

  9. New Results from the Magellan IMACS Spectroscopic Lyα Survey: NICMOS Observations of Lyα Emitters at z = 5.7

    Science.gov (United States)

    Henry, Alaina L.; Martin, Crystal L.; Dressler, Alan; McCarthy, Patrick; Sawicki, Marcin

    2010-08-01

    We present NICMOS J 110 (rest-frame 1200-2100 Å) observations of the three z = 5.7 Lyα emitters discovered in the blind multislit spectroscopic survey by Martin et al. These images confirm the presence of the two sources that were previously only seen in spectroscopic observations. The third source, which is undetected in our J 110 observations, has been detected in narrowband imaging of the Cosmic Origins Survey, so our non-detection implies a rest-frame equivalent width >146 Å (3σ). The two J 110-detected sources have more modest rest-frame equivalent widths of 30-40 Å, but all three are typical of high-redshift Lyα emitters. In addition, the J 110-detected sources have UV luminosities that are within a factor of 2 of L*UV, and sizes that appear compact (r hl~ 0farcs15) in our NIC2 images—consistent with a redshift of 5.7. We use these UV-continuum and Lyα measurements to estimate the i 775-z 850 colors of these galaxies and show that at least one and possibly all three would be missed by the i-dropout Lyman break galaxy selection. These observations help demonstrate the utility of multislit narrowband spectroscopy as a technique for finding faint emission-line galaxies. This work is based in part on observations made with the NASA/ESA Hubble Space Telescope, obtained from the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy Inc., under NASA contract NAS 5-26555. These observations are associated with proposal 11183.

  10. Lyα EMITTING GALAXIES AS EARLY STAGES IN GALAXY FORMATION

    International Nuclear Information System (INIS)

    Cowie, Lennox L.; Barger, Amy J.; Hu, Esther M.

    2011-01-01

    We present optical spectroscopy of two samples of Galaxy Evolution Explorer grism selected Lyα emitters (LAEs): one at z = 0.195-0.44 and the other at z = 0.65-1.25. We have also observed a comparison sample of galaxies in the same redshift intervals with the same UV magnitude distributions but with no detected Lyα. We use the optical spectroscopy to eliminate active galactic nuclei and to obtain the optical emission-line properties of the samples. We compare the luminosities of the LAEs in the two redshift intervals and show that there is dramatic evolution in the maximum Lyα luminosity over z = 0-1. Focusing on the z = 0.195-0.44 samples alone, we show that there are tightly defined relations between all of the galaxy parameters and the rest-frame equivalent width (EW) of Hα. The higher EW(Hα) sources all have lower metallicities, bluer colors, smaller sizes, and less extinction, consistent with their being in the early stages of the galaxy formation process. We find that 75% ± 12% of the LAEs have EW(Hα) >100 A and, conversely, that 31% ± 13% of galaxies with EW(Hα) >100 A are LAEs. We correct the broadband magnitudes for the emission-line contributions and use spectral synthesis fits to estimate the ages of the galaxies. We find a median age of 1.1 x 10 8 yr for the LAE sample and 1.4 x 10 9 yr for the UV-continuum sample without detected Lyα. The median metallicity of the LAE sample is 12 + log (O/H) = 8.24, or about 0.4 dex lower than the UV-continuum sample.

  11. Molecular Mechanism of Enhanced Anticancer Effect of Nanoparticle Formulated LY2835219 via p16-CDK4/6-pRb Pathway in Colorectal Carcinoma Cell Line

    Directory of Open Access Journals (Sweden)

    Xu Tang

    2016-01-01

    Full Text Available LY2835219 is a dual inhibitor to CDK4 and CDK6. This study was to prepare LY2835219-loaded chitosan nanoparticles (CNP/LY and LY2835219-loaded hyaluronic acid-conjugated chitosan nanoparticles (HACNP/LY and revealed their anticancer effect and influence on p16-CDK4/6-pRb pathway against colon cell line. The nanoparticle sizes of CNP/LY and HACNP/LY were approximately 195±39.6 nm and 217±31.1 nm, respectively. The zeta potentials of CNP/LY and HACNP/LY were 37.3±1.5 mV and 30.3±2.2 mV, respectively. And the preparation process showed considerable drug encapsulation efficiency and loading efficiency. LY2835219, CNP/LY, and HACNP/LY inhibited HT29 cell proliferation with 0.68, 0.54, and 0.30 μM of IC50, respectively. G1 phase was arrested by LY2835219 and its formulations. Furthermore, inhibition of CDK4/6 by LY2835219 formulations induced CDK4, CDK6, cyclin D1, and pRb decrease and p16 increase at both protein and mRNA levels. Overall, nanoparticle formulated LY2835219 could enhance the cytotoxicity and cell cycle arrest, and HACNP/LY strengthened the trend furtherly compared to CNP/LY. It is the first time to demonstrate the anticancer effect and mechanism against HT29 by LY2835219 and its nanoparticles. The drug and its nanoparticle formulations delay the cell growth and arrest cell cycle through p16-CDK4/6-pRb pathway, while the nanoparticle formulated LY2835219 could strengthen the process.

  12. Damped Lyα system toward QSO1854+116: A new type of absorber?

    Directory of Open Access Journals (Sweden)

    Ćirković M.M.

    1999-01-01

    Full Text Available A puzzle of the low-redshift damped Lyα absorption system toward QSO 1854+116 is presented. Problems which conventional intepretation of damped Lyα systems encounters in this case are sketched and a possible explanation, based on transience of the phenomenon, is suggested. It is shown that the detailed Hα tomography can observationally resolve the controversy in the very near future.

  13. Natural killer cell receptor genes in the family Equidae: not only Ly49.

    Directory of Open Access Journals (Sweden)

    Jan Futas

    Full Text Available Natural killer (NK cells have important functions in immunity. NK recognition in mammals can be mediated through killer cell immunoglobulin-like receptors (KIR and/or killer cell lectin-like Ly49 receptors. Genes encoding highly variable NK cell receptors (NKR represent rapidly evolving genomic regions. No single conservative model of NKR genes was observed in mammals. Single-copy low polymorphic NKR genes present in one mammalian species may expand into highly polymorphic multigene families in other species. In contrast to other non-rodent mammals, multiple Ly49-like genes appear to exist in the horse, while no functional KIR genes were observed in this species. In this study, Ly49 and KIR were sought and their evolution was characterized in the entire family Equidae. Genomic sequences retrieved showed the presence of at least five highly conserved polymorphic Ly49 genes in horses, asses and zebras. These findings confirmed that the expansion of Ly49 occurred in the entire family. Several KIR-like sequences were also identified in the genome of Equids. Besides a previously identified non-functional KIR-Immunoglobulin-like transcript fusion gene (KIR-ILTA and two putative pseudogenes, a KIR3DL-like sequence was analyzed. In contrast to previous observations made in the horse, the KIR3DL sequence, genomic organization and mRNA expression suggest that all Equids might produce a functional KIR receptor protein molecule with a single non-mutated immune tyrosine-based inhibition motif (ITIM domain. No evidence for positive selection in the KIR3DL gene was found. Phylogenetic analysis including rhinoceros and tapir genomic DNA and deduced amino acid KIR-related sequences showed differences between families and even between species within the order Perissodactyla. The results suggest that the order Perissodactyla and its family Equidae with expanded Ly49 genes and with a potentially functional KIR gene may represent an interesting model for

  14. Natural Killer Cell Receptor Genes in the Family Equidae: Not only Ly49

    Science.gov (United States)

    Futas, Jan; Horin, Petr

    2013-01-01

    Natural killer (NK) cells have important functions in immunity. NK recognition in mammals can be mediated through killer cell immunoglobulin-like receptors (KIR) and/or killer cell lectin-like Ly49 receptors. Genes encoding highly variable NK cell receptors (NKR) represent rapidly evolving genomic regions. No single conservative model of NKR genes was observed in mammals. Single-copy low polymorphic NKR genes present in one mammalian species may expand into highly polymorphic multigene families in other species. In contrast to other non-rodent mammals, multiple Ly49-like genes appear to exist in the horse, while no functional KIR genes were observed in this species. In this study, Ly49 and KIR were sought and their evolution was characterized in the entire family Equidae. Genomic sequences retrieved showed the presence of at least five highly conserved polymorphic Ly49 genes in horses, asses and zebras. These findings confirmed that the expansion of Ly49 occurred in the entire family. Several KIR-like sequences were also identified in the genome of Equids. Besides a previously identified non-functional KIR-Immunoglobulin-like transcript fusion gene (KIR-ILTA) and two putative pseudogenes, a KIR3DL-like sequence was analyzed. In contrast to previous observations made in the horse, the KIR3DL sequence, genomic organization and mRNA expression suggest that all Equids might produce a functional KIR receptor protein molecule with a single non-mutated immune tyrosine-based inhibition motif (ITIM) domain. No evidence for positive selection in the KIR3DL gene was found. Phylogenetic analysis including rhinoceros and tapir genomic DNA and deduced amino acid KIR-related sequences showed differences between families and even between species within the order Perissodactyla. The results suggest that the order Perissodactyla and its family Equidae with expanded Ly49 genes and with a potentially functional KIR gene may represent an interesting model for evolutionary biology of

  15. PREDICTING Lyα AND Mg II FLUXES FROM K AND M DWARFS USING GALAXY EVOLUTION EXPLORER ULTRAVIOLET PHOTOMETRY

    International Nuclear Information System (INIS)

    Shkolnik, Evgenya L.; Rolph, Kristina A.; Peacock, Sarah; Barman, Travis S.

    2014-01-01

    A star's ultraviolet (UV) emission can greatly affect the atmospheric chemistry and physical properties of closely orbiting planets with the potential for severe mass loss. In particular, the Lyα emission line at 1216 Å, which dominates the far-ultraviolet (FUV) spectrum, is a major source of photodissociation of important atmospheric molecules such as water and methane. The intrinsic flux of Lyα, however, cannot be directly measured due to the absorption of neutral hydrogen in the interstellar medium and contamination by geocoronal emission. To date, reconstruction of the intrinsic Lyα line based on Hubble Space Telescope spectra has been accomplished for 46 FGKM nearby stars, 28 of which have also been observed by the Galaxy Evolution Explorer (GALEX). Our investigation provides a correlation between published intrinsic Lyα and GALEX far- and near-ultraviolet (NUV) chromospheric fluxes for K and M stars. The negative correlations between the ratio of the Lyα to the GALEX fluxes reveal how the relative strength of Lyα compared to the broadband fluxes weakens as the FUV and NUV excess flux increase. We also correlate GALEX fluxes with the strong NUV Mg II h+k spectral emission lines formed at lower chromospheric temperatures than Lyα. The reported correlations provide estimates of intrinsic Lyα and Mg II fluxes for the thousands of K and M stars in the archived GALEX all-sky surveys. These will constrain new stellar upper atmosphere models for cool stars and provide realistic inputs to models describing exoplanetary photochemistry and atmospheric evolution in the absence of UV spectroscopy

  16. The Ar{sup 17+} Ly{sub {alpha}2}/Ly{sub {alpha}1} ratio in Alcator C-Mod tokamak plasmas

    Energy Technology Data Exchange (ETDEWEB)

    Rice, J E; Reinke, M L; Ince-Cushman, A C; Podpaly, Y A [Plasma Science and Fusion Center, MIT, Cambridge, MA (United States); Ashbourn, J M A [Mathematical Institute, University of Oxford, Oxford (United Kingdom); Gu, M F [SSL, University of California Berkeley, CA (United States); Bitter, M; Hill, K [Princeton Plasma Physics Laboratory, Princeton, NJ (United States); Rachlew, E, E-mail: rice@psfc.mit.edu [KTH, Stockholm (Sweden)

    2011-08-28

    High-quality spectra of hydrogen-like Ar{sup 17+} have been obtained from Alcator C-Mod tokamak plasmas using a spatially imaging high-resolution x-ray spectrometer system in an extensive study of the underlying high-n satellite lines. The ratio of Ly{sub {alpha}2} (1S{sub 1/2}-2P{sub 1/2}) to Ly{sub {alpha}1} (1S{sub 1/2}-2P{sub 3/2}) was found to be {approx}0.52 regardless of plasma parameters, which is somewhat greater than the ratio of the statistical weights of the upper n = 2 levels, 0.5. This difference is mainly due to the effects of collisional excitation of fine-structure sub-levels. For the observations presented here, electron densities were in an extended range from 3x10{sup 19} to 4x10{sup 20} m{sup -3} with electron and ion temperatures between 1 and 4 keV. Experimental results are compared to calculations from COLRAD, a collisional-radiative modelling code, and good agreement is shown.

  17. The HETDEX pilot survey. V. The physical origin of Lyα emitters probed by near-infrared spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Song, Mimi; Finkelstein, Steven L.; Gebhardt, Karl; Hill, Gary J.; Drory, Niv; Chonis, Taylor; Jogee, Shardha; Livermore, Rachael [Department of Astronomy, The University of Texas at Austin, 2515 Speedway, Stop C1400, Austin, TX 78712 (United States); Ashby, Matthew L. N.; Fazio, Giovanni G.; Huang, Jia-Sheng [Harvard-Smithsonian Center for Astrophysics, 60 Garden Street, Cambridge, MA 02138 (United States); Blanc, Guillermo A. [Observatories of the Carnegie Institution of Washington, 813 Santa Barbara Street, Pasadena, CA 91101 (United States); Bridge, Joanna; Ciardullo, Robin; Gronwall, Caryl; Hagen, Alex; Schneider, Donald P. [Department of Astronomy and Astrophysics, The Pennsylvania State University, University Park, PA 16802 (United States); Fabricius, Maximilian; Gawiser, Eric [Department of Physics and Astronomy, Rutgers University, Piscataway, NJ 08854 (United States); Salmon, Brett, E-mail: mmsong@astro.as.utexas.edu [Department of Physics and Astronomy, Texas A and M University, College Station, TX 77843 (United States); and others

    2014-08-10

    We present the results from a Very Large Telescope/SINFONI and Keck/NIRSPEC near-infrared spectroscopic survey of 16 Lyα emitters (LAEs) at z = 2.1-2.5 in the COSMOS and GOODS-N fields discovered from the Hobby Eberly Telescope Dark Energy Experiment Pilot Survey. We detect rest-frame optical nebular lines (Hα and/or [O III] λ5007) for 10 of the LAEs and measure physical properties, including the star formation rate (SFR), gas-phase metallicity, gas mass fraction, and Lyα velocity offset. We find that LAEs may lie below the mass-metallicity relation for continuum-selected star-forming galaxies at the same redshift. The LAEs all show velocity shifts of Lyα relative to the systemic redshift ranging between +85 and +296 km s{sup –1} with a mean of +180 km s{sup –1}. This value is smaller than measured for continuum-selected star-forming galaxies at similar redshifts. The Lyα velocity offsets show a moderate correlation with the measured SFR (2.5σ), but no significant correlations are seen with the SFR surface density, specific SFR, stellar mass, or dynamical mass (≲1.5σ). Exploring the role of dust, kinematics of the interstellar medium (ISM), and geometry on the escape of Lyα photons, we find no signature of selective quenching of resonantly scattered Lyα photons. However, we also find no evidence that a clumpy ISM is enhancing the Lyα equivalent width. Our results suggest that the low metallicity in LAEs may be responsible for yielding an environment with a low neutral hydrogen column density and less dust, easing the escape of Lyα photons over that in continuum-selected star-forming galaxies.

  18. The HETDEX pilot survey. V. The physical origin of Lyα emitters probed by near-infrared spectroscopy

    International Nuclear Information System (INIS)

    Song, Mimi; Finkelstein, Steven L.; Gebhardt, Karl; Hill, Gary J.; Drory, Niv; Chonis, Taylor; Jogee, Shardha; Livermore, Rachael; Ashby, Matthew L. N.; Fazio, Giovanni G.; Huang, Jia-Sheng; Blanc, Guillermo A.; Bridge, Joanna; Ciardullo, Robin; Gronwall, Caryl; Hagen, Alex; Schneider, Donald P.; Fabricius, Maximilian; Gawiser, Eric; Salmon, Brett

    2014-01-01

    We present the results from a Very Large Telescope/SINFONI and Keck/NIRSPEC near-infrared spectroscopic survey of 16 Lyα emitters (LAEs) at z = 2.1-2.5 in the COSMOS and GOODS-N fields discovered from the Hobby Eberly Telescope Dark Energy Experiment Pilot Survey. We detect rest-frame optical nebular lines (Hα and/or [O III] λ5007) for 10 of the LAEs and measure physical properties, including the star formation rate (SFR), gas-phase metallicity, gas mass fraction, and Lyα velocity offset. We find that LAEs may lie below the mass-metallicity relation for continuum-selected star-forming galaxies at the same redshift. The LAEs all show velocity shifts of Lyα relative to the systemic redshift ranging between +85 and +296 km s –1 with a mean of +180 km s –1 . This value is smaller than measured for continuum-selected star-forming galaxies at similar redshifts. The Lyα velocity offsets show a moderate correlation with the measured SFR (2.5σ), but no significant correlations are seen with the SFR surface density, specific SFR, stellar mass, or dynamical mass (≲1.5σ). Exploring the role of dust, kinematics of the interstellar medium (ISM), and geometry on the escape of Lyα photons, we find no signature of selective quenching of resonantly scattered Lyα photons. However, we also find no evidence that a clumpy ISM is enhancing the Lyα equivalent width. Our results suggest that the low metallicity in LAEs may be responsible for yielding an environment with a low neutral hydrogen column density and less dust, easing the escape of Lyα photons over that in continuum-selected star-forming galaxies.

  19. Stacking the Cosmic Web in fluorescent Ly α emission with MUSE

    Science.gov (United States)

    Gallego, Sofia G.; Cantalupo, Sebastiano; Lilly, Simon; Marino, Raffaella Anna; Pezzulli, Gabriele; Schaye, Joop; Wisotzki, Lutz; Bacon, Roland; Inami, Hanae; Akhlaghi, Mohammad; Tacchella, Sandro; Richard, Johan; Bouche, Nicolas F.; Steinmetz, Matthias; Carollo, Marcella

    2018-04-01

    Cosmological simulations suggest that most of the matter in the Universe is distributed along filaments connecting galaxies. Illuminated by the cosmic UV background (UVB), these structures are expected to glow in fluorescent Ly α emission with a surface brightness (SB) that is well below current limits for individual detections. Here, we perform a stacking analysis of the deepest MUSE/VLT data using three-dimensional regions (subcubes) with orientations determined by the position of neighbouring Ly α galaxies at 3 < z < 4. Our method increase the probability of detecting filamentary Ly α emission, provided that these structures are Lyman-limit systems (LLSs). By stacking 390 oriented subcubes we reach a 2σ sensitivity level of SB ≈ 0.44 × 10-20 erg s-1 cm-2 arcsec-2 in an aperture of 1 arcsec2 × 6.25 Å, three times below the expected fluorescent Ly α signal from the Haardt & Madau UVB at z ˜ 3.5. No detectable emission is found on intergalactic scales, implying that at least two thirds of our subcubes do not contain oriented LLSs. On the other hand, significant emission is detected in the circumgalactic medium (CGM) in the direction of the neighbours. The signal is stronger for galaxies with a larger number of neighbours and appears to be independent of any other galaxy properties. We estimate that preferentially oriented satellite galaxies cannot contribute significantly to this signal, suggesting instead that gas densities in the CGM are typically larger in the direction of neighbouring galaxies on cosmological scales.

  20. A DEEP NARROWBAND IMAGING SEARCH FOR C iv AND He ii EMISSION FROM Lyα BLOBS

    International Nuclear Information System (INIS)

    Battaia, Fabrizio Arrigoni; Yang, Yujin; Hennawi, Joseph F.; Prochaska, J. Xavier; Matsuda, Yuichi; Yamada, Toru; Hayashino, Tomoki

    2015-01-01

    We conduct a deep narrowband imaging survey of 13 Lyα blobs (LABs) located in the SSA22 proto-cluster at z ∼ 3.1 in the C iv and He ii emission lines in an effort to constrain the physical process powering the Lyα emission in LABs. Our observations probe down to unprecedented surface brightness (SB) limits of (2.1–3.4) × 10 −18 erg s −1 cm −2 arcsec −2 per 1 arcsec 2 aperture (5σ) for the He ii λ1640 and C iv λ1549 lines, respectively. We do not detect extended He ii and C iv emission in any of the LABs, placing strong upper limits on the He ii/Lyα and C iv/Lyα line ratios, of 0.11 and 0.16, for the brightest two LABs in the field. We conduct detailed photoionization modeling of the expected line ratios and find that, although our data constitute the deepest ever observations of these lines, they are still not deep enough to rule out a scenario where the Lyα emission is powered by the ionizing radiation from an obscured active galactic nucleus. Our models can accommodate He ii/Lyα and C iv/Lyα ratios as low as ≃0.05 and ≃0.07, respectively, implying that one needs to reach SB as low as (1–1.5) × 10 −18 erg s −1 cm −2 arcsec −2  (at 5σ) in order to rule out a photoionization scenario. These depths will be achievable with the new generation of image-slicing integral field units such as the Multi Unit Spectroscopic Explorer (MUSE) on VLT and the Keck Cosmic Web Imager (KCWI). We also model the expected He ii/Lyα and C iv/Lyα in a different scenario, where Lyα emission is powered by shocks generated in a large-scale superwind, but find that our observational constraints can only be met for shock velocities v s ≳ 250 km s −1 , which appear to be in conflict with recent observations of quiescent kinematics in LABs

  1. TRANSITING THE SUN. II. THE IMPACT OF STELLAR ACTIVITY ON Lyα TRANSITS

    International Nuclear Information System (INIS)

    Llama, J.; Shkolnik, E. L.

    2016-01-01

    High-energy observations of the Sun provide an opportunity to test the limits of our ability to accurately measure the properties of transiting exoplanets in the presence of stellar activity. Here we insert the transit of a hot Jupiter into continuous disk integrated data of the Sun in Lyα from NASA’s Solar Dynamics Observatory/EVE instrument to assess the impact of stellar activity on the measured planet-to-star radius ratio (R p /R ⋆ ). In 75% of our simulated light curves, we measure the correct radius ratio; however, incorrect values can be measured if there is significant short-term variability in the light curve. The maximum measured value of R p /R ⋆ is 50% larger than the input value, which is much smaller than the large Lyα transit depths that have been reported in the literature, suggesting that for stars with activity levels comparable to the Sun, stellar activity alone cannot account for these deep transits. We ran simulations without a transit and found that stellar activity cannot mimic the Lyα transit of 55 Cancari b, strengthening the conclusion that this planet has a partially transiting exopshere. We were able to compare our simulations to more active stars by artificially increasing the variability in the Solar Lyα light curve. In the higher variability data, the largest value of R p /R ⋆ we measured is <3× the input value, which again is not large enough to reproduce the Lyα transit depth reported for the more active stars HD 189733 and GJ 436, supporting the interpretation that these planets have extended atmospheres and possible cometary tails

  2. A novel small molecular STAT3 inhibitor, LY5, inhibits cell viability, cell migration, and angiogenesis in medulloblastoma cells.

    Science.gov (United States)

    Xiao, Hui; Bid, Hemant Kumar; Jou, David; Wu, Xiaojuan; Yu, Wenying; Li, Chenglong; Houghton, Peter J; Lin, Jiayuh

    2015-02-06

    Signal transducers and activators of transcription 3 (STAT3) signaling is persistently activated and could contribute to tumorigenesis of medulloblastoma. Numerous studies have demonstrated that inhibition of the persistent STAT3 signaling pathway results in decreased proliferation and increased apoptosis in human cancer cells, indicating that STAT3 is a viable molecular target for cancer therapy. In this study, we investigated a novel non-peptide, cell-permeable small molecule, named LY5, to target STAT3 in medulloblastoma cells. LY5 inhibited persistent STAT3 phosphorylation and induced apoptosis in human medulloblastoma cell lines expressing constitutive STAT3 phosphorylation. The inhibition of STAT3 signaling by LY5 was confirmed by down-regulating the expression of the downstream targets of STAT3, including cyclin D1, bcl-XL, survivin, and micro-RNA-21. LY5 also inhibited the induction of STAT3 phosphorylation by interleukin-6 (IL-6), insulin-like growth factor (IGF)-1, IGF-2, and leukemia inhibitory factor in medulloblastoma cells, but did not inhibit STAT1 and STAT5 phosphorylation stimulated by interferon-γ (IFN-γ) and EGF, respectively. In addition, LY5 blocked the STAT3 nuclear localization induced by IL-6, but did not block STAT1 and STAT5 nuclear translocation mediated by IFN-γ and EGF, respectively. A combination of LY5 with cisplatin or x-ray radiation also showed more potent effects than single treatment alone in the inhibition of cell viability in human medulloblastoma cells. Furthermore, LY5 demonstrated a potent inhibitory activity on cell migration and angiogenesis. Taken together, these findings indicate LY5 inhibits persistent and inducible STAT3 phosphorylation and suggest that LY5 is a promising therapeutic drug candidate for medulloblastoma by inhibiting persistent STAT3 signaling. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. A potential germ cell-specific marker in Japanese flounder, Paralichthys olivaceus: identification and characterization of lymphocyte antigen 75 (Ly75/CD205)

    Science.gov (United States)

    Yang, Yang; Liu, Qinghua; Ma, Daoyuan; Song, Zongchen; Li, Jun

    2018-04-01

    Some germ cell marker genes, such as vasa, nanos, and dead end (dnd), have been identified in fish. Recently, lymphocyte antigen 75 (Ly75/CD205) has been identified as a mitotic germ cell-specific cell-surface marker in several fish species. In this study, the Japanese flounder ly75 homolog (ly75) was cloned and its expression pattern in gonads was analyzed. The full-length cDNA of ly75 was 7 346 bp, with an open reading frame (ORF) of 5 229 bp. The ORF encoded a protein containing 1 742 amino acids with a predicted molecular mass of 196.89 kDa. In adult tissues, ly75 transcripts were detected in all analyzed tissues but abundantly in the testis. In in-situ hybridization analyses, ly75 mRNA was predominantly localized in oocytes in the ovary and spermatogonia in the testis, but ly75 mRNA was not detected in oogonia, spermatocytes, spermatids, or spermatozoa. These results indicated that ly75 could be a potential germ cell-specific marker in P. olivaceus, as in other fishes.

  4. CD11b⁺, Ly6G⁺ cells produce type I interferon and exhibit tissue protective properties following peripheral virus infection.

    Directory of Open Access Journals (Sweden)

    Matthew A Fischer

    2011-11-01

    Full Text Available The goal of the innate immune system is containment of a pathogen at the site of infection prior to the initiation of an effective adaptive immune response. However, effector mechanisms must be kept in check to combat the pathogen while simultaneously limiting undesirable destruction of tissue resulting from these actions. Here we demonstrate that innate immune effector cells contain a peripheral poxvirus infection, preventing systemic spread of the virus. These innate immune effector cells are comprised primarily of CD11b⁺Ly6C⁺Ly6G⁻ monocytes that accumulate initially at the site of infection, and are then supplemented and eventually replaced by CD11b⁺Ly6C⁺Ly6G⁺ cells. The phenotype of the CD11b⁺Ly6C⁺Ly6G⁺ cells resembles neutrophils, but the infiltration of neutrophils typically occurs prior to, rather than following, accumulation of monocytes. Indeed, it appears that the CD11b⁺Ly6C⁺Ly6G⁺ cells that infiltrated the site of VACV infection in the ear are phenotypically distinct from the classical description of both neutrophils and monocyte/macrophages. We found that CD11b⁺Ly6C⁺Ly6G⁺ cells produce Type I interferons and large quantities of reactive oxygen species. We also observed that depletion of Ly6G⁺ cells results in a dramatic increase in tissue damage at the site of infection. Tissue damage is also increased in the absence of reactive oxygen species, although reactive oxygen species are typically thought to be damaging to tissue rather than protective. These data indicate the existence of a specialized population of CD11b⁺Ly6C⁺Ly6G⁺ cells that infiltrates a site of virus infection late and protects the infected tissue from immune-mediated damage via production of reactive oxygen species. Regulation of the action of this population of cells may provide an intervention to prevent innate immune-mediated tissue destruction.

  5. Identities of P2 and P3 Residues of H-2Kb-Bound Peptides Determine Mouse Ly49C Recognition.

    Directory of Open Access Journals (Sweden)

    Elsa A Marquez

    Full Text Available Ly49 receptors can be peptide selective in their recognition of MHC-I-peptide complexes, affording them a level of discrimination beyond detecting the presence or absence of specific MHC-I allele products. Despite this ability, little is understood regarding the properties that enable some peptides, when bound to MHC-I molecules, to support Ly49 recognition, but not others. Using RMA-S target cells expressing MHC-I molecules loaded with individual peptides and effector cells expressing the ectodomain of the inhibitory Ly49C receptor, we found that two adjacent amino acid residues, P2 and P3, both buried in the peptide binding groove of H-2Kb, determine mouse Ly49C specificity. If both are aliphatic residues, this is supportive. Whereas, small amino acids at P2 and aromatic amino acids at the P3 auxiliary anchor residue are detrimental to Ly49C recognition. These results resemble those with a rat Ly49 where the identity of a peptide anchor residue determines recognition, suggesting that dependence on specific peptide residues buried in the MHC-I peptide-binding groove may be fundamental to Ly49 peptide selectivity and recognition.

  6. Extended and broad Ly α emission around a BAL quasar at z ˜ 5

    Science.gov (United States)

    Ginolfi, M.; Maiolino, R.; Carniani, S.; Arrigoni Battaia, F.; Cantalupo, S.; Schneider, R.

    2018-05-01

    In this work we report deep MUSE observations of a broad absorption line (BAL) quasar at z ˜ 5, revealing a Ly α nebula with a maximum projected linear size of ˜60 kpc around the quasar (down to our 2σ SB limit per layer of ˜ 9× 10^{-19} erg s^{-1} cm^{-2} arcsec^{-2} for a 1 arcsec2 aperture). After correcting for the cosmological surface brightness dimming, we find that our nebula, at z ˜ 5, has an intrinsically less extended Ly α emission than nebulae at lower redshift. However, such a discrepancy is greatly reduced when referring to comoving distances, which take into account the cosmological growth of dark matter (DM) haloes, suggesting a positive correlation between the size of Ly α nebulae and the sizes of DM haloes/structures around quasars. Differently from the typical nebulae around radio-quiet non-BAL quasars, in the inner regions (˜10 kpc) of the circumgalactic medium of our source, the velocity dispersion of the Ly α emission is very high (FWHM > 1000 km s-1), suggesting that in our case we may be probing outflowing material associated with the quasar.

  7. Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F

    International Nuclear Information System (INIS)

    Ma, L; Clayton, J R; Walgren, R A; Zhao, B; Evans, R J; Smith, M C; Heinz-Taheny, K M; Kreklau, E L; Bloem, L; Pitou, C; Shen, W; Strelow, J M; Halstead, C; Rempala, M E; Parthasarathy, S; Gillig, J R; Heinz, L J; Pei, H; Wang, Y; Stancato, L F; Dowless, M S; Iversen, P W; Burkholder, T P

    2013-01-01

    Owing to the prevalence of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs), its constitutive activity, and ability to recapitulate the MPN phenotype in mouse models, JAK2V617F kinase is an attractive therapeutic target. We report the discovery and initial characterization of the orally bioavailable imidazopyridazine, LY2784544, a potent, selective and ATP-competitive inhibitor of janus kinase 2 (JAK2) tyrosine kinase. LY2784544 was discovered and characterized using a JAK2-inhibition screening assay in tandem with biochemical and cell-based assays. LY2784544 in vitro selectivity for JAK2 was found to be equal or superior to known JAK2 inhibitors. Further studies showed that LY2784544 effectively inhibited JAK2V617F-driven signaling and cell proliferation in Ba/F3 cells (IC 50 =20 and 55 nM, respectively). In comparison, LY2784544 was much less potent at inhibiting interleukin-3-stimulated wild-type JAK2-mediated signaling and cell proliferation (IC 50 =1183 and 1309 nM, respectively). In vivo, LY2784544 effectively inhibited STAT5 phosphorylation in Ba/F3-JAK2V617F-GFP (green fluorescent protein) ascitic tumor cells (TED 50 =12.7 mg/kg) and significantly reduced (P<0.05) Ba/F3-JAK2V617F-GFP tumor burden in the JAK2V617F-induced MPN model (TED 50 =13.7 mg/kg, twice daily). In contrast, LY2784544 showed no effect on erythroid progenitors, reticulocytes or platelets. These data suggest that LY2784544 has potential for development as a targeted agent against JAK2V617F and may have properties that allow suppression of JAK2V617F-induced MPN pathogenesis while minimizing effects on hematopoietic progenitor cells

  8. A Faraday rotation search for magnetic fields in quasar damped Ly alpha absorption systems

    Science.gov (United States)

    Oren, Abraham L.; Wolfe, Arthur M.

    1995-01-01

    We present the results of a Faraday rotation survey of 61 radio-bright QSOs conducted at the National Radio Astronomy Observatory (NRAO) Very Large Array (VLA). The Galactic contribution to the Faraday rotation is estimated and subtracted to determine the extragalactic rotation measure (RRM) for each source. Eleven of these QSOs are known to exhibit damped Ly alpha absorption. The rate of incidence of significant Faraday rotation of these 11 sources is compared to the remaining 50 and is found to be higher at the 99.8% confidence level. However, as this is based upon only two detections of Faraday rotation in the damped Ly alpha sample, the result is only tentative. If the two detections in the damped Ly alpha sample are dug to the absorbing systems, then the inferred rotation measure induced by these systems is roughly 250 rad/sq m. The two detections were for the two lowest redshift absorbers in the sample. We find that a rotation measure of 250 rad/sq m would have gone undetected for any other absorber in the damped Ly alpha sample due to the 1/(1 + 2) squared dilution of the observed RRM with redshift. Thus the data are consistent with, but do not prove, the hypothesis that Faraday rotation is a generic property of damped Ly alpha absorbers. We do not confirm the suggestion that the amplitude of RRMs increases with redshift. Rather, the data are consistent with no redshift evolution. We find that the uncertainty in the estimation of the Galactic rotation measure (GRM) is a more serious problem than previously realized for extra-galactic Faraday rotation studies of QSO absorbers. A careful analysis of current methods for estimating GRM indicate that it can be determined to an accuracy of about 15 - 20 rad/sq m. Previous studies underestimated this uncertainty by more than a factor of 2. Due to this uncertainty, rotation measures such as we suspect are associated with damped Ly alpha absorption systems can only be detected at redshifts less than z approximately

  9. TRANSITING THE SUN. II. THE IMPACT OF STELLAR ACTIVITY ON Lyα TRANSITS

    Energy Technology Data Exchange (ETDEWEB)

    Llama, J.; Shkolnik, E. L., E-mail: joe.llama@lowell.edu [Lowell Observatory, 1400 W Mars Hill Road, Flagstaff, AZ 86001 (United States)

    2016-01-20

    High-energy observations of the Sun provide an opportunity to test the limits of our ability to accurately measure the properties of transiting exoplanets in the presence of stellar activity. Here we insert the transit of a hot Jupiter into continuous disk integrated data of the Sun in Lyα from NASA’s Solar Dynamics Observatory/EVE instrument to assess the impact of stellar activity on the measured planet-to-star radius ratio (R{sub p}/R{sub ⋆}). In 75% of our simulated light curves, we measure the correct radius ratio; however, incorrect values can be measured if there is significant short-term variability in the light curve. The maximum measured value of R{sub p}/R{sub ⋆} is 50% larger than the input value, which is much smaller than the large Lyα transit depths that have been reported in the literature, suggesting that for stars with activity levels comparable to the Sun, stellar activity alone cannot account for these deep transits. We ran simulations without a transit and found that stellar activity cannot mimic the Lyα transit of 55 Cancari b, strengthening the conclusion that this planet has a partially transiting exopshere. We were able to compare our simulations to more active stars by artificially increasing the variability in the Solar Lyα light curve. In the higher variability data, the largest value of R{sub p}/R{sub ⋆} we measured is <3× the input value, which again is not large enough to reproduce the Lyα transit depth reported for the more active stars HD 189733 and GJ 436, supporting the interpretation that these planets have extended atmospheres and possible cometary tails.

  10. A submillimeter galaxy illuminating its circumgalactic medium: Lyα scattering in a cold, clumpy outflow

    Energy Technology Data Exchange (ETDEWEB)

    Geach, J. E.; Coppin, K. E. K.; Smith, D. J. B. [Center for Astrophysics Research, Science and Technology Research Institute, University of Hertfordshire, Hatfield AL10 9AB (United Kingdom); Bower, R. G.; Alexander, D. M.; Swinbank, A. M. [Institute for Computational Cosmology, Department of Physics, Durham University, South Road, Durham DH1 3LE (United Kingdom); Blain, A. W. [Department of Physics and Astronomy, University of Leicester, University Road, Leicester LE1 7RH (United Kingdom); Bremer, M. N. [School of Physics, HH Wills Physics Laboratory, Tyndall Avenue, Bristol BS8 1TL (United Kingdom); Chapin, E. L. [XMM SOC, ESAC, Apartado 78, E-28691 Villanueva de la Canada, Madrid (Spain); Chapman, S. C. [Department of Physics and Atmospheric Science, Dalhousie University Halifax, NS B3H 3J5 (Canada); Clements, D. L. [Astrophysics Group, Imperial College London, Blackett Laboratory, Prince Consort Road, London SW7 2AZ (United Kingdom); Dunlop, J. S.; Koprowski, M. P.; Michałowski, M. J. [Institute for Astronomy, University of Edinburgh, Royal Observatory, Blackford Hill, Edinburgh EH9 3HJ (United Kingdom); Farrah, D. [Virginia Polytechnic Institute and State University Department of Physics, MC 0435, 910 Drillfield Drive, Blacksburg, VA 24061 (United States); Jenness, T. [Joint Astronomy Centre, 660 North A' ohoku Place University Park, Hilo, HI 96720 (United States); Robson, E. I. [UK Astronomy Technology Centre, Royal Observatory, Blackford Hill, Edinburgh EH9 3HJ (United Kingdom); Scott, D. [Department of Physics and Astronomy, University of British Columbia, 6224 Agricultural Road, Vancouver, BC V6T 1Z1 (Canada); Spaans, M. [Kapteyn Institute, University of Groningen, PO Box 800, 9700 AV Groningen (Netherlands); Van der Werf, P., E-mail: j.geach@herts.ac.uk [Leiden Observatory, Leiden University, PO box 9513, 2300 RA Leiden (Netherlands)

    2014-09-20

    We report the detection at 850 μm of the central source in SSA22-LAB1, the archetypal 'Lyman-α Blob' (LAB), a 100 kpc scale radio-quiet emission-line nebula at z = 3.1. The flux density of the source, S {sub 850} = 4.6 ± 1.1 mJy, implies the presence of a galaxy or group of galaxies with a total luminosity of L {sub IR} ≈ 10{sup 12} L {sub ☉}. The position of an active source at the center of a ∼50 kpc radius ring of linearly polarized Lyα emission detected by Hayes et al. suggests that the central source is leaking Lyα photons preferentially in the plane of the sky, which undergo scattering in H I clouds at a large galactocentric radius. The Lyα morphology around the submillimeter detection is reminiscent of a biconical outflow, and the average Lyα line profiles of the two 'lobes' are dominated by a red peak, which is expected for a resonant line emerging from a medium with a bulk velocity gradient that is outflowing relative to the line center. Taken together, these observations provide compelling evidence that the central active galaxy (or galaxies) is responsible for a large fraction of the extended Lyα emission and morphology. Less clear is the history of the cold gas in the circumgalactic medium being traced by Lyα: is it mainly pristine material accreting into the halo that has not yet been processed through an interstellar medium (ISM), now being blown back as it encounters an outflow, or does it mainly comprise gas that has been swept-up within the ISM and expelled from the galaxy?.

  11. A DEEP NARROWBAND IMAGING SEARCH FOR C iv AND He ii EMISSION FROM Lyα BLOBS

    Energy Technology Data Exchange (ETDEWEB)

    Battaia, Fabrizio Arrigoni; Yang, Yujin; Hennawi, Joseph F. [Max-Planck-Institut für Astronomie, Königstuhl 17, D-69117 Heidelberg (Germany); Prochaska, J. Xavier [Department of Astronomy and Astrophysics, University of California, 1156 High Street, Santa Cruz, California 95064 (United States); Matsuda, Yuichi [National Astronomical Observatory of Japan, 2-21-1 Osawa, Mitaka, Tokyo 181-8588 (Japan); Yamada, Toru [Astronomical Institute, Tohoku University, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578 (Japan); Hayashino, Tomoki, E-mail: arrigoni@mpia.de [Research Center for Neutrino Science, Graduate School of Science, Tohoku University, Sendai 980-8578 (Japan)

    2015-05-01

    We conduct a deep narrowband imaging survey of 13 Lyα blobs (LABs) located in the SSA22 proto-cluster at z ∼ 3.1 in the C iv and He ii emission lines in an effort to constrain the physical process powering the Lyα emission in LABs. Our observations probe down to unprecedented surface brightness (SB) limits of (2.1–3.4) × 10{sup −18} erg s{sup −1} cm{sup −2} arcsec{sup −2} per 1 arcsec{sup 2} aperture (5σ) for the He ii λ1640 and C iv λ1549 lines, respectively. We do not detect extended He ii and C iv emission in any of the LABs, placing strong upper limits on the He ii/Lyα and C iv/Lyα line ratios, of 0.11 and 0.16, for the brightest two LABs in the field. We conduct detailed photoionization modeling of the expected line ratios and find that, although our data constitute the deepest ever observations of these lines, they are still not deep enough to rule out a scenario where the Lyα emission is powered by the ionizing radiation from an obscured active galactic nucleus. Our models can accommodate He ii/Lyα and C iv/Lyα ratios as low as ≃0.05 and ≃0.07, respectively, implying that one needs to reach SB as low as (1–1.5) × 10{sup −18} erg s{sup −1} cm{sup −2} arcsec{sup −2} (at 5σ) in order to rule out a photoionization scenario. These depths will be achievable with the new generation of image-slicing integral field units such as the Multi Unit Spectroscopic Explorer (MUSE) on VLT and the Keck Cosmic Web Imager (KCWI). We also model the expected He ii/Lyα and C iv/Lyα in a different scenario, where Lyα emission is powered by shocks generated in a large-scale superwind, but find that our observational constraints can only be met for shock velocities v{sub s} ≳ 250 km s{sup −1}, which appear to be in conflict with recent observations of quiescent kinematics in LABs.

  12. Effect of intrathecal non-NMDA EAA receptor antagonist LY293558 in rats: a new class of drugs for spinal anesthesia.

    Science.gov (United States)

    Von Bergen, Nicholas H; Subieta, Alberto; Brennan, Timothy J

    2002-07-01

    Excitatory amino acid receptors are important for both sensory and motor function in the spinal cord. We studied the effects of intrathecal LY293558, a competitive non-N-methyl-D-aspartate excitatory amino acid receptor antagonist, on motor and sensory function in rats to determine whether drugs blocking these receptors could potentially be used as alternative agents to local anesthetics for spinal anesthesia. Rats were tested before and 15-240 min after intrathecal injection of 5 nmol (in 10 microl) LY293558. Sensory function was tested at the hind paw using withdrawal response to pin prick and withdrawal to pinch with sharp forceps. Motor performance (ambulation, placing reflex, and Rotorod time), blood pressure, and heart rate were also evaluated. Some tests were repeated the next day. Responses after LY293558 were compared to injection of 40 microl bupivacaine, 0.75%. Pin-prick responses at the forepaw, chest, abdomen, hind leg, and hind paw were also examined after intrathecal LY293558. Intrathecal LY293558 blocked both sensory and motor responses through 180 min; complete recovery was present the following day. No change in blood pressure or heart rate occurred. The effects of LY293558 were more pronounced and sustained than those of bupivacaine. Segmental blockade of the response to pin prick was present after LY293558. Drugs like LY293558 that block alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)/kainate receptors may be an alternative to local anesthetics for spinal anesthesia in humans.

  13. Protection against amphetamine-induced neurotoxicity toward striatal dopamine neurons in rodents by LY274614, an excitatory amino acid antagonist.

    Science.gov (United States)

    Fuller, R W; Hemrick-Luecke, S K; Ornstein, P L

    1992-10-01

    LY274614, 3SR,4aRS,6SR,8aRS-6-[phosphonomethyl]decahydr oisoquinoline-3- carboxylic acid, has been described as a potent antagonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Here its ability to antagonize the prolonged depletion of dopamine in the striatum by amphetamine in iprindole-treated rats is reported. A single 18.4 mg/kg (i.p.) dose of (+/-)-amphetamine hemisulfate, given to rats pretreated with iprindole, resulted in persistent depletion of dopamine in the striatum 1 week later. This prolonged depletion of dopamine in the striatum was antagonized by dizocilpine (MK-801, a non-competitive antagonist of NMDA receptors) or by LY274614 (a competitive antagonist of NMDA receptors). The protective effect of LY274614 was dose-dependent, being maximum at 10-40 mgkg (i.p.). A 10 mg/kg dose of LY274614 was effective in antagonizing the depletion of dopamine in the striatum, when given as long as 8 hr prior to amphetamine but not when given 24 hr prior to amphetamine. Depletion of dopamine in the striatum was also antagonized when LY274614 was given after the injection of amphetamine; LY274614 protected when given up to 4 hr after but not when given 8 or 24 hr after amphetamine. The prolonged depletion of dopamine in the striatum in mice, given multiple injections of methamphetamine, was also antagonized dose-dependently and completely by LY274614. The data strengthen the evidence that the neurotoxic effect of amphetamine and related compounds toward nigrostriatal dopamine neurons involves NMDA receptors and that LY274614 is an NMDA receptor antagonist with long-lasting in vivo effects in rats.

  14. Physical and morphological properties of z ~ 3 Lyman break galaxies: dependence on Lyα line emission

    Science.gov (United States)

    Pentericci, L.; Grazian, A.; Scarlata, C.; Fontana, A.; Castellano, M.; Giallongo, E.; Vanzella, E.

    2010-05-01

    Aims: We investigate the physical and morphological properties of Lyman break galaxies (LBGs) at redshift ~2.5 to ~3.5, to determine if and how they depend on the nature and strength of the Lyα emission. Methods: We selected U-dropout galaxies from the z-detected GOODS-MUSIC catalog by adapting the classical Lyman break criteria on the GOODS filter set. We kept only those galaxies with spectroscopic confirmation, mainly from VIMOS and FORS public observations. Using the full multi-wavelength 14-bands information (U to IRAC), we determined the physical properties of the galaxies through a standard spectral energy distribution fitting procedure with the updated Charlot & Bruzual (2009) templates. We also added other relevant observations of the GOODS field, i.e. the 24 μm observations from Spitzer/MIPS and the 2 MSec Chandra X-ray observations. Finally, using non parametric diagnostics (Gini, Concentration, Asymmetry, M20 and ellipticity), we characterized the rest-frame UV morphologies of the galaxies. We then analyzed how these physical and morphological properties correlate with the presence of the Lyα emission line in the optical spectra. Results: We find that unlike at higher redshift, the dependence of physical properties on the Lyα line is milder: galaxies without Lyα in emission tend to be more massive and dustier than the rest of the sample, but all other parameters, ages, star formation rates (SFR), X-ray emission and UV morphology do not depend strongly on the presence of the Lyα emission. A simple scenario where all LBGs have intrinsically high Lyα emission, but where the dust and neutral hydrogen content (which shapes the final appearance of the Lyα) depend on the mass of the galaxies, is able to reproduce the majority of the observed properties at z˜3. Some modification might be needed to account for the observed evolution of these properties with cosmic epoch, which is also discussed.

  15. A Case of Posterior Reversible Encephalopathy Syndrome Induced by Cisplatin/Pemetrexed Chemotherapy for Lung Cancer

    Directory of Open Access Journals (Sweden)

    Masashi Ishihara

    2017-03-01

    Full Text Available This report presents the case of a 60-year-old woman who was diagnosed with stage IV lung adenocarcinoma with asymptomatic brain metastases and commenced chemotherapy with cisplatin/pemetrexed (CDDP/Pem. She experienced tonic-clonic convulsions on day 9 of the first cycle, which were accompanied by increased blood pressure (173/69 mm Hg and headache. Therefore, brain MRI was performed to check for stroke or progression of brain metastatic foci. T2-weighted, FLAIR, and ADC map images showed high-intensity areas in the subcortical region of the bilateral parieto-occipital lobes, leading to a diagnosis of posterior reversible encephalopathy syndrome (PRES. The symptoms improved after treatment with antihypertensive and antiepileptic drugs. Clinicians should keep it in mind that central nervous system symptoms during anticancer therapy containing Pem may indicate possible PRES.

  16. Target specificity, in vivo pharmacokinetics, and efficacy of the putative STAT3 inhibitor LY5 in osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma.

    Directory of Open Access Journals (Sweden)

    Peter Y Yu

    Full Text Available STAT3 is a transcription factor involved in cytokine and receptor kinase signal transduction that is aberrantly activated in a variety of sarcomas, promoting metastasis and chemotherapy resistance. The purpose of this work was to develop and test a novel putative STAT3 inhibitor, LY5.An in silico fragment-based drug design strategy was used to create LY5, a small molecule inhibitor that blocks the STAT3 SH2 domain phosphotyrosine binding site, inhibiting homodimerization. LY5 was evaluated in vitro demonstrating good biologic activity against rhabdomyosarcoma, osteosarcoma and Ewing's sarcoma cell lines at high nanomolar/low micromolar concentrations, as well as specific inhibition of STAT3 phosphorylation without effects on other STAT3 family members. LY5 exhibited excellent oral bioavailability in both mice and healthy dogs, and drug absorption was enhanced in the fasted state with tolerable dosing in mice at 40 mg/kg BID. However, RNAi-mediated knockdown of STAT3 did not phenocopy the biologic effects of LY5 in sarcoma cell lines. Moreover, concentrations needed to inhibit ex vivo metastasis growth using the PuMA assay were significantly higher than those needed to inhibit STAT3 phosphorylation in vitro. Lastly, LY5 treatment did not inhibit the growth of sarcoma xenografts or prevent pulmonary metastasis in mice.LY5 is a novel small molecule inhibitor that effectively inhibits STAT3 phosphorylation and cell proliferation at nanomolar concentrations. LY5 demonstrates good oral bioavailability in mice and dogs. However LY5 did not decrease tumor growth in xenograft mouse models and STAT3 knockdown did not induce concordant biologic effects. These data suggest that the anti-cancer effects of LY5 identified in vitro were not mediated through STAT3 inhibition.

  17. Target specificity, in vivo pharmacokinetics, and efficacy of the putative STAT3 inhibitor LY5 in osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma.

    Science.gov (United States)

    Yu, Peter Y; Gardner, Heather L; Roberts, Ryan; Cam, Hakan; Hariharan, Seethalakshmi; Ren, Ling; LeBlanc, Amy K; Xiao, Hui; Lin, Jiayuh; Guttridge, Denis C; Mo, Xiaokui; Bennett, Chad E; Coss, Christopher C; Ling, Yonghua; Phelps, Mitch A; Houghton, Peter; London, Cheryl A

    2017-01-01

    STAT3 is a transcription factor involved in cytokine and receptor kinase signal transduction that is aberrantly activated in a variety of sarcomas, promoting metastasis and chemotherapy resistance. The purpose of this work was to develop and test a novel putative STAT3 inhibitor, LY5. An in silico fragment-based drug design strategy was used to create LY5, a small molecule inhibitor that blocks the STAT3 SH2 domain phosphotyrosine binding site, inhibiting homodimerization. LY5 was evaluated in vitro demonstrating good biologic activity against rhabdomyosarcoma, osteosarcoma and Ewing's sarcoma cell lines at high nanomolar/low micromolar concentrations, as well as specific inhibition of STAT3 phosphorylation without effects on other STAT3 family members. LY5 exhibited excellent oral bioavailability in both mice and healthy dogs, and drug absorption was enhanced in the fasted state with tolerable dosing in mice at 40 mg/kg BID. However, RNAi-mediated knockdown of STAT3 did not phenocopy the biologic effects of LY5 in sarcoma cell lines. Moreover, concentrations needed to inhibit ex vivo metastasis growth using the PuMA assay were significantly higher than those needed to inhibit STAT3 phosphorylation in vitro. Lastly, LY5 treatment did not inhibit the growth of sarcoma xenografts or prevent pulmonary metastasis in mice. LY5 is a novel small molecule inhibitor that effectively inhibits STAT3 phosphorylation and cell proliferation at nanomolar concentrations. LY5 demonstrates good oral bioavailability in mice and dogs. However LY5 did not decrease tumor growth in xenograft mouse models and STAT3 knockdown did not induce concordant biologic effects. These data suggest that the anti-cancer effects of LY5 identified in vitro were not mediated through STAT3 inhibition.

  18. BROAD Lyα EMISSION FROM THREE NEARBY BL LACERTAE OBJECTS

    International Nuclear Information System (INIS)

    Stocke, John T.; Danforth, Charles W.; Perlman, Eric S.

    2011-01-01

    We present far-UV HST/COS spectra of four nearby BL Lac objects. BL Lac spectra are dominated by a smooth, power-law continuum which arises in a relativistic jet. However, the spectra are not necessarily featureless; weak, broad- and/or narrow-line emission is sometimes seen in high-quality optical spectra. We present detections of Lyα emission in HST/COS spectra of Mrk 421 (z = 0.030) and PKS 2005-489 (z = 0.071) as well as an archival HST/GHRS observation of Mrk 501 (z = 0.0337). Archival HST/STIS observations of PKS 2155-304 (z = 0.116) show no Lyα emission to a very low upper limit. Using the assumption that the broad-line region (BLR) clouds are symmetrically placed around the active galactic nucleus (AGN), we use these measured Lyα emission features to constrain either the relativistic Γ values for the ionizing continuum produced by the jet (in the ionization-bounded case) or the mass of warm gas (in the density-bounded case). While realistic Γ values can be obtained for all four cases, the values for Mrk 421 and PKS 2155-304 are high enough to suggest that covering factors of BLR clouds of ∼1%-2% might be required to provide consistency with earlier values of Doppler boosting and viewing angles suggested for this class of BL Lacs. This discrepancy also exists in the case of M 87, where the amount of Doppler boosting in our direction is expected to be minimal, again suggestive of a small covering factor of BLR clouds. If, as these small covering factors might suggest, the assumptions of a density-bounded model could be more correct, then the observed Lyα luminosities require that BL Lac/FR 1 nuclei possess very little warm gas (10 -4 to 10 -5 M sun ) as suggested by Guilbert et al. If these clouds are in pressure balance with a hotter (∼10 6 K) gas, the BLR contains too little mass to power the AGN by accretion alone.

  19. ALMA OBSERVATIONS OF Ly α BLOB 1: HALO SUBSTRUCTURE ILLUMINATED FROM WITHIN

    Energy Technology Data Exchange (ETDEWEB)

    Geach, J. E. [Centre for Astrophysics Research, University of Hertfordshire, Hatfield, AL10 9AB (United Kingdom); Narayanan, D. [Dept. of Physics and Astronomy, Haverford College, PA 19041 (United States); Matsuda, Y.; Ao, Y.; Kubo, M. [National Astronomical Observatory of Japan, Osawa, Mitaka, Tokyo 181-8588 (Japan); Hayes, M. [Stockholm University, Dept. of Astronomy and Oskar Klein Centre for Cosmoparticle Physics, SE-10691, Stockholm (Sweden); Mas-Ribas, Ll.; Dijkstra, M. [Institute of Theoretical Astrophysics, University of Oslo, P.O. Box 1029 Blindern, NO-0315 Oslo (Norway); Steidel, C. C. [California Institute of Technology, 1216 East California Boulevard, MS 249-17, Pasadena, CA 91125 (United States); Chapman, S. C. [Dept. of Physics and Atmospheric Science, Dalhousie University, Halifax, NS B3H 4R2 (Canada); Feldmann, R. [Dept. of Astronomy, University of California Berkeley, CA 94720 (United States); Avison, A. [UK ALMA Regional Centre Node, Manchester (United Kingdom); Agertz, O. [Dept. of Physics, University of Surrey, GU2 7XH, Surrey (United Kingdom); Birkinshaw, M.; Bremer, M. N. [H. H. Wills Physics Laboratory, University of Bristol, Tyndall Avenue, Bristol, BS8 1TL (United Kingdom); Clements, D. L. [Astrophysics Group, Imperial College London, Blackett Laboratory, Prince Consort Road, London SW7 2AZ (United Kingdom); Dannerbauer, H. [Instituto de Astrofísica de Canarias, La Laguna, Tenerife (Spain); Farrah, D. [Dept. of Physics, Virginia Tech, Blacksburg, VA 24061 (United States); Harrison, C. M. [Centre for Extragalactic Astronomy, Dept. of Physics, Durham University, South Road, Durham, DH1 3LE (United Kingdom); Michałowski, M. J., E-mail: j.geach@herts.ac.uk [Institute for Astronomy, University of Edinburgh, Royal Observatory, Blackford Hill, Edinburgh, EH9 3HJ (United Kingdom); and others

    2016-11-20

    We present new Atacama Large Millimeter/Submillimeter Array (ALMA) 850 μ m continuum observations of the original Ly α Blob (LAB) in the SSA22 field at z = 3.1 (SSA22-LAB01). The ALMA map resolves the previously identified submillimeter source into three components with a total flux density of S {sub 850} = 1.68 ± 0.06 mJy, corresponding to a star-formation rate of ∼150 M {sub ⊙} yr{sup -1}. The submillimeter sources are associated with several faint ( m ≈ 27 mag) rest-frame ultraviolet sources identified in Hubble Space Telescope Imaging Spectrograph (STIS) clear filter imaging ( λ ≈ 5850 Å). One of these companions is spectroscopically confirmed with the Keck Multi-Object Spectrometer For Infra-Red Exploration to lie within 20 projected kpc and 250 km s{sup -1} of one of the ALMA components. We postulate that some of these STIS sources represent a population of low-mass star-forming satellites surrounding the central submillimeter sources, potentially contributing to their growth and activity through accretion. Using a high-resolution cosmological zoom simulation of a 10{sup 13} M {sub ⊙} halo at z = 3, including stellar, dust, and Ly α radiative transfer, we can model the ALMA+STIS observations and demonstrate that Ly α photons escaping from the central submillimeter sources are expected to resonantly scatter in neutral hydrogen, the majority of which is predicted to be associated with halo substructure. We show how this process gives rise to extended Ly α emission with similar surface brightness and morphology to observed giant LABs.

  20. More than Solfège and Hand Signs: Philosophy, Tools, and Lesson Planning in the Authentic Kodály Classroom

    Science.gov (United States)

    Bowyer, James

    2015-01-01

    Four components of the Kodály concept are delineated here: philosophy, objectives, essential tools, and lesson planning process. After outlining the tenets of the Kodály philosophy and objectives, the article presents the Kodály concept's essential tools, including singing, movable "do" solfège, rhythm syllables, hand signs, singing on…

  1. A phase I trial of sorafenib combined with cisplatin/etoposide or carboplatin/pemetrexed in refractory solid tumor patients.

    Science.gov (United States)

    Davies, Janine M; Dhruva, Nirav S; Walko, Christine M; Socinski, Mark A; Bernard, Stephen; Hayes, D Neil; Kim, William Y; Ivanova, Anastasia; Keller, Kimberly; Hilbun, Layla R; Chiu, Michael; Dees, E Claire; Stinchcombe, Thomas E

    2011-02-01

    Sorafenib has demonstrated single agent activity in non-small cell (NSCLC) and small cell lung cancer (SCLC). Carboplatin/pemetrexed (CbP) and cisplatin/etoposide (PE) are commonly used in the treatment of these diseases. A phase I trial escalating doses of sorafenib in combination with fixed doses of PE (Arm A) or CbP (Arm B) was performed using a 3-patient cohort design to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT); DLT were assessed in the first cycle. The trial was subsequently amended with closure of Arm B and to include Arm C with a reduced dose of carboplatin. Between 9/2007 and 9/2008, 20 pts were treated on the trial; median age 62 (range 42-73), male/female ratio 12/8, PS 0/1 ratio 6/14, and median number of prior therapies 2 (range 1-4). The most common tumor types were NSCLC and SCLC. On Arm A at dose level 0 (sorafenib 200 mg BID), 2 of 4 patients experienced DLT; 2 patients were enrolled at dose level -1 (sorafenib 200 mg QD) without DLT, but this arm was closed due to slow accrual. On Arm B, 2 of 3 patients experienced DLT at dose level 0 (sorafenib 200 mg BID). On Arm C at dose level 0 (sorafenib 200 mg BID), 1 of 6 patients experienced DLT, and at dose level +1 (sorafenib 400 mg BID) 2 of 5 patients experienced a DLT. The MTD of sorafenib was 200 mg BID continuously in combination with carboplatin (AUC of 5) and pemetrexed 500 mg/m² every 3 weeks. However, only 6 patients were treated at this dose level, and the results should be interpreted cautiously. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  2. THE LYMAN ALPHA REFERENCE SAMPLE. V. THE IMPACT OF NEUTRAL ISM KINEMATICS AND GEOMETRY ON Lyα ESCAPE

    International Nuclear Information System (INIS)

    Rivera-Thorsen, Thøger E.; Hayes, Matthew; Östlin, Göran; Duval, Florent; Sandberg, Andreas; Guaita, Lucia; Adamo, Angela; Orlitová, Ivana; Verhamme, Anne; Schaerer, Daniel; Mas-Hesse, J. Miguel; Cannon, John M.; Otí-Floranes, Héctor; Atek, Hakim; Herenz, E. Christian; Kunth, Daniel

    2015-01-01

    We present high-resolution far-UV spectroscopy of the 14 galaxies of the Lyα Reference Sample; a sample of strongly star-forming galaxies at low redshifts (0.028 < z < 0.18). We compare the derived properties to global properties derived from multi-band imaging and 21 cm H i interferometry and single-dish observations, as well as archival optical SDSS spectra. Besides the Lyα line, the spectra contain a number of metal absorption features allowing us to probe the kinematics of the neutral ISM and evaluate the optical depth and and covering fraction of the neutral medium as a function of line of sight velocity. Furthermore, we show how this, in combination with the precise determination of systemic velocity and good Lyα spectra, can be used to distinguish a model in which separate clumps together fully cover the background source, from the “picket fence” model named by Heckman et al. We find that no one single effect dominates in governing Lyα radiative transfer and escape. Lyα escape in our sample coincides with a maximum velocity-binned covering fraction of ≲0.9 and bulk outflow velocities of ≳50 km s −1 , although a number of galaxies show these characteristics and yet little or no Lyα escape. We find that Lyα peak velocities, where available, are not consistent with a strong backscattered component, but rather with a simpler model of an intrinsic emission line overlaid by a blueshifted absorption profile from the outflowing wind. Finally, we find a strong anticorrelation between Hα equivalent width and maximum velocity-binned covering factor, and propose a heuristic explanatory model

  3. THE LYMAN ALPHA REFERENCE SAMPLE. V. THE IMPACT OF NEUTRAL ISM KINEMATICS AND GEOMETRY ON Lyα ESCAPE

    Energy Technology Data Exchange (ETDEWEB)

    Rivera-Thorsen, Thøger E.; Hayes, Matthew; Östlin, Göran; Duval, Florent; Sandberg, Andreas; Guaita, Lucia; Adamo, Angela [Department of Astronomy, Oskar Klein Centre, Stockholm University, AlbaNova University Centre, SE-106 91 Stockholm (Sweden); Orlitová, Ivana [Astronomical Institute, Academy of Sciences of the Czech Republic, Boční II, CZ-14131 Prague (Czech Republic); Verhamme, Anne; Schaerer, Daniel [Geneva Observatory, University of Geneva, 51 Chemin des Maillettes, CH-1290 Versoix (Switzerland); Mas-Hesse, J. Miguel [Centro de Astrobiología (CSIC–INTA), Departamento de Astrofísica, P.O. Box 78, E-28691 Villanueva de la Cañada (Spain); Cannon, John M. [Department of Physics and Astronomy, Macalester College, 1600 Grand Avenue, Saint Paul, MN 55105 (United States); Otí-Floranes, Héctor [Instituto de Astronomía, Universidad Nacional Autónoma de México, Apdo. Postal 106, B. C. 22800 Ensenada (Mexico); Atek, Hakim [Laboratoire d’Astrophysique, École Polytechnique Fédérale de Lausanne (EPFL), Observatoire, CH-1290 Sauverny (Switzerland); Herenz, E. Christian [Leibniz-Institut für Astrophysik (AIP), An der Sternwarte 16, D-14482 Potsdam (Germany); Kunth, Daniel, E-mail: trive@astro.su.se [Institut d’Astrophysique de Paris, UMR 7095 CNRS and UPMC, 98 bis Bd Arago, F-75014 Paris (France); and others

    2015-05-20

    We present high-resolution far-UV spectroscopy of the 14 galaxies of the Lyα Reference Sample; a sample of strongly star-forming galaxies at low redshifts (0.028 < z < 0.18). We compare the derived properties to global properties derived from multi-band imaging and 21 cm H i interferometry and single-dish observations, as well as archival optical SDSS spectra. Besides the Lyα line, the spectra contain a number of metal absorption features allowing us to probe the kinematics of the neutral ISM and evaluate the optical depth and and covering fraction of the neutral medium as a function of line of sight velocity. Furthermore, we show how this, in combination with the precise determination of systemic velocity and good Lyα spectra, can be used to distinguish a model in which separate clumps together fully cover the background source, from the “picket fence” model named by Heckman et al. We find that no one single effect dominates in governing Lyα radiative transfer and escape. Lyα escape in our sample coincides with a maximum velocity-binned covering fraction of ≲0.9 and bulk outflow velocities of ≳50 km s{sup −1}, although a number of galaxies show these characteristics and yet little or no Lyα escape. We find that Lyα peak velocities, where available, are not consistent with a strong backscattered component, but rather with a simpler model of an intrinsic emission line overlaid by a blueshifted absorption profile from the outflowing wind. Finally, we find a strong anticorrelation between Hα equivalent width and maximum velocity-binned covering factor, and propose a heuristic explanatory model.

  4. THE MUSCLES TREASURY SURVEY. II. INTRINSIC LY α AND EXTREME ULTRAVIOLET SPECTRA OF K AND M DWARFS WITH EXOPLANETS

    Energy Technology Data Exchange (ETDEWEB)

    Youngblood, Allison; France, Kevin; Loyd, R. O. Parke [Laboratory for Atmospheric and Space Physics, University of Colorado, 600 UCB, Boulder, CO 80309 (United States); Linsky, Jeffrey L. [JILA, University of Colorado and NIST, 440 UCB, Boulder, CO 80309 (United States); Redfield, Seth [Astronomy Department and Van Vleck Observatory, Wesleyan University, Middletown, CT 06459-0123 (United States); Schneider, P. Christian [European Space Research and Technology Centre (ESA/ESTEC), Keplerlaan 1, 2201 AZ Noordwijk (Netherlands); Wood, Brian E. [Naval Research Laboratory, Space Science Division, Washington, DC 20375 (United States); Brown, Alexander [Center for Astrophysics and Space Astronomy, University of Colorado, 389 UCB, Boulder, CO 80309 (United States); Froning, Cynthia [Dept. of Astronomy C1400, University of Texas, Austin, TX 78712 (United States); Miguel, Yamila [Laboratoire Lagrange, Universite de Nice-Sophia Antipolis, Observatoire de la Cote d’Azur, CNRS, Blvd de l’Observatoire, CS 34229, F-06304 Nice cedex 4 (France); Rugheimer, Sarah [Department of Earth and Environmental Sciences, Irvine Building, University of St. Andrews, St. Andrews KY16 9AL (United Kingdom); Walkowicz, Lucianne, E-mail: allison.youngblood@colorado.edu [The Adler Planetarium, 1300 S Lakeshore Dr, Chicago, IL 60605 (United States)

    2016-06-20

    The ultraviolet (UV) spectral energy distributions (SEDs) of low-mass (K- and M-type) stars play a critical role in the heating and chemistry of exoplanet atmospheres, but are not observationally well-constrained. Direct observations of the intrinsic flux of the Ly α line (the dominant source of UV photons from low-mass stars) are challenging, as interstellar H i absorbs the entire line core for even the closest stars. To address the existing gap in empirical constraints on the UV flux of K and M dwarfs, the MUSCLES Hubble Space Telescope Treasury Survey has obtained UV observations of 11 nearby M and K dwarfs hosting exoplanets. This paper presents the Ly α and extreme-UV spectral reconstructions for the MUSCLES targets. Most targets are optically inactive, but all exhibit significant UV activity. We use a Markov Chain Monte Carlo technique to correct the observed Ly α profiles for interstellar absorption, and we employ empirical relations to compute the extreme-UV SED from the intrinsic Ly α flux in ∼100 Å bins from 100–1170 Å. The reconstructed Ly α profiles have 300 km s{sup −1} broad cores, while >1% of the total intrinsic Ly α flux is measured in extended wings between 300 and 1200 km s{sup −1}. The Ly α surface flux positively correlates with the Mg ii surface flux and negatively correlates with the stellar rotation period. Stars with larger Ly α surface flux also tend to have larger surface flux in ions formed at higher temperatures, but these correlations remain statistically insignificant in our sample of 11 stars. We also present H i column density measurements for 10 new sightlines through the local interstellar medium.

  5. KECK SPECTROSCOPY OF LYMAN-BREAK GALAXIES AND ITS IMPLICATIONS FOR THE UV-CONTINUUM AND Ly{alpha} LUMINOSITY FUNCTIONS AT z > 6

    Energy Technology Data Exchange (ETDEWEB)

    Jiang Linhua; Egami, Eiichi; Walth, Gregory [Steward Observatory, University of Arizona, 933 North Cherry Avenue, Tucson, AZ 85721 (United States); Kashikawa, Nobunari [Optical and Infrared Astronomy Division, National Astronomical Observatory, Mitaka, Tokyo 181-8588 (Japan); Matsuda, Yuichi [Department of Physics, Durham University, South Road, Durham DH1 3LE (United Kingdom); Shimasaku, Kazuhiro [Department of Astronomy, University of Tokyo, Hongo, Tokyo 113-0033 (Japan); Nagao, Tohru [Research Center for Space and Cosmic Evolution, Ehime University, Bunkyo-cho, Matsuyama 790-8577 (Japan); Ota, Kazuaki [Department of Astronomy, Kyoto University, Kitashirakawa-Oiwake-cho, Sakyo-ku, Kyoto 606-8502 (Japan); Ouchi, Masami [Institute for Cosmic Ray Research, University of Tokyo, 5-1-5 Kashiwa-no-Ha, Kashiwa City, Chiba 77-8582 (Japan)

    2011-12-10

    We present Keck spectroscopic observations of z > 6 Lyman-break galaxy (LBG) candidates in the Subaru Deep Field (SDF). The candidates were selected as i'-dropout objects down to z' = 27 AB magnitudes from an ultra-deep SDF z'-band image. With the Keck spectroscopy we identified 19 LBGs with prominent Ly{alpha} emission lines at 6 {<=} z {<=} 6.4. The median value of the Ly{alpha} rest-frame equivalent widths (EWs) is {approx}50 A, with four EWs >100 A. This well-defined spectroscopic sample spans a UV-continuum luminosity range of -21.8 {<=} M{sub UV} {<=} -19.5 (0.6 {approx} 5 L*{sub UV}) and a Ly{alpha} luminosity range of (0.3-3) Multiplication-Sign 10{sup 43} erg s{sup -1} (0.3-3 L*{sub Ly{alpha}}). We derive the UV and Ly{alpha} luminosity functions (LFs) from our sample at (z) {approx} 6.2 after we correct for sample incompleteness. We find that our measurement of the UV LF is consistent with the results of previous studies based on photometric LBG samples at 5 < z < 7. Our Ly{alpha} LF is also generally in agreement with the results of Ly{alpha}-emitter surveys at z {approx} 5.7 and 6.6. This study shows that deep spectroscopic observations of LBGs can provide unique constraints on both the UV and Ly{alpha} LFs at z > 6.

  6. Early-type semidetached system LY Aurigae

    International Nuclear Information System (INIS)

    Li, Y.F.; Leung, K.C.

    1985-01-01

    In an effort to resolve a controversy regarding the configuration, mass ratio, and evolutionary status of the early-type close binary system LY Aur, the six bandpass OAO 2 observations of Heap and the ground-based observations combined by Eaton were analyzed. The Wilson and Devinney approach was used. The system is found to be semidetached, with the cooler and less massive component filling its Roche lobe, while the hotter component is close to its Roche surface. The system is not an early-type zero-age contact, as was suspected earlier. 20 references

  7. Lyα EMITTERS IN HIERARCHICAL GALAXY FORMATION. II. ULTRAVIOLET CONTINUUM LUMINOSITY FUNCTION AND EQUIVALENT WIDTH DISTRIBUTION

    International Nuclear Information System (INIS)

    Kobayashi, Masakazu A. R.; Totani, Tomonori; Nagashima, Masahiro

    2010-01-01

    We present theoretical predictions of the UV continuum luminosity function (UV LF) and Lyα equivalent width (EW) distribution of Lyα emitters (LAEs) in the framework of the hierarchical clustering model of galaxy formation. The model parameters for the LAEs were determined by fitting to the observed Lyα LF at z = 5.7 in our previous study, and the fit indicates that extinction of Lyα photons by dust is significantly less effective than that of UV continuum photons, implying a clumpy dust distribution in the interstellar medium. We then compare the predictions about UV LFs and EW distributions with a variety of observations at z∼ 3-6, allowing no more free parameters and paying careful attention to the selection conditions of LAEs in each survey. We find that the predicted UV LFs and EW distributions are in nice agreement with observed data, and especially, our model naturally reproduces the existence of large EW LAEs (∼> 240 A) without introducing Pop III stars or top-heavy initial mass function. We show that both the stellar population (young age and low metallicity) and extinction by clumpy dust are the keys to reproducing large EW LAEs. The evidence of EW enhancement by clumpy dust is further strengthened by the quantitative agreement between our model and recent observations about a positive correlation between EW and extinction. The observed trend that brighter LAEs in the UV continuum tend to have smaller mean EW is also reproduced, and the clumpy dust plays an important role again for this trend. We suggested in our previous study that the transmission of the intergalactic medium for Lyα emission rapidly decreases from z ∼ 6 to 7 by fitting to Lyα LFs, and this evidence is quantitatively strengthened by the comparison with the UV LF and EW distribution at z ∼ 6.6.

  8. First Spectroscopic Confirmations of z ∼ 7.0 Ly α Emitting Galaxies in the LAGER Survey

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Weida; Wang, Junxian; Kang, Wenyong; Kong, Xu; Yang, Huan [CAS Key Laboratory for Research in Galaxies and Cosmology, Department of Astronomy, University of Science and Technology of China, Hefei, Anhui 230026 (China); Zheng, Zhen-Ya; Jiang, Chunyan [CAS Key Laboratory for Research in Galaxies and Cosmology, Shanghai Astronomical Observatory, Shanghai 200030 (China); Malhotra, Sangeeta; Rhoads, James; Gonzalez, Alicia; Tilvi, Vithal [School of Earth and Space Exploration, Arizona State University, Tempe, AZ 85287 (United States); Infante, Leopoldo [Las Campanas Observatory, Carnegie Institution for Science, Casilla 601, La Serena (Chile); Walker, Alistair R. [Cerro Tololo Inter-American Observatory, Casilla 603, La Serena (Chile); Jiang, Linhua [The Kavli Institute for Astronomy and Astrophysics, Peking University, Beijing 100871 (China); Hibon, Pascale [European Southern Observatory, Alonso de Cordova 3107, Casilla 19001, Santiago (Chile); Barrientos, L. Felipe; Galaz, Gaspar [Centro de Astroingeniería, Facultad de Física, Pontificia Universidad Católica de Chile, Santiago (Chile); Finkelstein, Steven [Department of Astronomy, The University of Texas at Austin, Austin, TX 78712 (United States); Zheng, XianZhong, E-mail: urverda@mail.ustc.edu.cn, E-mail: jxw@ustc.edu.cn, E-mail: zhengzy@shao.ac.cn, E-mail: Sangeeta.Malhotra@asu.edu, E-mail: James.Rhoads@asu.edu, E-mail: linfante@carnegiescience.edu [Purple Mountain Observatory, Chinese Academy of Sciences, Nanjing 210008 (China)

    2017-08-20

    Narrowband imaging is a highly successful approach for finding large numbers of high-redshift Ly α emitting galaxies (LAEs) up to z ∼ 6.6. However, at z ≳ 7 there are as of yet only three narrowband selected LAEs with spectroscopic confirmations (two at z ∼ 6.9–7.0, one at z ∼ 7.3), which hinders extensive studies on cosmic reionization and galaxy evolution at this key epoch. We have selected 23 candidate z ∼ 6.9 LAEs in COSMOS field with the large area narrowband survey Lyman-Alpha Galaxies at the End of Reionization (LAGER). In this work, we present spectroscopic follow-up observations of 12 candidates using the Inamori Magellan Areal Camera and Spectrograph on Magellan. For nine of these, the observations are sufficiently deep to detect the expected lines. Ly α emission lines are identified in six sources (yielding a success rate of 2/3), including three luminous LAEs with Ly α luminosities of L {sub Lyα} ∼ 10{sup 43.5} erg s{sup −1}, the highest among known spectroscopically confirmed galaxies at ≳7.0. This triples the sample size of spectroscopically confirmed narrowband selected LAEs at z ≳ 7, and confirms the bright-end bump in the Ly α luminosity function we previously derived based on the photometric sample, supporting a patchy reionization scenario. Two luminous LAEs appear physically linked with a projected distance of 1.1 pMpc and velocity difference of ∼170 km s{sup −1}. They likely sit in a common ionized bubble produced by themselves or with close neighbors, which reduces the intergalactic medium attenuation of Ly α . A tentative narrow N v λ 1240 line is seen in one source, hinting at activity of a central massive black hole with metal-rich line-emitting gas.

  9. Probing natural killer cell education by Ly49 receptor expression analysis and computational modelling in single MHC class I mice.

    Directory of Open Access Journals (Sweden)

    Sofia Johansson

    Full Text Available Murine natural killer (NK cells express inhibitory Ly49 receptors for MHC class I molecules, which allows for "missing self" recognition of cells that downregulate MHC class I expression. During murine NK cell development, host MHC class I molecules impose an "educating impact" on the NK cell pool. As a result, mice with different MHC class I expression display different frequency distributions of Ly49 receptor combinations on NK cells. Two models have been put forward to explain this impact. The two-step selection model proposes a stochastic Ly49 receptor expression followed by selection for NK cells expressing appropriate receptor combinations. The sequential model, on the other hand, proposes that each NK cell sequentially expresses Ly49 receptors until an interaction of sufficient magnitude with self-class I MHC is reached for the NK cell to mature. With the aim to clarify which one of these models is most likely to reflect the actual biological process, we simulated the two educational schemes by mathematical modelling, and fitted the results to Ly49 expression patterns, which were analyzed in mice expressing single MHC class I molecules. Our results favour the two-step selection model over the sequential model. Furthermore, the MHC class I environment favoured maturation of NK cells expressing one or a few self receptors, suggesting a possible step of positive selection in NK cell education. Based on the predicted Ly49 binding preferences revealed by the model, we also propose, that Ly49 receptors are more promiscuous than previously thought in their interactions with MHC class I molecules, which was supported by functional studies of NK cell subsets expressing individual Ly49 receptors.

  10. The Lyα properties of faint galaxies at z ∼ 2-3 with systemic redshifts and velocity dispersions from Keck-MOSFIRE

    Energy Technology Data Exchange (ETDEWEB)

    Erb, Dawn K. [Center for Gravitation, Cosmology and Astrophysics, Department of Physics, University of Wisconsin Milwaukee, 1900 East Kenwood Boulevard, Milwaukee, WI 53211 (United States); Steidel, Charles C.; Trainor, Ryan F.; Strom, Allison L.; Konidaris, Nicholas P.; Matthews, Keith [Cahill Center for Astrophysics, California Institute of Technology, 1216 East California Boulevard, MS 249-17, Pasadena, CA 91125 (United States); Bogosavljević, Milan [Astronomical Observatory, Volgina 7, 11060 Belgrade (Serbia); Shapley, Alice E.; Nestor, Daniel B.; Mace, Gregory; McLean, Ian S. [Department of Physics and Astronomy, University of California, Los Angeles, 430 Portola Plaza, Los Angeles, CA 90095 (United States); Kulas, Kristin R. [NASA Ames Research Center, Bldg. 211, Room 112, Moffett Field, CA 94035-1000 (United States); Law, David R. [Dunlap Institute for Astronomy and Astrophysics, University of Toronto, 50 St. George Street, Toronto, Ontario M5S 3H4 (Canada); Rudie, Gwen C. [Carnegie Observatories, 813 Santa Barbara Street, Pasadena, CA 91101 (United States); Reddy, Naveen A. [Department of Physics and Astronomy, University of California, Riverside, 900 University Avenue, Riverside, CA 92521 (United States); Pettini, Max, E-mail: erbd@uwm.edu [Institute of Astronomy, Madingley Road, Cambridge CB3 0HA (United Kingdom)

    2014-11-01

    We study the Lyα profiles of 36 spectroscopically detected Lyα-emitters (LAEs) at z ∼ 2-3, using Keck MOSFIRE to measure systemic redshifts and velocity dispersions from rest-frame optical nebular emission lines. The sample has a median optical magnitude R=26.0, and ranges from R≃23 to R>27, corresponding to rest-frame UV absolute magnitudes M {sub UV} ≅ –22 to M {sub UV} > –18.2. Dynamical masses range from M {sub dyn} < 1.3 × 10{sup 8} M {sub ☉} to M {sub dyn} = 6.8 × 10{sup 9} M {sub ☉}, with a median value of M {sub dyn} = 6.3 × 10{sup 8} M {sub ☉}. Thirty of the 36 Lyα emission lines are redshifted with respect to the systemic velocity with at least 1σ significance, and the velocity offset with respect to systemic Δv {sub Lyα} is correlated with the R-band magnitude, M {sub UV}, and the velocity dispersion measured from nebular emission lines with >3σ significance: brighter galaxies with larger velocity dispersions tend to have larger values of Δv {sub Lyα}. We also make use of a comparison sample of 122 UV-color-selected R<25.5 galaxies at z ∼ 2, all with Lyα emission and systemic redshifts measured from nebular emission lines. Using the combined LAE and comparison samples for a total of 158 individual galaxies, we find that Δv {sub Lyα} is anti-correlated with the Lyα equivalent width with 7σ significance. Our results are consistent with a scenario in which the Lyα profile is determined primarily by the properties of the gas near the systemic redshift; in such a scenario, the opacity to Lyα photons in lower mass galaxies may be reduced if large gaseous disks have not yet developed and if the gas is ionized by the harder spectrum of young, low metallicity stars.

  11. The MUSE-Wide survey: a measurement of the Ly α emitting fraction among z > 3 galaxies

    Science.gov (United States)

    Caruana, Joseph; Wisotzki, Lutz; Herenz, Edmund Christian; Kerutt, Josephine; Urrutia, Tanya; Schmidt, Kasper Borello; Bouwens, Rychard; Brinchmann, Jarle; Cantalupo, Sebastiano; Carollo, Marcella; Diener, Catrina; Drake, Alyssa; Garel, Thibault; Marino, Raffaella Anna; Richard, Johan; Saust, Rikke; Schaye, Joop; Verhamme, Anne

    2018-01-01

    We present a measurement of the fraction of Lyman α (Ly α) emitters (XLy α) amongst HST continuum-selected galaxies at 3 Multi-Unit Spectroscopic Explorer (MUSE) on the VLT. Making use of the first 24 MUSE-Wide pointings in GOODS-South, each having an integration time of 1 h, we detect 100 Ly α emitters and find XLy α ≳ 0.5 for most of the redshift range covered, with 29 per cent of the Ly α sample exhibiting rest equivalent widths (rest-EWs) ≤ 15 Å. Adopting a range of rest-EW cuts (0-75 Å), we find no evidence of a dependence of XLy α on either redshift or ultraviolet luminosity.

  12. Randomized Phase II Study of Pemetrexed, Carboplatin, and Thoracic Radiation With or Without Cetuximab in Patients With Locally Advanced Unresectable Non–Small-Cell Lung Cancer: Cancer and Leukemia Group B Trial 30407

    Science.gov (United States)

    Govindan, Ramaswamy; Bogart, Jeffrey; Stinchcombe, Thomas; Wang, Xiaofei; Hodgson, Lydia; Kratzke, Robert; Garst, Jennifer; Brotherton, Timothy; Vokes, Everett E.

    2011-01-01

    Purpose Cancer and Leukemia Group B conducted a randomized phase II trial to investigate two novel chemotherapy regimens in combination with concurrent thoracic radiation therapy (TRT). Patients and Methods Patients with unresectable stage III non–small-cell lung cancer (NSCLC) were randomly assigned to carboplatin (area under the curve, 5) and pemetrexed (500 mg/m2) every 21 days for four cycles and TRT (70 Gy; arm A) or the same treatment with cetuximab administered concurrent only with TRT (arm B). Patients in both arms received up to four cycles of pemetrexed as consolidation therapy. The primary end point was the 18-month overall survival (OS) rate; if the 18-month OS rate was ≥ 55%, the regimen(s) would be considered for further study. Results Of the 101 eligible patients enrolled (48 in arm A and 53 in arm B), 60% were male; the median age was 66 years (range, 32 to 81 years); 44% and 35% had adenocarcinoma and squamous carcinoma, respectively; and more patients enrolled onto arm A compared with arm B had a performance status of 0 (58% v 34%, respectively; P = .04). The 18-month OS rate was 58% (95% CI, 46% to 74%) in arm A and 54% (95% CI, 42% to 70%) in arm B. No significant difference in OS between patients with squamous and nonsquamous NSCLC was observed (P = .667). The toxicities observed were consistent with toxicities associated with concurrent chemoradiotherapy. Conclusion The combination of pemetrexed, carboplatin, and TRT met the prespecified criteria for further evaluation. This regimen should be studied further in patients with locally advanced unresectable nonsquamous NSCLC. PMID:21747084

  13. Delayed K562 cell apoptosis promoted by cleaved LyGDI after 60Co γ-rays irradiation

    International Nuclear Information System (INIS)

    Sun Huali; Duan Weiming; Shao Yanyan; Xiao Hainan; Zhou Xinwen

    2010-01-01

    Objective: To elucidate the function and regulatory mechanism of LyGDI involved delayed cell death in the human K562 cells and HL-60 cells induced by 60 Co γ-rays. Methods: Erythrosine B cells staining was used to count the apoptosis rate. PI staining and flow cytometry were applied to check the cell cycle. The expression of LYGDI and Rac1 was resolved by Western blot by using monoclonal antibody of LyGDI and Rac1. The distribution of Rac1 protein in cells was observed with immunofluorescence by using the confocal microscope. Results: The K562 cells showed G 2 /M phase arrest and the percent age was 71.3%. The apoptosis rate was very low at early post-irradiation stage in the K562 cells. The apoptosis rate was 14% in the K562 cells at 24 h post-irradiation with 8 Gy of γ-rays, and delayed cell apoptosis was present. LyGDI was cleaved in the K562 cells irradiated by 4 Gy 60 Co γ-rays after 24 hours post-irradiation. The expression of Rac1 protein was not altered at all, but the distribution was changed in the irradiated cells while the Rac1 protein moved to cell membrane and a little in cell nucleus. The Rac1 was activated with the losing the binding affinity with the LyGDI. Conclusion: LyGDI could promote the delayed cell apoptosis, which is through the activation of the Rac1. (authors)

  14. The Kinematics of Multiple-peaked Lyα Emission in Star-forming Galaxies at z ~ 2-3

    Science.gov (United States)

    Kulas, Kristin R.; Shapley, Alice E.; Kollmeier, Juna A.; Zheng, Zheng; Steidel, Charles C.; Hainline, Kevin N.

    2012-01-01

    We present new results on the Lyα emission-line kinematics of 18 z ~ 2-3 star-forming galaxies with multiple-peaked Lyα profiles. With our large spectroscopic database of UV-selected star-forming galaxies at these redshifts, we have determined that ~30% of such objects with detectable Lyα emission display multiple-peaked emission profiles. These profiles provide additional constraints on the escape of Lyα photons due to the rich velocity structure in the emergent line. Despite recent advances in modeling the escape of Lyα from star-forming galaxies at high redshifts, comparisons between models and data are often missing crucial observational information. Using Keck II NIRSPEC spectra of Hα (z ~ 2) and [O III]λ5007 (z ~ 3), we have measured accurate systemic redshifts, rest-frame optical nebular velocity dispersions, and emission-line fluxes for the objects in the sample. In addition, rest-frame UV luminosities and colors provide estimates of star formation rates and the degree of dust extinction. In concert with the profile sub-structure, these measurements provide critical constraints on the geometry and kinematics of interstellar gas in high-redshift galaxies. Accurate systemic redshifts allow us to translate the multiple-peaked Lyα profiles into velocity space, revealing that the majority (11/18) display double-peaked emission straddling the velocity-field zero point with stronger red-side emission. Interstellar absorption-line kinematics suggest the presence of large-scale outflows for the majority of objects in our sample, with an average measured interstellar absorption velocity offset of langΔv absrang = -230 km s-1. A comparison of the interstellar absorption kinematics for objects with multiple- and single-peaked Lyα profiles indicate that the multiple-peaked objects are characterized by significantly narrower absorption line widths. We compare our data with the predictions of simple models for outflowing and infalling gas distributions around

  15. Phase II trial of neoadjuvant pemetrexed plus cisplatin followed by surgery and radiation in the treatment of pleural mesothelioma

    International Nuclear Information System (INIS)

    Federico, Rea; Matteo, Ceccarelli; Gbenga, Kazeem; Paolo, Marchi; Francesco, Facciolo; Adolfo, Favaretto; Giuseppe, Marulli; Lorenzo, Spaggiari; Martino, DePas Tommaso; Anna, Ceribelli; Adriano, Paccagnella; Gino, Crivellari; Francesca, Russo

    2013-01-01

    Malignant pleural mesothelioma is an aggressive tumor that has a poor prognosis and is resistant to unimodal approaches. Multimodal treatment has provided encouraging results. Phase II, open-label study of the combination of chemotherapy (pemetrexed 500 mg/m 2 +cisplatin 75 mg/m 2 IV every 21 days × 3 cycles), followed by surgery (en-bloc extrapleural pneumonectomy, 3–8 weeks after chemotherapy) and hemithoracic radiation (total radiation beam 54 Gy, received 4–8 weeks post-surgery). The primary endpoint was event-free survival, defined as the time from enrollment to time of first observation of disease progression, death due to any cause, or early treatment discontinuation. Fifty-four treatment-naïve patients with T1-3 N0-2 malignant pleural mesothelioma were enrolled, 52 (96.3%) completed chemotherapy, 45 (83.3%) underwent surgery, 22 (40.7%) completed the whole treatment including 90-day post-radiation follow-up. The median event-free survival was 6.9 months (95%CI: 5.0-10.5), median overall survival was 15.5 months (95%CI 11.0-NA) while median time-to-tumor response was 4.8 months (95%CI: 2.5-8.0). Eighteen (33.3%) and 13 (24.1%) patients were still event-free after 1 and 2 years, respectively. The most common treatment-emergent adverse events were nausea (63.0%), anemia (51.9%) and hypertension (42.6%). Following two cardiopulmonary radiation-related deaths the protocol was amended (21 [38.9%] patients were already enrolled in the study): the total radiation beam was reduced from 54 Gy to 50.4 Gy and a more accurate selection of patients was recommended. The combination of pemetrexed plus cisplatin followed by surgery and hemithoracic radiation is feasible and has a manageable toxicity profile in carefully selected patients. It may be worthy of further investigation. Clinicaltrial.com registrationID #NCT00087698

  16. Study of liquid scintillator in detecting the PMN-CL, Ly-CL and extracellular matrix in liver fibrosis

    International Nuclear Information System (INIS)

    Li Tianxing; Cao Rui; Liang Qizhong; Zou Xiaowei

    1997-01-01

    Chemiluminescence (CL) of polymorphonuclear (PMN) and lymphocyte(Ly) in blood of patients with cirrhosis has two peaks. Basic peak value of PMN-CL and Ly-CL is increased, the maximal peak values of Zym-PMN and PHA-Ly are decreased, phagolyosis and opsonic function is also decreased, extracellular matrix (ECM) is all increased, HA is positively correlated with 'child' sort (r = 0.96, A>B>C). It suggests that OR is produced and released during CL and superoxide phosphatides is produced by OR in ECM of cirrhosis. It injures the membrane of cells and tissue. Analysis of CL is aided to study the development mechanism of liver fibrosis

  17. Eclipsing damped Lyα systems in the Sloan Digital Sky Survey Data Release 12★

    Science.gov (United States)

    Fathivavsari, H.; Petitjean, P.; Jamialahmadi, N.; Khosroshahi, H. G.; Rahmani, H.; Finley, H.; Noterdaeme, P.; Pâris, I.; Srianand, R.

    2018-04-01

    We present the results of our automatic search for proximate damped Lyα absorption (PDLA) systems in the quasar spectra from the Sloan Digital Sky Survey Data Release 12. We constrain our search to those PDLAs lying within 1500 km s-1 from the quasar to make sure that the broad DLA absorption trough masks most of the strong Lyα emission from the broad line region (BLR) of the quasar. When the Lyα emission from the BLR is blocked by these so-called eclipsing DLAs, narrow Lyα emission from the host galaxy could be revealed as a narrow emission line (NEL) in the DLA trough. We define a statistical sample of 399 eclipsing DLAs with log N(H I) ≥ 21.10. We divide our statistical sample into three subsamples based on the strength of the NEL detected in the DLA trough. By studying the stacked spectra of these subsamples, we found that absorption from high ionization species are stronger in DLAs with stronger NEL in their absorption core. Moreover, absorption from the excited states of species like Si II are also stronger in DLAs with stronger NEL. We also found no correlation between the luminosity of the Lyα NEL and the quasar luminosity. These observations are consistent with a scenario in which the DLAs with stronger NEL are denser and physically closer to the quasar. We propose that these eclipsing DLAs could be the product of the interaction between infalling and outflowing gas. High resolution spectroscopic observation would be needed to shed some light on the nature of these eclipsing DLAs.

  18. Interaktiivne võrguõpik "Võnkumised ja lained" / Ly Sõõrd

    Index Scriptorium Estoniae

    Sõõrd, Ly

    2000-01-01

    Interaktiivne võrguõpik "Võnkumised ja lained" on mõeldud gümnaasiumi 10. kl. füüsikakursuse osa "Mehaanilised võnkumised ja lained" õppimiseks iseseisvalt interneti vahendusel ning asub aadressil : http://www.physic.ut.ee/̃ly/xklass/opik.html

  19. Mouse NK cell-mediated rejection of bone marrow allografts exhibits patterns consistent with Ly49 subset licensing.

    Science.gov (United States)

    Sun, Kai; Alvarez, Maite; Ames, Erik; Barao, Isabel; Chen, Mingyi; Longo, Dan L; Redelman, Doug; Murphy, William J

    2012-02-09

    Natural killer (NK) cells can mediate the rejection of bone marrow allografts and exist as subsets based on expression of inhibitory/activating receptors that can bind MHC. In vitro data have shown that NK subsets bearing Ly49 receptors for self-MHC class I have intrinsically higher effector function, supporting the hypothesis that NK cells undergo a host MHC-dependent functional education. These subsets also play a role in bone marrow cell (BMC) allograft rejection. Thus far, little in vivo evidence for this preferential licensing across mouse strains with different MHC haplotypes has been shown. We assessed the intrinsic response potential of the different Ly49(+) subsets in BMC rejection by using β2-microglobulin deficient (β2m(-/-)) mice as donors. Using congenic and allogeneic mice as recipients and depleting the different Ly49 subsets, we found that NK subsets bearing Ly49s, which bind "self-MHC" were found to be the dominant subset responsible for β2m(-/-) BMC rejection. This provides in vivo evidence for host MHC class I-dependent functional education. Interestingly, all H2(d) strain mice regardless of background were able to resist significantly greater amounts of β2m(-/-), but not wild-type BMC than H2(b) mice, providing evidence that the rheostat hypothesis regarding Ly49 affinities for MHC and NK-cell function impacts BMC rejection capability.

  20. The nature of luminous Ly α emitters at z ˜ 2-3: maximal dust-poor starbursts and highly ionizing AGN

    Science.gov (United States)

    Sobral, David; Matthee, Jorryt; Darvish, Behnam; Smail, Ian; Best, Philip N.; Alegre, Lara; Röttgering, Huub; Mobasher, Bahram; Paulino-Afonso, Ana; Stroe, Andra; Oteo, Iván

    2018-06-01

    Deep narrow-band surveys have revealed a large population of faint Ly α emitters (LAEs) in the distant Universe, but relatively little is known about the most luminous sources ({L}_{Lyα } ≳ 10^{42.7} erg s-1; L_{Lyα }≳ L^*_{Lyα }). Here we present the spectroscopic follow-up of 21 luminous LAEs at z ˜ 2-3 found with panoramic narrow-band surveys over five independent extragalactic fields (≈4 × 106 Mpc3 surveyed at z ˜ 2.2 and z ˜ 3.1). We use WHT/ISIS, Keck/DEIMOS, and VLT/X-SHOOTER to study these sources using high ionization UV lines. Luminous LAEs at z ˜ 2-3 have blue UV slopes (β =-2.0^{+0.3}_{-0.1}) and high Ly α escape fractions (50^{+20}_{-15} per cent) and span five orders of magnitude in UV luminosity (MUV ≈ -19 to -24). Many (70 per cent) show at least one high ionization rest-frame UV line such as C IV, N V, C III], He II or O III], typically blue-shifted by ≈100-200 km s-1 relative to Ly α. Their Ly α profiles reveal a wide variety of shapes, including significant blue-shifted components and widths from 200 to 4000 km s-1. Overall, 60 ± 11 per cent appear to be active galactic nucleus (AGN) dominated, and at LLyα > 1043.3 erg s-1 and/or MUV sharp transition in the nature of LAEs, from star formation dominated to AGN dominated.

  1. DISCOVERY OF MASSIVE, MOSTLY STAR FORMATION QUENCHED GALAXIES WITH EXTREMELY LARGE Lyα EQUIVALENT WIDTHS AT z ∼ 3

    Energy Technology Data Exchange (ETDEWEB)

    Taniguchi, Yoshiaki; Kajisawa, Masaru; Kobayashi, Masakazu A. R.; Nagao, Tohru; Shioya, Yasuhiro [Research Center for Space and Cosmic Evolution, Ehime University, Bunkyo-cho, Matsuyama 790-8577 (Japan); Scoville, Nick Z.; Capak, Peter L. [Department of Astronomy, California Institute of Technology, MS 105-24, Pasadena, CA 91125 (United States); Sanders, David B. [Institute for Astronomy, University of Hawaii, 2680 Woodlawn Drive, Honolulu, HI 96822 (United States); Koekemoer, Anton M. [Space Telescope Science Institute, 3700 San Martin Drive, Baltimore, MD 21218 (United States); Toft, Sune [Dark Cosmology Centre, Niels Bohr Institute, University of Copenhagen, Juliane Mariesvej 30, DK-2100 Copenhagen (Denmark); McCracken, Henry J. [Institut d’Astrophysique de Paris, UMR7095 CNRS, Université Pierre et Marie Curie, 98 bis Boulevard Arago, F-75014 Paris (France); Le Fèvre, Olivier; Tasca, Lidia; Ilbert, Olivier [Aix Marseille Université, CNRS, LAM (Laboratoire d’Astrophysique de Marseille), UMR 7326, F-13388 Marseille (France); Sheth, Kartik [National Radio Astronomy Observatory, 520 Edgemont Road, Charlottesville, VA 22903 (United States); Renzini, Alvio [Dipartimento di Astronomia, Universita di Padova, vicolo dell’Osservatorio 2, I-35122 Padua (Italy); Lilly, Simon; Carollo, Marcella; Kovač, Katarina [Department of Physics, ETH Zurich, 8093 Zurich (Switzerland); Schinnerer, Eva, E-mail: tani@cosmos.phys.sci.ehime-u.ac.jp [MPI for Astronomy, Königstuhl 17, D-69117 Heidelberg (Germany); and others

    2015-08-10

    We report a discovery of six massive galaxies with both extremely large Lyα equivalent widths (EWs) and evolved stellar populations at z ∼ 3. These MAssive Extremely STrong Lyα emitting Objects (MAESTLOs) have been discovered in our large-volume systematic survey for strong Lyα emitters (LAEs) with 12 optical intermediate-band data taken with Subaru/Suprime-Cam in the COSMOS field. Based on the spectral energy distribution fitting analysis for these LAEs, it is found that these MAESTLOs have (1) large rest-frame EWs of EW{sub 0} (Lyα) ∼ 100–300 Å, (2) M{sub ⋆} ∼ 10{sup 10.5}–10{sup 11.1} M{sub ⊙}, and (3) relatively low specific star formation rates of SFR/M{sub ⋆} ∼ 0.03–1 Gyr{sup −1}. Three of the six MAESTLOs have extended Lyα emission with a radius of several kiloparsecs, although they show very compact morphology in the HST/ACS images, which correspond to the rest-frame UV continuum. Since the MAESTLOs do not show any evidence for active galactic nuclei, the observed extended Lyα emission is likely to be caused by a star formation process including the superwind activity. We suggest that this new class of LAEs, MAESTLOs, provides a missing link from star-forming to passively evolving galaxies at the peak era of the cosmic star formation history.

  2. The Role of PPAR Receptors and Leukotriene B4 Receptors in Mediating the Effects of LY293111 in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Thomas E. Adrian

    2008-01-01

    Full Text Available Pancreatic cancer is a devastating disease in which current therapies are inadequate. Separate lines of research have identified the 5-lipoxygenase/leukotriene B4 receptor pathway and the PPAR pathway as potential targets for prevention or treatment of this disease. LY293111 was originally designed as a potent leukotriene B4 receptor antagonist for treatment of inflammatory conditions. LY293111 was also known to have inhibitory effects on 5-lipoxygenase, which is upstream of the production of leukotrienes. LY293111 was shown to have potent anticancer effects in pancreatic cancer and several other solid malignancies, where it caused cell cycle arrest and marked apoptosis. Subsequently, it came to light that LY293111 exhibited PPAR agonist activity in addition to its effects on the 5-lipoxygenase pathway. This raises the question of which of the two targets is of greatest importance with regard to the anticancer effects of this agent. The evidence to date is not conclusive, but suggests that the effects of LY293111 may be mediated by both LTB4 receptors and PPAR.

  3. Chemical dampening of Ly6C(hi) monocytes in the periphery produces anti-depressant effects in mice.

    Science.gov (United States)

    Zheng, Xiao; Ma, Sijing; Kang, An; Wu, Mengqiu; Wang, Lin; Wang, Qiong; Wang, Guangji; Hao, Haiping

    2016-01-19

    The involvement of systemic immunity in depression pathogenesis promises a periphery-targeting paradigm in novel anti-depressant discovery. However, relatively little is known about druggable targets in the periphery for mental and behavioral control. Here we report that targeting Ly6C(hi) monocytes in blood can serve as a strategy for anti-depressant purpose. A natural compound, ginsenoside Rg1 (Rg1), was firstly validated as a periphery-restricted chemical probe. Rg1 selectively suppressed Ly6C(hi) monocytes recruitment to the inflamed mice brain. The proinflammatory potential of Ly6C(hi) monocytes to activate astrocytes was abrogated by Rg1, which led to a blunted feedback release of CCL2 to recruit the peripheral monocytes. In vitro study demonstrated that Rg1 pretreatment on activated THP-1 monocytes retarded their ability to trigger CCL2 secretion from co-cultured U251 MG astrocytes. CCL2-triggered p38/MAPK and PI3K/Akt activation were involved in the action of Rg1. Importantly, in mice models, we found that dampening Ly6C(hi) monocytes at the periphery ameliorated depression-like behavior induced by neuroinflammation or chronic social defeat stress. Together, our work unravels that blood Ly6C(hi) monocytes may serve as the target to enable remote intervention on the depressed brain, and identifies Rg1 as a lead compound for designing drugs targeting peripheral CCL2 signals.

  4. The Spectroscopic Properties of Lyα-Emitters at z ˜2.7: Escaping Gas and Photons from Faint Galaxies

    Science.gov (United States)

    Trainor, Ryan F.; Steidel, Charles C.; Strom, Allison L.; Rudie, Gwen C.

    2015-08-01

    We present a spectroscopic survey of 318 faint ({R}˜ 27, L˜ 0.1{L}*), Lyα-emission-selected galaxies (LAEs) in regions centered on the positions of hyperluminous QSOs (HLQSOs) at 2.5\\lt z\\lt 3. A sample of 32 LAEs with rest-frame optical emission line spectra from Keck/Multi-Object Spectrometer For InfraRed Exploration (MOSFIRE) are used to interpret the LAE spectra in the context of their systemic redshifts. The fields are part of the Keck Baryonic Structure Survey, which includes substantial ancillary multi-wavelength imaging from both the ground and space. From a quantitative analysis of the diverse Lyα spectral morphologies, including line widths, asymmetries, and multi-peaked profiles, we find that peak widths and separations are typically smaller than among samples of more luminous continuum-selected galaxies (Lyman-break galaxies and their analogs; LBGs) at similar redshifts. We find tentative evidence for an association between Lyα spectral morphology and external illumination by the nearby HLQSO. Using the MOSFIRE subsample, we find that the peak of the resolved (R ≈ 1300) Lyα line is shifted by +200 km s-1 with respect to systemic across a diverse set of galaxies including both LAEs and LBGs. We also find a small number of objects with significantly blueshifted Lyα emission, a potential indicator of accreting gas. The Lyα-to-Hα line ratios measured for the MOSFIRE subset suggest that the LAEs in this sample have Lyα escape fractions {f}{esc,{Ly}α } ≈ 30%, significantly higher than typical LBG samples. Using redshifts calibrated by our MOSFIRE sample, we construct composite LAE spectra, finding the first evidence for metal-enriched outflows in such intrinsically faint high-redshift galaxies. These outflows have smaller continuum covering fractions ({f}{{c}}≈ 0.3) and velocities ({v}{ave} ≈ 100-200 km s-1, {v}{max} ≈ 500 km s-1) than those associated with typical LBGs, suggesting that the gas covering fraction is a likely driver of

  5. Second-line Treatment of Stage III/IV Non-Small-Cell Lung Cancer (NSCLC with pemetrexed in routine clinical practice: Evaluation of performance status and health-related quality of life

    Directory of Open Access Journals (Sweden)

    Schuette Wolfgang

    2012-01-01

    Full Text Available Abstract Background Second-line treatment of advanced non-small-cell lung cancer (NSCLC improves overall survival. There is a lack of data regarding the impact on patients' overall health condition. This prospective, non-interventional study evaluated performance status (PS and health-related quality of life (HR-QoL during second-line pemetrexed treatment in routine clinical practice. Methods Stage III/IV NSCLC patients who initiated second-line pemetrexed (standard vitamin and dexamethasone supplementation were observed for a maximum of 9 treatment cycles. The primary objective was to evaluate the proportion of patients achieving improvement of Karnofsky Index (KI of ≥ 10% (absolute or maintaining KI ≥ 80% after the second treatment cycle ("KI benefit response". HR-QoL was self-rated using the EuroQoL-5D questionnaire (EQ-5D. Factors potentially associated with KI benefit response were evaluated using logistic regression models. Results Of 521 eligible patients (73.5% Stage IV, median age 66.3 yrs, 36.1% ≥ 70 yrs, 62.0% with KI ≥ 80%, 471 (90.4% completed at least 2 treatment cycles. 58.0% (95%CI 53.6%;62.2% achieved KI benefit response after the second cycle. Patients with baseline KI ≥ 80%, no Grade 3/4 toxicities during the first 2 cycles, or combination regimen as prior first-line therapy were more likely to achieve a KI benefit response. EQ-5D scores improved over time. Grade 3/4 toxicities were reported in 23.8% of patients (mainly fatigue/asthenia 15.9%, neutropenia 8.7%. Conclusions In this large prospective, non-interventional study of second-line pemetrexed treatment in patients with advanced NSCLC, including 36% elderly patients ( ≥ 70 years, physician-rated PS and self-rated HR-QoL were maintained or improved in the majority of patients. Trial registration Registered on ClinicalTrials.gov (NCT00540241 on October 4, 2007

  6. Targeting PI3K-AKT-mTOR by LY3023414 inhibits human skin squamous cell carcinoma cell growth in vitro and in vivo.

    Science.gov (United States)

    Zou, Ying; Ge, Minggai; Wang, Xuemin

    2017-08-19

    Abnormal activation of PI3K-AKT-mTOR signaling is detected in human skin squamous cell carcinoma (SCC). LY3023414 is a novel, potent, and orally bio-available PI3K-AKT-mTOR inhibitor. Its activity against human skin SCC cells was tested. We demonstrated that LY3023414 was cytotoxic when added to established (A431 line) and primary (patient-derived) human skin SCC cells. LY3023414 induced G0/1-S arrest and inhibited proliferation of skin SCC cells. Moreover, LY3023414 induced activation of caspase-3/-9 and apoptosis in skin SCC cells. Intriguingly, LY3023414 was yet non-cytotoxic nor pro-apoptotic to normal human skin cells (melanocytes, keratinocytes and fibroblasts). At the molecular level, LY3023414 blocked PI3K-AKT-mTOR activation in skin SCC cells, as it dephosphorylated PI3K-AKT-mTOR substrates: P85, AKT and S6K1. In vivo studies showed that oral administration of LY3023414 at well-tolerated doses inhibited A431 xenograft tumor growth in severe combined immunodeficiency (SCID) mice. AKT-mTOR activation in LY3023414-treated tumors was also largely inhibited. Together, these results suggest that targeting PI3K-AKT-mTOR by LY3023414 inhibits human skin SCC cell growth in vitro and in vivo, establishing the rationale for further clinical testing. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. On the lack of correlation between Mg II 2796, 2803 Å and Lyα emission in lensed star-forming galaxies

    Energy Technology Data Exchange (ETDEWEB)

    Rigby, J. R. [Astrophysics Science Division, Goddard Space Flight Center, 8800 Greenbelt Road, Greenbelt, MD 20771 (United States); Bayliss, M. B. [Department of Physics, Harvard University, 17 Oxford Street, Cambridge, MA 02138 (United States); Gladders, M. D. [Department of Astronomy and Astrophysics, University of Chicago, 5640 S. Ellis Avenue, Chicago, IL 60637 (United States); Sharon, K. [Department of Astronomy, University of Michigan, 500 Church Street, Ann Arbor, MI 48109 (United States); Wuyts, E. [Max Plank Institute for Extraterrestrial Physics, Giessenbachstrasse 1, D-85748 Garching (Germany); Dahle, H. [Institute of Theoretical Astrophysics, University of Oslo, P.O. Box 1029, Blindern, NO-0315 Oslo (Norway)

    2014-07-20

    We examine the Mg II 2796, 2803 Å, Lyα, and nebular line emission in five bright star-forming galaxies at 1.66 < z < 1.91 that have been gravitationally lensed by foreground galaxy clusters. All five galaxies show prominent Mg II emission and absorption in a P Cygni profile. We find no correlation between the equivalent widths of Mg II and Lyα emission. The Mg II emission has a broader range of velocities than do the nebular emission line profiles; the Mg II emission is redshifted with respect to systemic by 100-200 km s{sup –1}. When present, Lyα is even more redshifted. The reddest components of Mg II and Lyα emission have tails to 500-600 km s{sup –1}, implying a strong outflow. The lack of correlation in the Mg II and Lyα equivalent widths, the differing velocity profiles, and the high ratios of Mg II to nebular line fluxes together suggest that the bulk of Mg II emission does not ultimately arise as nebular line emission, but may instead be reprocessed stellar continuum emission.

  8. Rational design of a fibroblast growth factor 21-based clinical candidate, LY2405319.

    Directory of Open Access Journals (Sweden)

    Alexei Kharitonenkov

    Full Text Available Fibroblast growth factor 21 is a novel hormonal regulator with the potential to treat a broad variety of metabolic abnormalities, such as type 2 diabetes, obesity, hepatic steatosis, and cardiovascular disease. Human recombinant wild type FGF21 (FGF21 has been shown to ameliorate metabolic disorders in rodents and non-human primates. However, development of FGF21 as a drug is challenging and requires re-engineering of its amino acid sequence to improve protein expression and formulation stability. Here we report the design and characterization of a novel FGF21 variant, LY2405319. To enable the development of a potential drug product with a once-daily dosing profile, in a preserved, multi-use formulation, an additional disulfide bond was introduced in FGF21 through Leu118Cys and Ala134Cys mutations. FGF21 was further optimized by deleting the four N-terminal amino acids, His-Pro-Ile-Pro (HPIP, which was subject to proteolytic cleavage. In addition, to eliminate an O-linked glycosylation site in yeast a Ser167Ala mutation was introduced, thus allowing large-scale, homogenous protein production in Pichia pastoris. Altogether re-engineering of FGF21 led to significant improvements in its biopharmaceutical properties. The impact of these changes was assessed in a panel of in vitro and in vivo assays, which confirmed that biological properties of LY2405319 were essentially identical to FGF21. Specifically, subcutaneous administration of LY2405319 in ob/ob and diet-induced obese (DIO mice over 7-14 days resulted in a 25-50% lowering of plasma glucose coupled with a 10-30% reduction in body weight. Thus, LY2405319 exhibited all the biopharmaceutical and biological properties required for initiation of a clinical program designed to test the hypothesis that administration of exogenous FGF21 would result in effects on disease-related metabolic parameters in humans.

  9. KECK SPECTROSCOPY OF LYMAN-BREAK GALAXIES AND ITS IMPLICATIONS FOR THE UV-CONTINUUM AND Lyα LUMINOSITY FUNCTIONS AT z > 6

    International Nuclear Information System (INIS)

    Jiang Linhua; Egami, Eiichi; Walth, Gregory; Kashikawa, Nobunari; Matsuda, Yuichi; Shimasaku, Kazuhiro; Nagao, Tohru; Ota, Kazuaki; Ouchi, Masami

    2011-01-01

    We present Keck spectroscopic observations of z > 6 Lyman-break galaxy (LBG) candidates in the Subaru Deep Field (SDF). The candidates were selected as i'-dropout objects down to z' = 27 AB magnitudes from an ultra-deep SDF z'-band image. With the Keck spectroscopy we identified 19 LBGs with prominent Lyα emission lines at 6 ≤ z ≤ 6.4. The median value of the Lyα rest-frame equivalent widths (EWs) is ∼50 Å, with four EWs >100 Å. This well-defined spectroscopic sample spans a UV-continuum luminosity range of –21.8 ≤ M UV ≤ –19.5 (0.6 ∼ 5 L* UV ) and a Lyα luminosity range of (0.3-3) × 10 43 erg s –1 (0.3-3 L* Lyα ). We derive the UV and Lyα luminosity functions (LFs) from our sample at (z) ∼ 6.2 after we correct for sample incompleteness. We find that our measurement of the UV LF is consistent with the results of previous studies based on photometric LBG samples at 5 6.

  10. An Intercomparison Study of Two Proximate Damped Lyα Systems with Residual Flux upon the Lyα Absorption Trough toward Quasars

    Science.gov (United States)

    Xie, Xiaoyi; Zhou, Hongyan; Pan, Xiang; Jiang, Peng; Shi, Xiheng; Ji, Tuo; Zhang, Shaohua; Wu, Shengmiao; Zhong, Zhihao

    2018-05-01

    In this paper, we present an intercomparison study of two quasars, SDSS J145618.32+340037.2 and SDSS J215331.50–025514.1, which have proximate damped Lyα systems (PDLAs) with residual flux upon the Lyα absorption trough. Though they both have residual flux as luminous as 1043 erg s‑1, their PDLAs are quite different in, e.g., neutral hydrogen column density, metal line absorption strength, high-ionization absorption lines as well as residual flux strength. For J1456+3400, the H I column density is log(N H I /cm–2) = 20.6 ± 0.2, with z abs = 2.3138, nearly identical to the quasar redshift (z = 2.3142) determined from the [O III] emission line. The metallicity of this system is typical of DLAs and there is high ionization therein, suggesting that the PDLA system is multiphase, putting it in the quasar environment. For J2153–0255, we measure the H I column density to be log(N H I /cm–2) = 21.5 ± 0.1 at z abs = 3.511, slightly redshifted with respect to the quasar (z = 3.490) measured from C III]. The metallicity of this system is quite low and there is a lack of significant high-ionization absorption lines therein, suggesting that the system is beyond the quasar host galaxy. The residual flux is wide (∼1000 km s‑1) in J1456, with a significance of ∼8σ, while also wide (∼1500 km s‑1) but with a smaller significance of ∼3σ in J2153. Among many explanations, we find that Lyα fuzz or resonant scattering can be used to explain the residual flux in the two sources while partial coverage cannot be excluded for J1456. By comparing these two cases, together with a similar case reported previously, we suggest that the strength of the residual flux is related to properties such as metallicity and high-ionization absorption lines of PDLAs. The residual flux recorded upon the PDLA absorption trough opens a window for us to see the physical conditions and processes of the quasar environment, and their profile and strength further remind us of their

  11. Anticonvulsant actions of LY 367385 ((+)-2-methyl-4-carboxyphenylglycine) and AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid).

    Science.gov (United States)

    Chapman, A G; Yip, P K; Yap, J S; Quinn, L P; Tang, E; Harris, J R; Meldrum, B S

    1999-02-26

    We have studied the effects in three rodent models of generalised convulsive or absence epilepsy of two antagonists of group I metabotropic glutamate receptors that are selective for the mGlu1 receptor. LY 367385 ((+)-2-methyl-4-carboxyphenylglycine) and AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid) have been administered intracerebroventricularly (i.c.v.) to DBA/2 mice and lethargic mice (lh/lh), and focally into the inferior colliculus of genetically epilepsy prone rats (GEPR). In DBA/2 mice both compounds produce a rapid, transient suppression of sound-induced clonic seizures (LY 367385: ED50 = 12 nmol, i.c.v., 5 min; AIDA: ED50 = 79 nmol, i.c.v., 15 min). In lethargic mice both compounds significantly reduce the incidence of spontaneous spike and wave discharges on the electroencephalogram, from 150 min after the administration of AIDA, 500 nmol, i.c.v., and from 30 to >150 min after the administration of LY 367385, 250 nmol, i.c.v. LY 367385, 50 nmol, suppresses spontaneous spike and wave discharges from 30 to 60 min. In genetically epilepsy prone rats both compounds reduce sound-induced clonic seizures. LY 367385, 160 nmol bilaterally, fully suppresses clonic seizures after 2-4 h. AIDA is fully effective 30 min after 100 nmol bilaterally. It is concluded that antagonists of mGlu1 receptors are potential anticonvulsant agents and that activation of mGlu1 receptors probably contributes to a variety of epileptic syndromes.

  12. Novel LY Converter Topologies for High Gain Transfer Ratio - A New Breed of XY Family

    DEFF Research Database (Denmark)

    Bhaskar, M.S.; Padmanaban, S.; Kulkarni, R.

    2016-01-01

    gain and minimum internal resistance; such as a photovoltaic MLI system, high voltage applications and electrical drives. The conspicuous features of proposed LY converter topologies are i) Single power control switch ii) Single Input source iii) Inverting output voltage iv) Transformer-less converter...... topologies v) High inverting voltage gain with moderate duty ratio vi) Less number of power devices and components. The proposed topologies have minimum internal resistance and its effect on voltage gain of LY converter is also discussed in detail. The simulation results are presented and the result...

  13. Inspiraling halo accretion mapped in Ly α emission around a z ˜ 3 quasar

    Science.gov (United States)

    Arrigoni Battaia, Fabrizio; Prochaska, J. Xavier; Hennawi, Joseph F.; Obreja, Aura; Buck, Tobias; Cantalupo, Sebastiano; Dutton, Aaron A.; Macciò, Andrea V.

    2018-01-01

    In an effort to search for Ly α emission from circum- and intergalactic gas on scales of hundreds of kpc around z ∼ 3 quasars, and thus characterize the physical properties of the gas in emission, we have initiated an extensive fast survey with the Multi-Unit Spectroscopic Explorer (MUSE): Quasar Snapshot Observations with MUse: Search for Extended Ultraviolet eMission (QSO MUSEUM). In this work, we report the discovery of an enormous Ly α nebula (ELAN) around the quasar SDSS J102009.99+104002.7 at z = 3.164, which we followed-up with deeper MUSE observations. This ELAN spans ∼297 projected kpc, has an average Ly α surface brightness SBLy α ∼ 6.04 × 10-18 erg s-1 cm-2 arcsec-2(within the 2σ isophote) and is associated with an additional four previously unknown embedded sources: two Ly α emitters and two faint active galactic nuclei (one type-1 and one type-2 quasar). By mapping at high significance, the line-of-sight velocity in the entirety of the observed structure, we unveiled a large-scale coherent rotation-like pattern spanning ∼300 km s-1 with a velocity dispersion of <270 km s-1, which we interpret as a signature of the inspiraling accretion of substructures within the quasar's host halo. Future multiwavelength data will complement our MUSE observations and are definitely needed to fully characterize such a complex system. None the less, our observations reveal the potential of new sensitive integral-field spectrographs to characterize the dynamical state of diffuse gas on large scales in the young Universe, and thereby witness the assembly of galaxies.

  14. Chronic treatment with LY341495 decreases 5-HT2A receptor binding and hallucinogenic effects of LSD in mice

    Science.gov (United States)

    Moreno, José L.; Holloway, Terrell; Rayannavar, Vinayak; Sealfon, Stuart C.; González-Maeso, Javier

    2013-01-01

    Hallucinogenic drugs, such as lysergic acid diethylamide (LSD), mescaline and psilocybin, alter perception and cognitive processes. All hallucinogenic drugs have in common a high affinity for the serotonin 5-HT2A receptor. Metabotropic glutamate 2/3 (mGlu2/3) receptor ligands show efficacy in modulating the cellular and behavioral responses induced by hallucinogenic drugs. Here, we explored the effect of chronic treatment with the mGlu2/3 receptor antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)-propionic acid (LY341495) on the hallucinogenic-like effects induced by LSD (0.24 mg/kg). Mice were chronically (21 days) treated with LY341495 (1.5 mg/kg), or vehicle, and experiments were carried out one day after the last injection. Chronic treatment with LY341495 down-regulated [3H]ketanserin binding in somatosensory cortex of wild-type, but not mGlu2 knockout (KO), mice. Head-twitch behavior, and expression of c-fos, egr-1 and egr-2, which are responses induced by hallucinogenic 5-HT2A agonists, were found to be significantly decreased by chronic treatment with LY341495. These findings suggest that repeated blockade of the mGlu2 receptor by LY341495 results in reduced 5-HT2A receptor-dependent hallucinogenic effects of LSD. PMID:23333599

  15. Chronic treatment with LY341495 decreases 5-HT(2A) receptor binding and hallucinogenic effects of LSD in mice.

    Science.gov (United States)

    Moreno, José L; Holloway, Terrell; Rayannavar, Vinayak; Sealfon, Stuart C; González-Maeso, Javier

    2013-03-01

    Hallucinogenic drugs, such as lysergic acid diethylamide (LSD), mescaline and psilocybin, alter perception and cognitive processes. All hallucinogenic drugs have in common a high affinity for the serotonin 5-HT(2A) receptor. Metabotropic glutamate 2/3 (mGlu2/3) receptor ligands show efficacy in modulating the cellular and behavioral responses induced by hallucinogenic drugs. Here, we explored the effect of chronic treatment with the mGlu2/3 receptor antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)-propionic acid (LY341495) on the hallucinogenic-like effects induced by LSD (0.24mg/kg). Mice were chronically (21 days) treated with LY341495 (1.5mg/kg), or vehicle, and experiments were carried out one day after the last injection. Chronic treatment with LY341495 down-regulated [(3)H]ketanserin binding in somatosensory cortex of wild-type, but not mGlu2 knockout (KO), mice. Head-twitch behavior, and expression of c-fos, egr-1 and egr-2, which are responses induced by hallucinogenic 5-HT(2A) agonists, were found to be significantly decreased by chronic treatment with LY341495. These findings suggest that repeated blockade of the mGlu2 receptor by LY341495 results in reduced 5-HT(2A) receptor-dependent hallucinogenic effects of LSD. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  16. PROBING THE EPOCH OF REIONIZATION WITH THE Lyα FOREST AT z ∼ 4-5

    International Nuclear Information System (INIS)

    Cen Renyue; McDonald, Patrick; Trac, Hy; Loeb, Abraham

    2009-01-01

    The inhomogeneous cosmological reionization process leaves tangible imprints in the intergalactic medium (IGM) down to z ∼ 4-5. The Lyα forest flux power spectrum provides a potentially powerful probe of the epoch of reionization. With the existing Sloan Digital Sky Survey I/II quasar sample, we show that two cosmological reionization scenarios, one completing reionization at z = 6 and the other at z = 9, can be distinguished at ∼7σ level by utilizing Lyα forest absorption spectra at z = 3.9-4.1 in the absence of other physical processes that may also affect the Lyα flux power spectrum. The difference may not be distinguishable at such high significance after marginalization over other effects, but, in any case, one will need to consider this effect in order to correctly interpret the power spectrum in this redshift range. The redshift range z = 4-5 may provide the best window because there are still enough transmitted flux and quasars to measure precise statistics of the flux fluctuations, and the IGM still retains a significant amount of memory of reionization.

  17. Noise estimates for measurements of weak lensing from the Ly α forest

    Science.gov (United States)

    Metcalf, R. Benton; Croft, Rupert A. C.; Romeo, Alessandro

    2018-06-01

    Lensing changes the apparent separation between pixels in the Ly α forest of separate quasars or high-redshift objects by changing their observed positions on the sky. This changes the implied correlations in the absorption and in particular makes the Ly α forest correlation function, or power spectrum, locally anisotropic in the plane of the sky. We have proposed a method for measuring weak lensing using this effect. Here, we estimate the noise expected in weak lensing maps and power spectra for different sets of observational parameters. We find that surveys of the size and quality of the ones being done today and ones planned for the future will be able to measure the lensing power spectrum at a source redshift of z ≃ 2.5 with high precision and even be able to image the distribution of foreground matter with high fidelity on degree scales. For example, we predict that Ly α forest lensing measurements from the DESI and WEAVE surveys should yield the mass fluctuation amplitude with a statistical error of ˜3 per cent, eBOSS ˜6 per cent. and the proposed MSE survey less than 1 per cent. By dividing the redshift range into multiple bins, some tomographic lensing information should be accessible as well. This would allow for cosmological lensing measurements at higher redshift than are accessible with galaxy shear surveys and correspondingly better constraints on the evolution of dark energy at relatively early times.

  18. Pharmacological characterization of LY233053: A structurally novel tetrazole-substituted competitive N-methyl-D-aspartic acid antagonist with a short duration of action

    International Nuclear Information System (INIS)

    Schoepp, D.D.; Ornstein, P.L.; Leander, J.D.; Lodge, D.; Salhoff, C.R.; Zeman, S.; Zimmerman, D.M.

    1990-01-01

    This study reports the activity of a structurally novel excitatory amino acid receptor antagonist, LY233053 [cis-(+-)-4-[(2H-tetrazol-5-yl)methyl]piperidine-2-carboxylic acid], the first tetrazole-containing competitive N-methyl-D-aspartic acid (NMDA) antagonist. LY233053 potently inhibited NMDA receptor binding to rat brain membranes as shown by the in vitro displacement of [3H] CGS19755 (IC50 = 107 +/- 7 nM). No appreciable affinity in [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or [3H]kainate binding assays was observed (IC50 values greater than 10,000 nM). In vitro NMDA receptor antagonist activity was further demonstrated by selective inhibition of NMDA-induced depolarization in cortical wedges (IC50 = 4.2 +/- 0.4 microM vs. 40 microM NMDA). LY233053 was effective after in vivo systemic administration in a number of animal models. In neonatal rats, LY233053 selectively blocked NMDA-induced convulsions (ED50 = 14.5 mg/kg i.p.) with a relatively short duration of action (2-4 hr). In pigeons, LY233053 potently antagonized (ED50 = 1.3 mg/kg i.m.) the behavioral suppressant effects of 10 mg/kg of NMDA. However, a dose of 160 mg/kg, i.m., was required to produce phencyclidine-like catalepsy in pigeons. In mice, LY233053 protected against maximal electroshock-induced seizures at lower doses (ED50 = 19.9 mg/kg i.p.) than those that impaired horizontal screen performance (ED50 = 40.9 mg/kg i.p.). Cholinergic and GABAergic neuronal degenerations after striatal infusion of NMDA were prevented by single or multiple i.p. doses of LY233053. In summary, the antagonist activity of LY233053 after systemic administration demonstrates potential therapeutic value in conditions of neuronal cell loss due to NMDA receptor excitotoxicity

  19. Evolution of Lyα Forest in Redshift Range 0.5

    Indian Academy of Sciences (India)

    represents the number of Lyα absorption lines in the interval width of unit redshift (z); when z is equal to zero,. ( dn dz. ) is represented by. ( dn dz. ) 0. , and γ is the evolution index. In general, we are using maximum likelihood estimation to do a statistical research. For 1.7 Lyα forest is very strong when ...

  20. PHYSICAL PROPERTIES OF Ly{alpha} EMITTERS AT z {approx} 0.3 FROM UV-TO-FIR MEASUREMENTS

    Energy Technology Data Exchange (ETDEWEB)

    Oteo, I.; Bongiovanni, A.; Perez Garcia, A. M.; Cepa, J.; Pintos-Castro, I. [Instituto de Astrofisica de Canarias (IAC), E-38200 La Laguna, Tenerife (Spain); Ederoclite, A. [Centro de Estudios de Fisica del Cosmos de Aragon, Plaza San Juan 1, Planta 2, Teruel, 44001 (Spain); Sanchez-Portal, M.; Altieri, B. [Herschel Science Centre (ESAC), Villafranca del Castillo (Spain); Perez-Martinez, R. [XMM/Newton Science Operations Centre (ESAC), Villafranca del Castillo (Spain); Lutz, D.; Berta, S.; Foerster Schreiber, N.; Genzel, R.; Magnelli, B. [Max-Planck-Institut fuer Extraterrestrische Physik (MPE), Postfach 1312, 85741 Garching (Germany); Andreani, P. [ESO, Karl-Schwarzchild-Str. 2, D-85748 Garching (Germany); Aussel, H.; Daddi, E.; Elbaz, D.; Le Floc' h, E. [Commissariat a l' Energie Atomique (CEA-SAp) Saclay (France); Cimatti, A. [Dipartimento di Astronomia, Universita di Bologna, Via Ranzani 1, 40127 Bologna (Italy); and others

    2012-06-01

    The analysis of the physical properties of low-redshift Ly{alpha} emitters (LAEs) can provide clues in the study of their high-redshift analogs. At z {approx} 0.3, LAEs are bright enough to be detected over almost the entire electromagnetic spectrum and it is possible to carry out a more precise and complete study than at higher redshifts. In this work, we examine the UV and IR emission, dust attenuation, star formation rate (SFR), and morphology of a sample of 23 GALEX-discovered star-forming LAEs at z {approx} 0.3 with direct UV (GALEX), optical (ACS), and FIR (PACS and MIPS) data. Using the same UV and IR limiting luminosities, we find that LAEs at z {approx} 0.3 tend to be less dusty, have slightly higher total SFRs, have bluer UV continuum slopes, and are much smaller than other galaxies that do not exhibit Ly{alpha} emission in their spectrum (non-LAEs). These results suggest that at z {approx} 0.3, Ly{alpha} photons tend to escape from small galaxies with low dust attenuation. Regarding their morphology, LAEs belong to Irr/merger classes, unlike non-LAEs. Size and morphology represent the most noticeable difference between LAEs and non-LAEs at z {approx} 0.3. Furthermore, the comparison of our results with those obtained at higher redshifts indicates either that the Ly{alpha} technique picks up different kind of galaxies at different redshifts or that the physical properties of LAEs are evolving with redshift.

  1. The CALYMHA survey: Lyα escape fraction and its dependence on galaxy properties at z = 2.23

    Science.gov (United States)

    Matthee, Jorryt; Sobral, David; Oteo, Iván; Best, Philip; Smail, Ian; Röttgering, Huub; Paulino-Afonso, Ana

    2016-05-01

    We present the first results from our CAlibrating LYMan α with Hα (CALYMHA) pilot survey at the Isaac Newton Telescope. We measure Lyα emission for 488 Hα selected galaxies at z = 2.23 from High-z Emission Line Survey in the COSMOS and UDS fields with a specially designed narrow-band filter (λc = 3918 Å, Δλ = 52 Å). We find 17 dual Hα-Lyα emitters [fLyα > 5 × 10-17 erg s-1 cm-2, of which five are X-ray active galactic nuclei (AGN)]. For star-forming galaxies, we find a range of Lyα escape fractions (fesc, measured with 3 arcsec apertures) from 2 to 30 per cent. These galaxies have masses from 3 × 108 M⊙ to 1011 M⊙ and dust attenuations E(B - V) = 0-0.5. Using stacking, we measure a median escape fraction of 1.6 ± 0.5 per cent (4.0 ± 1.0 per cent without correcting Hα for dust), but show that this depends on galaxy properties. The stacked fesc tends to decrease with increasing star formation rate and dust attenuation. However, at the highest masses and dust attenuations, we detect individual galaxies with fesc much higher than the typical values from stacking, indicating significant scatter in the values of fesc. Relations between fesc and UV slope are bimodal, with high fesc for either the bluest or reddest galaxies. We speculate that this bimodality and large scatter in the values of fesc is due to additional physical mechanisms such as outflows facilitating fesc for dusty/massive systems. Lyα is significantly more extended than Hα and the UV. fesc continues to increase up to at least 20 kpc (3σ, 40 kpc [2σ]) for typical star-forming galaxies and thus the aperture is the most important predictor of fesc.

  2. Spatially Resolved Patchy Ly α Emission within the Central Kiloparsec of a Strongly Lensed Quasar Host Galaxy at z = 2.8

    Energy Technology Data Exchange (ETDEWEB)

    Bayliss, Matthew B.; Bordoloi, Rongmon [Kavli Institute for Astrophysics and Space Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139 (United States); Sharon, Keren; Runnoe, Jessie; Johnson, Traci; Paterno-Mahler, Rachel [Department of Astronomy, University of Michigan, 1085 S. University Avenue, Ann Arbor, MI 48109 (United States); Acharyya, Ayan; Bian, Fuyan; Kewley, Lisa [RSAA, Australian National University, Cotter Road, Weston Creek, ACT 2611 (Australia); Gladders, Michael D. [Kavli Institute for Cosmological Physics, University of Chicago, Chicago, IL 60637 (United States); Rigby, Jane R. [Astrophysics Science Division, NASA Goddard Space Flight Center, 8800 Greenbelt Road, Greenbelt, MD 20771 (United States); Dahle, Hakon [Institute of Theoretical Astrophysics, University of Oslo, P.O. Box 1029, Blindern, NO-0315 Oslo (Norway); Florian, Michael, E-mail: mbayliss@mit.edu [Department of Astronomy and Astrophysics, University of Chicago, Chicago, IL 60637 (United States)

    2017-08-20

    We report the detection of extended Ly α emission from the host galaxy of SDSS J2222+2745, a strongly lensed quasar at z = 2.8. Spectroscopic follow-up clearly reveals extended Ly α in emission between two images of the central active galactic nucleus (AGN). We reconstruct the lensed quasar host galaxy in the source plane by applying a strong lens model to HST imaging and resolve spatial scales as small as ∼200 pc. In the source plane, we recover the host galaxy morphology to within a few hundred parsecs of the central AGN and map the extended Ly α emission to its physical origin on one side of the host galaxy at radii ∼0.5–2 kpc from the central AGN. There are clear morphological differences between the Ly α and rest-frame ultraviolet stellar continuum emission from the quasar host galaxy. Furthermore, the relative velocity profiles of quasar Ly α , host galaxy Ly α , and metal lines in outflowing gas reveal differences in the absorbing material affecting the AGN and host galaxy. These data indicate the presence of patchy local intervening gas in front of the central quasar and its host galaxy. This interpretation is consistent with the central luminous quasar being obscured across a substantial fraction of its surrounding solid angle, resulting in strong anisotropy in the exposure of the host galaxy to ionizing radiation from the AGN. This work demonstrates the power of strong-lensing-assisted studies to probe spatial scales that are currently inaccessible by other means.

  3. Spatially Resolved Patchy Ly α Emission within the Central Kiloparsec of a Strongly Lensed Quasar Host Galaxy at z = 2.8

    International Nuclear Information System (INIS)

    Bayliss, Matthew B.; Bordoloi, Rongmon; Sharon, Keren; Runnoe, Jessie; Johnson, Traci; Paterno-Mahler, Rachel; Acharyya, Ayan; Bian, Fuyan; Kewley, Lisa; Gladders, Michael D.; Rigby, Jane R.; Dahle, Hakon; Florian, Michael

    2017-01-01

    We report the detection of extended Ly α emission from the host galaxy of SDSS J2222+2745, a strongly lensed quasar at z = 2.8. Spectroscopic follow-up clearly reveals extended Ly α in emission between two images of the central active galactic nucleus (AGN). We reconstruct the lensed quasar host galaxy in the source plane by applying a strong lens model to HST imaging and resolve spatial scales as small as ∼200 pc. In the source plane, we recover the host galaxy morphology to within a few hundred parsecs of the central AGN and map the extended Ly α emission to its physical origin on one side of the host galaxy at radii ∼0.5–2 kpc from the central AGN. There are clear morphological differences between the Ly α and rest-frame ultraviolet stellar continuum emission from the quasar host galaxy. Furthermore, the relative velocity profiles of quasar Ly α , host galaxy Ly α , and metal lines in outflowing gas reveal differences in the absorbing material affecting the AGN and host galaxy. These data indicate the presence of patchy local intervening gas in front of the central quasar and its host galaxy. This interpretation is consistent with the central luminous quasar being obscured across a substantial fraction of its surrounding solid angle, resulting in strong anisotropy in the exposure of the host galaxy to ionizing radiation from the AGN. This work demonstrates the power of strong-lensing-assisted studies to probe spatial scales that are currently inaccessible by other means.

  4. Dose study of the multikinase inhibitor, LY2457546, in patients with relapsed acute myeloid leukemia to assess safety, pharmacokinetics, and pharmacodynamics

    International Nuclear Information System (INIS)

    Wacheck, Volker; Lahn, Michael; Dickinson, Gemma; Füreder, Wolfgang; Meyer, Renata; Herndlhofer, Susanne; Füreder, Thorsten; Dorfner, Georg; Pillay, Sada; André, Valérie; Burkholder, Timothy P; Akunda, Jacqueline K; Flye-Blakemore, Leann; Van Bockstaele, Dirk; Schlenk, Richard F; Sperr, Wolfgang R; Valent, Peter

    2011-01-01

    Acute myeloid leukemia (AML) is a life-threatening malignancy with limited treatment options in chemotherapy-refractory patients. A first-in-human dose study was designed to investigate a safe and biologically effective dose range for LY2457546, a novel multikinase inhibitor, in patients with relapsed AML. In this nonrandomized, open-label, dose escalation Phase I study, LY2457546 was administered orally once a day. Safety, pharmacokinetics, changes in phosphorylation of target kinases in AML blasts, and risk of drug–drug interactions (DDI) were assessed. Five patients were treated at the starting and predicted minimal biologically effective dose of 50 mg/day. The most commonly observed adverse events were febrile neutropenia, epistaxis, petechiae, and headache. The majority of adverse events (81%) were Grade 1 or 2. One patient had generalized muscle weakness (Grade 3), which was deemed to be a dose-limiting toxicity. Notably, the pharmacokinetic profile of LY2457546 showed virtually no elimination of LY2457546 within 24 hours, and thus prevented further dose escalation. No significant DDI were observed. Ex vivo flow cytometry studies showed downregulation of the phosphoproteins, pcKIT, pFLT3, and pS6, in AML blasts after LY2457546 administration. No medically relevant responses were observed in the five treated patients. No biologically effective dose could be established for LY2457546 in chemotherapy-resistant AML patients. Lack of drug clearance prevented safe dose escalation, and the study was terminated early. Future efforts should be made to develop derivatives with a more favorable pharmacokinetic profile

  5. T cell antigen receptor expression by subsets of Ly-2-L3T4- (CD8-CD4-) thymocytes

    DEFF Research Database (Denmark)

    Wilson, A; Ewing, T; Owens, T

    1988-01-01

    . No positive cells were detected among Ly-2-L3T4- thymocytes from V beta 8-negative SJL mice. In contrast to the adult thymus, Ly-2-L3T4- cells from embryonic CBA thymus lacked F23.1-positive cells. Subsets of adult CBA Ly-2-L3T4- thymocytes were separated to determine which expressed V beta 8. The major...... B2A2-M1/69- and Pgp-1+ all included strongly F23.1-positive cells. A minor subset, negative for most markers except Pgp-1 and presumed on the basis of this phenotype and some reconstitution studies to include the earliest intrathymic precursors, contained 28% F23.1-positive cells. However, no F.23...

  6. A Luminous Lyα-emitting Galaxy at Redshift z = 6.535: Discovery and Spectroscopic Confirmation

    Science.gov (United States)

    Rhoads, James E.; Xu, Chun; Dawson, Steve; Dey, Arjun; Malhotra, Sangeeta; Wang, JunXian; Jannuzi, Buell T.; Spinrad, Hyron; Stern, Daniel

    2004-08-01

    We present a redshift z=6.535 galaxy discovered by its Lyα emission in a 9180 Å narrowband image from the Large Area Lyman Alpha survey. The Lyα line luminosity (1.1×1043 ergs s-1) is among the largest known for star-forming galaxies at z~6.5. The line shows the distinct asymmetry that is characteristic of high-redshift Lyα. The 2 σ lower bound on the observer-frame equivalent width is greater than 530 Å. This is hard to reconcile with a neutral intergalactic medium (IGM) unless the Lyα line is intrinsically strong and is emitted from its host galaxy with an intrinsic Doppler shift of several hundred km s-1. If the IGM is ionized, it corresponds to a rest-frame equivalent width greater than 40 Å after correcting for Lyα forest absorption. We also present a complete spectroscopic follow-up of the remaining candidates with line flux greater than 2×10-17 ergs cm-2 s-1 in our 1200 arcmin2 narrowband image. These include another galaxy with a strong emission line at 9136 Å and no detected continuum flux, which, however, is most likely an [O III] λ5007 source at z=0.824, on the basis of a weak detection of the [O III] λ4959 line. The data presented in this paper were obtained at the Kitt Peak National Observatory, the Gemini Observatory, and the W. M. Keck Observatory. Kitt Peak National Observatory, National Optical Astronomy Observatory, is operated by the Association of Universities for Research in Astronomy, Inc. (AURA), under cooperative agreement with the National Science Foundation (NSF). The Gemini Observatory is operated by AURA under a cooperative agreement with the NSF on behalf of the Gemini partnership: the NSF (United States), the Particle Physics and Astronomy Research Council (United Kingdom), the National Research Council (Canada), CONICYT (Chile), the Australian Research Council, CNPq (Brazil), and CONICET (Argentina). The W. M. Keck Observatory is operated as a scientific partnership among the California Institute of Technology, the

  7. Meta-analysis of pemetrexed plus carboplatin doublet safety profile in first-line non-squamous non-small cell lung cancer studies.

    Science.gov (United States)

    Okamoto, Isamu; Schuette, Wolfgang H W; Stinchcombe, Thomas E; Rodrigues-Pereira, José; San Antonio, Belén; Chen, Jian; Liu, Jingyi; John, William J; Zinner, Ralph G

    2017-05-01

    This meta-analysis compared safety profiles (selected drug-related treatment-emergent adverse events [TEAEs]) of first-line pemetrexed plus carboplatin (PCb) area under the concentration-time curve 5 mg/min•mL (PCb5) or 6 mg/min•mL (PCb6), two widely used regimens in clinical practice for advanced non-squamous non-small cell lung cancer. All patients received pemetrexed 500 mg/m 2 every 21 days with either of two carboplatin doses for up to 4-6 cycles. Safety profiles of PCb doses were compared using three statistical analysis methods: frequency table analysis (FTA), generalized linear mixed effect model (GLMM), and the propensity score method. Efficacy outcomes of PCb5 and PCb6 regimens were summarized. A total of 486 patients mainly from the US, Europe, and East Asia were included in the analysis; 22% (n = 105) received PCb5 in one trial and 78% (n = 381) received PCb6 in four trials. The FTA comparison demonstrated that PCb5 vs PCb6 was associated with a statistically significantly lower incidence of TEAEs, including all-grade thrombocytopenia, anemia, fatigue, and vomiting, and grade 3/4 thrombocytopenia. In the GLMM analysis, PCb5 patients were numerically less likely to experience all-grade and grade 3/4 neutropenia, anemia, and thrombocytopenia. The propensity score regression analysis showed PCb5 group patients were significantly less likely than PCb6 group patients to experience all-grade hematologic TEAEs and grade 3/4 thrombocytopenia and anemia. After applying propensity score 1:1 matching, FTA analysis showed that the PCb5 group had significantly less all-grade and grade 3/4 hematologic toxicities. Overall efficacy outcomes, including overall survival, progression-free survival, and response rate, were similar between the two carboplatin doses. Acknowledging the limitations of this meta-analysis of five trials, heterogeneous in patient's characteristics and trial designs, the results show that the PCb5 regimen was generally associated

  8. Pemetrexed plus platinum as the first-line treatment option for advanced non-small cell lung cancer: a meta-analysis of randomized controlled trials.

    Directory of Open Access Journals (Sweden)

    Ming Li

    Full Text Available To compare the efficacy and toxicities of pemetrexed plus platinum with other platinum regimens in patients with previously untreated advanced non-small cell lung cancer (NSCLC.A meta-analysis was performed using trials identified through PubMed, EMBASE, and Cochrane databases. Two investigators independently assessed the quality of the trials and extracted data. The outcomes included overall survival (OS, progression-free survival (PFS, response rate (RR, and different types of toxicity. Hazard ratios (HRs, odds ratios (ORs and their 95% confidence intervals (CIs were pooled using RevMan software.Four trials involving 2,518 patients with previously untreated advanced NSCLC met the inclusion criteria. Pemetrexed plus platinum chemotherapy (PPC improved survival compared with other platinum-based regimens (PBR in patients with advanced NSCLC (HR = 0.91, 95% CI: 0.83-1.00, p = 0.04, especially in those with non-squamous histology (HR = 0.87, 95% CI: 0.77-0.98, p = 0.02. No statistically significant improvement in either PFS or RR was found in PPC group as compared with PBR group (HR = 1.03, 95% CI: 0.94-1.13, p = 0.57; OR = 1.15, 95% CI: 0.95-1.39, p = 0.15, respectively. Compared with PBR, PPC led to less grade 3-4 neutropenia and leukopenia but more grade 3-4 nausea. However, hematological toxicity analysis revealed significant heterogeneities.Our results suggest that PPC in the first-line setting leads to a significant survival advantage with acceptable toxicities for advanced NSCLC patients, especially those with non-squamous histology, as compared with other PRB. PPC could be considered as the first-line treatment option for advanced NSCLC patients, especially those with non-squamous histology.

  9. SPECTROSCOPIC CONFIRMATION OF THREE z-DROPOUT GALAXIES AT z = 6.844-7.213: DEMOGRAPHICS OF Lyα EMISSION IN z ∼ 7 GALAXIES

    International Nuclear Information System (INIS)

    Ono, Yoshiaki; Shimasaku, Kazuhiro; Nakajima, Kimihiko; Ouchi, Masami; Mobasher, Bahram; Nayyeri, Hooshang; Dickinson, Mark; Kartaltepe, Jeyhan S.; Penner, Kyle; Weiner, Benjamin J.; Stern, Daniel; Kashikawa, Nobunari; Spinrad, Hyron

    2012-01-01

    We present the results of our ultra-deep Keck/DEIMOS spectroscopy of z-dropout galaxies in the Subaru Deep Field and Great Observatories Origins Deep Survey's northern field. For 3 out of 11 objects, we detect an emission line at ∼1 μm with a signal-to-noise ratio of ∼10. The lines show asymmetric profiles with high weighted skewness values, consistent with being Lyα, yielding redshifts of z = 7.213, 6.965, and 6.844. Specifically, we confirm the z = 7.213 object in two independent DEIMOS runs with different spectroscopic configurations. The z = 6.965 object is a known Lyα emitter, IOK-1, for which our improved spectrum at a higher resolution yields a robust skewness measurement. The three z-dropouts have Lyα fluxes of 3 × 10 –17 erg s –1 cm –2 and rest-frame equivalent widths EW Lyα 0 = 33-43 Å. Based on the largest spectroscopic sample of 43 z-dropouts, which is the combination of our and previous data, we find that the fraction of Lyα-emitting galaxies (EW Lyα 0 > 25 Å) is low at z ∼ 7; 17% ± 10% and 24% ± 12% for bright (M UV ≅ –21) and faint (M UV ≅ –19.5) galaxies, respectively. The fractions of Lyα-emitting galaxies drop from z ∼ 6 to 7 and the amplitude of the drop is larger for faint galaxies than for bright galaxies. These two pieces of evidence would indicate that the neutral hydrogen fraction of the intergalactic medium increases from z ∼ 6 to 7 and that the reionization proceeds from high- to low-density environments, as suggested by an inside-out reionization model.

  10. SPECTROSCOPIC CONFIRMATION OF THREE z-DROPOUT GALAXIES AT z = 6.844-7.213: DEMOGRAPHICS OF Ly{alpha} EMISSION IN z {approx} 7 GALAXIES

    Energy Technology Data Exchange (ETDEWEB)

    Ono, Yoshiaki; Shimasaku, Kazuhiro; Nakajima, Kimihiko, E-mail: ono@astron.s.u-tokyo.ac.jp [Department of Astronomy, Graduate School of Science, University of Tokyo, Tokyo 113-0033 (Japan); Ouchi, Masami [Institute for Cosmic Ray Research, University of Tokyo, Kashiwa 277-8582 (Japan); Mobasher, Bahram; Nayyeri, Hooshang [Department of Physics and Astronomy, University of California, Riverside, CA 92521 (United States); Dickinson, Mark; Kartaltepe, Jeyhan S. [National Optical Astronomical Observatories, Tucson, AZ 85719 (United States); Penner, Kyle [Department of Astronomy, University of Arizona, Tucson, AZ 85721 (United States); Weiner, Benjamin J. [Steward Observatory, University of Arizona, Tucson, AZ 85721 (United States); Stern, Daniel [Jet Propulsion Laboratory, California Institute of Technology, Pasadena, CA 91109 (United States); Kashikawa, Nobunari [Optical and Infrared Astronomy Division, National Astronomical Observatory of Japan, Tokyo 181-8588 (Japan); Spinrad, Hyron [Department of Astronomy, University of California, Berkeley, CA 94720 (United States)

    2012-01-10

    We present the results of our ultra-deep Keck/DEIMOS spectroscopy of z-dropout galaxies in the Subaru Deep Field and Great Observatories Origins Deep Survey's northern field. For 3 out of 11 objects, we detect an emission line at {approx}1 {mu}m with a signal-to-noise ratio of {approx}10. The lines show asymmetric profiles with high weighted skewness values, consistent with being Ly{alpha}, yielding redshifts of z = 7.213, 6.965, and 6.844. Specifically, we confirm the z = 7.213 object in two independent DEIMOS runs with different spectroscopic configurations. The z = 6.965 object is a known Ly{alpha} emitter, IOK-1, for which our improved spectrum at a higher resolution yields a robust skewness measurement. The three z-dropouts have Ly{alpha} fluxes of 3 Multiplication-Sign 10{sup -17} erg s{sup -1} cm{sup -2} and rest-frame equivalent widths EW{sup Ly{alpha}}{sub 0} = 33-43 A. Based on the largest spectroscopic sample of 43 z-dropouts, which is the combination of our and previous data, we find that the fraction of Ly{alpha}-emitting galaxies (EW{sup Ly{alpha}}{sub 0} > 25 A) is low at z {approx} 7; 17% {+-} 10% and 24% {+-} 12% for bright (M{sub UV} {approx_equal} -21) and faint (M{sub UV} {approx_equal} -19.5) galaxies, respectively. The fractions of Ly{alpha}-emitting galaxies drop from z {approx} 6 to 7 and the amplitude of the drop is larger for faint galaxies than for bright galaxies. These two pieces of evidence would indicate that the neutral hydrogen fraction of the intergalactic medium increases from z {approx} 6 to 7 and that the reionization proceeds from high- to low-density environments, as suggested by an inside-out reionization model.

  11. Trahv? Herned klassinurgas? Või hoopis ihunuhtlus? / Pilme, Lea; Kivistik, Ly; Sirgmets, Raili; Part, Aivar

    Index Scriptorium Estoniae

    2008-01-01

    Suhtumisest koolijuhtidele trahvimisõiguse andmise ideesse vestlevad Rakvere Põhikooli direktor Lea Pilme, Uhtna Põhikooli direktor Ly Kivistik, Väike-Maarja Gümnaasiumi direktor Raili Sirgmets ja Rakvere Gümnaasiumi direktor Aivar Part

  12. Changing Traditions and Village Development in Kalotaszentkirály

    Directory of Open Access Journals (Sweden)

    Wayne Kraft

    2011-10-01

    Full Text Available The continuity of village traditions depends on the stability and cohesion of village communities. Since the opening of Transylvania after the fall of Nicolae Ceauşescu, there has been a sort of revival of Hungarian village dance and music, on the one hand, but, on the longer term, the communities themselves are threatened by economic challenges and by consequent demographic changes. This essay is based on field research conducted in Kalotaszentkirály (Sincraiu from 1995 to 2010.

  13. SPECTROPOLARIMETRY CONFIRMS CENTRAL POWERING IN A Lyα NEBULA AT z = 3.09

    International Nuclear Information System (INIS)

    Beck, Melanie; Scarlata, Claudia; Jones, Terry J.; Hayes, Matthew; Dijkstra, Mark

    2016-01-01

    We present a follow-up study to the imaging polarimetry performed by Hayes et al. on LAB1 in the SSA22 protocluster region. Arguably the most well-known Lyα “blob,” this radio-quiet emission-line nebula likely hosts a galaxy that either is undergoing significant star formation or hosts an active galactic nucleus, or both. We obtain deep, spatially resolved spectropolarimetry of the Lyα emission and detect integrated linear polarization of 9%–13% ± 2%–3% at a distance of approximately 15 kpc north and south of the peak of the Lyα surface brightness with polarization vectors lying tangential to the galactic central source. In these same regions, we also detect a wavelength dependence in the polarization that is low at the center of the Lyα line profile and rises substantially in the wings of the profile. These polarization signatures are easily explained by a weak outflowing shell model. The spectral dependence of the polarization presented here provides a framework for future observations and interpretations of the southern portion of LAB1 in that any model for this system must be able to reproduce this particular spectral dependence. However, questions still remain for the northernmost spur of LAB1. In this region we detect total linear polarization of between 3% and 20% at the 5% significance level. Simulations predict that polarization should increase with radius for a symmetric geometry. That the northern spur does not suggests either that this region is not symmetric (which is likely) and exhibits variations in columns density or that it is kinematically distinct from the rest of LAB1 and powered by another mechanism altogether

  14. SPECTROPOLARIMETRY CONFIRMS CENTRAL POWERING IN A Lyα NEBULA AT z = 3.09

    Energy Technology Data Exchange (ETDEWEB)

    Beck, Melanie; Scarlata, Claudia; Jones, Terry J. [Minnesota Institute for Astrophysics, School of Physics and Astronomy, University of Minnesota, 116 Church Street, Minneapolis, MN 55455 (United States); Hayes, Matthew [Department of Astronomy, Oskar Klein Centre, Stockholm University, AlbaNova University Centre, SE-106 91 Stockholm (Sweden); Dijkstra, Mark, E-mail: beck@astro.umn.edu [Institute of Theoretical Astrophysics, University of Oslo, P.O. Box 1029, Blindern, N-0315 Oslo (Norway)

    2016-02-20

    We present a follow-up study to the imaging polarimetry performed by Hayes et al. on LAB1 in the SSA22 protocluster region. Arguably the most well-known Lyα “blob,” this radio-quiet emission-line nebula likely hosts a galaxy that either is undergoing significant star formation or hosts an active galactic nucleus, or both. We obtain deep, spatially resolved spectropolarimetry of the Lyα emission and detect integrated linear polarization of 9%–13% ± 2%–3% at a distance of approximately 15 kpc north and south of the peak of the Lyα surface brightness with polarization vectors lying tangential to the galactic central source. In these same regions, we also detect a wavelength dependence in the polarization that is low at the center of the Lyα line profile and rises substantially in the wings of the profile. These polarization signatures are easily explained by a weak outflowing shell model. The spectral dependence of the polarization presented here provides a framework for future observations and interpretations of the southern portion of LAB1 in that any model for this system must be able to reproduce this particular spectral dependence. However, questions still remain for the northernmost spur of LAB1. In this region we detect total linear polarization of between 3% and 20% at the 5% significance level. Simulations predict that polarization should increase with radius for a symmetric geometry. That the northern spur does not suggests either that this region is not symmetric (which is likely) and exhibits variations in columns density or that it is kinematically distinct from the rest of LAB1 and powered by another mechanism altogether.

  15. Absorption and disposition of LY127210, an orally effective hypotensive agent, in laboratory animals

    International Nuclear Information System (INIS)

    Turner, J.C.; White, J.F.; Sullivan, H.R.

    1986-01-01

    The disposition, pharmacokinetics, and metabolic fate of LY127210, 7,8-dimethoxy-(1H)-3-benzazepin-2-amine hydrochloride, have been studied in mice, rats, dogs and monkeys. Pharmacokinetic and bioavailability studies in dogs and monkeys showed it to be well absorbed orally with maximum plasma levels of drug obtained within 4 hr. Following administration of 14 C-LY127210, the plasma half-lives of parent and radiocarbon in rat were 11 hr and 45 hr (β-phase), respectively. In dogs and monkeys parent half-lives were 11 hr (β-phase) and 5.2 hr (monophasic) while half-lives of total radiocarbon were 145 hr (β-phase) and 299 hr (β-phase), respectively. Plasma concentrations of parent compound in rat, dog, and monkey following oral administration accounted for approximately 15% of circulating radiocarbon. Renal excretion was the major route of elimination. The major urinary species was LY127210; metabolic mechanisms included oxidative O-demethylation and deamination, aliphatic oxidation, and reduction. Radiocarbon tissue level studies in rat indicated wide distribution of drug and/or metabolites. Similar studies in monkeys indicated that the half-life of radiocarbon in tissues was equal to or greater than that in plasma and red blood cells. The long half-life of radiocarbon in blood was due to irreversible dose dependent binding of drug and/or metabolites to plasma albumin and to cellular hemoglobin

  16. Activating the Wnt/β-Catenin Pathway for the Treatment of Melanoma--Application of LY2090314, a Novel Selective Inhibitor of Glycogen Synthase Kinase-3.

    Directory of Open Access Journals (Sweden)

    Jennifer M Atkinson

    Full Text Available It has previously been observed that a loss of β-catenin expression occurs with melanoma progression and that nuclear β-catenin levels are inversely proportional to cellular proliferation, suggesting that activation of the Wnt/β-catenin pathway may provide benefit for melanoma patients. In order to further probe this concept we tested LY2090314, a potent and selective small-molecule inhibitor with activity against GSK3α and GSK3β isoforms. In a panel of melanoma cell lines, nM concentrations of LY2090314 stimulated TCF/LEF TOPFlash reporter activity, stabilized β-catenin and elevated the expression of Axin2, a Wnt responsive gene and marker of pathway activation. Cytotoxicity assays revealed that melanoma cell lines are very sensitive to LY2090314 in vitro (IC50 ~10 nM after 72hr of treatment in contrast to other solid tumor cell lines (IC50 >10 uM as evidenced by caspase activation and PARP cleavage. Cell lines harboring mutant B-RAF or N-RAS were equally sensitive to LY2090314 as were those with acquired resistance to the BRAF inhibitor Vemurafenib. shRNA studies demonstrated that β-catenin stabilization is required for apoptosis following treatment with the GSK3 inhibitor since the sensitivity of melanoma cell lines to LY290314 could be overcome by β-catenin knockdown. We further demonstrate that in vivo, LY2090314 elevates Axin2 gene expression after a single dose and produces tumor growth delay in A375 melanoma xenografts with repeat dosing. The activity of LY2090314 in preclinical models suggests that the role of Wnt activators for the treatment of melanoma should be further explored.

  17. The physical properties of Lyα emitting galaxies: not just primeval galaxies?

    Science.gov (United States)

    Pentericci, L.; Grazian, A.; Fontana, A.; Castellano, M.; Giallongo, E.; Salimbeni, S.; Santini, P.

    2009-02-01

    Aims: We have analyzed a sample of Lyman break galaxies from z ~ 3.5 to z ~ 6 selected from the GOODS-S field as B, V, and i-dropouts, and with spectroscopic observations showing that they have the Lyα line in emission. Our main aim is to investigate their physical properties and their dependence on the emission line characteristic and to shed light on the relation between galaxies with Lyα emission and the general LBG population. Methods: The objects were selected from their optical continuum colors and then spectroscopically confirmed by the GOODS collaboration and other campaigns. From the public spectra we derived the main properties of the Lyα emission such as total flux and rest frame EW. We then used complete photometry, from U band to mid-infrared from the GOODS-MUSIC database, and through standard spectro-photometric techniques we derived the physical properties of the galaxies, such as total stellar mass, stellar ages, star formation rates, and dust content. Finally we investigated the relation between emission line and physical properties. Results: Although most galaxies are fit by young stellar populations, a small but non negligible fraction has SEDs that cannot be represented well by young models and require considerably older stellar component, up to ~1 Gyr. There is no apparent relation between age and EW: some of the oldest galaxies have high line EW, and should be also selected in narrow-band surveys. Therefore not all Lyα emitting galaxies are primeval galaxies in the very early stages of formation, as is commonly assumed. We also find a range of stellar populations, with masses from 5 × 108 M_⊙ to 5 × 1010 M_⊙ and SFR from few to 60 M_⊙ yr-1. Although there is no net correlation between mass and EW, we find a significant lack of massive galaxies with high EW, which could be explained if the most massive galaxies were either dustier and/or if they contained more neutral gas than less massive objects. Finally we find that more than

  18. In vitro activity of a new 'higher-Iactam' antibacterial agent LY 193239

    African Journals Online (AJOL)

    1991-03-16

    Mar 16, 1991 ... penicillin. Antimicrobial agents. Solutions of LY 193239 (supplied by Eli Lilly) and tetracycline were freshly prepared in sterile distilled water. Rifampicin was dissolved in dimethyl sul- phoxide and diluted in water. Ampicillin and penicillin were prepared in 0,05M phosphate buffer with final pH 7,0. MICs.

  19. EVIDENCE FOR PopIII-LIKE STELLAR POPULATIONS IN THE MOST LUMINOUS Lyα EMITTERS AT THE EPOCH OF REIONIZATION: SPECTROSCOPIC CONFIRMATION

    Energy Technology Data Exchange (ETDEWEB)

    Sobral, David; Santos, Sérgio [Instituto de Astrofísica e Ciências do Espaço, Universidade de Lisboa, OAL, Tapada da Ajuda, PT1349-018 Lisbon (Portugal); Matthee, Jorryt; Röttgering, Huub J. A. [Leiden Observatory, Leiden University, P.O. Box 9513, NL-2300 RA Leiden (Netherlands); Darvish, Behnam; Mobasher, Bahram; Hemmati, Shoubaneh [Department of Physics and Astronomy, University of California, 900 University Avenue, Riverside, CA 92521 (United States); Schaerer, Daniel, E-mail: sobral@iastro.pt [Observatoire de Genève, Département d’Astronomie, Université de Genève, 51 Ch. des Maillettes, 1290 Versoix (Switzerland)

    2015-08-01

    Faint Lyα emitters become increasingly rarer toward the reionization epoch (z ∼ 6–7). However, observations from a very large (∼5 deg{sup 2}) Lyα narrow-band survey at z = 6.6 show that this is not the case for the most luminous emitters, capable of ionizing their own local bubbles. Here we present follow-up observations of the two most luminous Lyα candidates in the COSMOS field: “MASOSA” and “CR7.” We used X-SHOOTER, SINFONI, and FORS2 on the Very Large Telescope, and DEIMOS on Keck, to confirm both candidates beyond any doubt. We find redshifts of z = 6.541 and z = 6.604 for “MASOSA” and “CR7,” respectively. MASOSA has a strong detection in Lyα with a line width of 386 ± 30 km s{sup −1} (FWHM) and with very high EW{sub 0} (>200 Å), but undetected in the continuum, implying very low stellar mass and a likely young, metal-poor stellar population. “CR7,” with an observed Lyα luminosity of 10{sup 43.92±0.05} erg s{sup −1} is the most luminous Lyα emitter ever found at z > 6 and is spatially extended (∼16 kpc). “CR7” reveals a narrow Lyα line with 266 ± 15 km s{sup −1} FWHM, being detected in the near-infrared (NIR) (rest-frame UV; β = −2.3 ± 0.1) and in IRAC/Spitzer. We detect a narrow He ii 1640 Å emission line (6σ, FWHM = 130 ± 30 km s{sup −1}) in CR7 which can explain the clear excess seen in the J-band photometry (EW{sub 0} ∼ 80 Å). We find no other emission lines from the UV to the NIR in our X-SHOOTER spectra (He ii/O iii] 1663 Å > 3 and He ii/C iii] 1908 Å > 2.5). We conclude that CR7 is best explained by a combination of a PopIII-like population, which dominates the rest-frame UV and the nebular emission, and a more normal stellar population, which presumably dominates the mass. Hubble Space Telescope/WFC3 observations show that the light is indeed spatially separated between a very blue component, coincident with Lyα and He ii emission, and two red components (∼5 kpc away), which

  20. The microstructural mechanism for mechanical property of LY2 aluminum alloy after laser shock processing

    International Nuclear Information System (INIS)

    Luo, Kai-yu; Lu, Jin-zhong; Zhang, Ling-feng; Zhong, Jun-wei; Guan, Hai-bing; Qian, Xiao-ming

    2010-01-01

    This paper described nanoindentation techniques for measuring thin films mechanical properties, including elastic modulus and nano-hardness. The effects of laser shock processing (LSP) on elastic modulus and nano-hardness of the sample manufactured by LY2 aluminum alloy were experimentally investigated by nanoindentation techniques. Transmission electron microscope (TEM) observations of the microstructures in different regions after LSP are carried out. Experimental results showed that the values of nano-hardness and elastic modulus in the laser-shocked region were obviously increased by 58.13% and 61.74% compared to those in the non-shocked region, respectively. The influences of LSP on microstructure and grain size of LY2 aluminum alloy were discussed, and the enhancement mechanism of LSP on nano-hardness and elastic modulus was also addressed.

  1. Evidence That Ly6C(hi) Monocytes are Protective in Acute Ischemic Stroke by Promoting M2 Macrophage Polarization.

    Science.gov (United States)

    Chu, Hannah X; Broughton, Brad R S; Kim, Hyun Ah; Lee, Seyoung; Drummond, Grant R; Sobey, Christopher G

    2015-07-01

    Ly6C(hi) monocytes are generally thought to exert a proinflammatory role in acute tissue injury, although their impact after injuries to the central nervous system is poorly defined. CC chemokine receptor 2 is expressed on Ly6C(hi) monocytes and plays an essential role in their extravasation and transmigration into the brain after cerebral ischemia. We used a selective CC chemokine receptor 2 antagonist, INCB3344, to assess the effect of Ly6C(hi) monocytes recruited into the brain early after ischemic stroke. Male C57Bl/6J mice underwent occlusion of the middle cerebral artery for 1 hour followed by 23 hours of reperfusion. Mice were administered either vehicle (dimethyl sulfoxide/carboxymethylcellulose) or INCB3344 (10, 30 or 100 mg/kg IP) 1 hour before ischemia and at 2 and 6 hours after ischemia. At 24 hours, we assessed functional outcomes, infarct volume, and quantified the immune cells in blood and brain by flow cytometry or immunofluorescence. Gene expression of selected inflammatory markers was assessed by quantitative polymerase chain reaction. Ly6C(hi) monocytes were increased 3-fold in the blood and 10-fold in the brain after stroke, and these increases were selectively prevented by INCB3344 in a dose-dependent manner. Mice treated with INCB3344 exhibited markedly worse functional outcomes and larger infarct volumes, in association with reduced M2 polarization and increased peroxynitrite production in macrophages, compared with vehicle-treated mice. Our data suggest that Ly6C(hi) monocytes exert an acute protective effect after ischemic stroke to limit brain injury and functional deficit that involves promotion of M2 macrophage polarization. © 2015 American Heart Association, Inc.

  2. CD11c(hi) Dendritic Cells Regulate Ly-6C(hi) Monocyte Differentiation to Preserve Immune-privileged CNS in Lethal Neuroinflammation.

    Science.gov (United States)

    Kim, Jin Hyoung; Choi, Jin Young; Kim, Seong Bum; Uyangaa, Erdenebelig; Patil, Ajit Mahadev; Han, Young Woo; Park, Sang-Youel; Lee, John Hwa; Kim, Koanhoi; Eo, Seong Kug

    2015-12-02

    Although the roles of dendritic cells (DCs) in adaptive defense have been defined well, the contribution of DCs to T cell-independent innate defense and subsequent neuroimmunopathology in immune-privileged CNS upon infection with neurotropic viruses has not been completely defined. Notably, DC roles in regulating innate CD11b(+)Ly-6C(hi) monocyte functions during neuroinflammation have not yet been addressed. Using selective ablation of CD11c(hi)PDCA-1(int/lo) DCs without alteration in CD11c(int)PDCA-1(hi) plasmacytoid DC number, we found that CD11c(hi) DCs are essential to control neuroinflammation caused by infection with neurotropic Japanese encephalitis virus, through early and increased infiltration of CD11b(+)Ly-6C(hi) monocytes and higher expression of CC chemokines. More interestingly, selective CD11c(hi) DC ablation provided altered differentiation and function of infiltrated CD11b(+)Ly-6C(hi) monocytes in the CNS through Flt3-L and GM-CSF, which was closely associated with severely enhanced neuroinflammation. Furthermore, CD11b(+)Ly-6C(hi) monocytes generated in CD11c(hi) DC-ablated environment had a deleterious rather than protective role during neuroinflammation, and were more quickly recruited into inflamed CNS, depending on CCR2, thereby exacerbating neuroinflammation via enhanced supply of virus from the periphery. Therefore, our data demonstrate that CD11c(hi) DCs provide a critical and unexpected role to preserve the immune-privileged CNS in lethal neuroinflammation via regulating the differentiation, function, and trafficking of CD11b(+)Ly-6C(hi) monocytes.

  3. Indication of the Hanle Effect by Comparing the Scattering Polarization Observed by CLASP in the Ly α and Si iii 120.65 nm Lines

    Energy Technology Data Exchange (ETDEWEB)

    Ishikawa, R.; Kubo, M.; Kano, R.; Narukage, N.; Bando, T.; Katsukawa, Y.; Giono, G.; Suematsu, Y.; Hara, H. [National Astronomical Observatory of Japan, National Institutes of Natural Science, 2-21-1 Osawa, Mitaka, Tokyo 181-8588 (Japan); Bueno, J. Trujillo [Instituto de Astrofísica de Canarias, E-38205 La Laguna, Tenerife (Spain); Uitenbroek, H. [National Solar Observatory, 3665 Discovery Drive, Boulder, CO 80303 (United States); Tsuneta, S.; Ishikawa, S.; Shimizu, T.; Sakao, T. [Institute of Space and Astronautical Science, Japan Aerospace Exploration Agency, 3-1-1 Yoshinodai, Chuo, Sagamihara, Kanagawa 252-5210 (Japan); Goto, M. [National Institute for Fusion Science, National Institutes of Natural Sciences, Toki, Gifu 509-5292 (Japan); Winebarger, A.; Kobayashi, K. [NASA Marshall Space Flight Center, ZP 13, Huntsville, AL 35812 (United States); Cirtain, J. [University of Virginia, Department of Astronomy, 530 McCormick Road, Charlottesville, VA 22904 (United States); Champey, P. [University of Alabama in Huntsville, 301 Sparkman Drive, Huntsville, AL 35899 (United States); and others

    2017-05-20

    The Chromospheric Lyman-Alpha Spectro-Polarimeter is a sounding rocket experiment that has provided the first successful measurement of the linear polarization produced by scattering processes in the hydrogen Ly α line (121.57 nm) radiation of the solar disk. In this paper, we report that the Si iii line at 120.65 nm also shows scattering polarization and we compare the scattering polarization signals observed in the Ly α and Si iii lines in order to search for observational signatures of the Hanle effect. We focus on four selected bright structures and investigate how the U / I spatial variations vary between the Ly α wing, the Ly α core, and the Si iii line as a function of the total unsigned photospheric magnetic flux estimated from Solar Dynamics Observatory /Helioseismic and Magnetic Imager observations. In an internetwork region, the Ly α core shows an antisymmetric spatial variation across the selected bright structure, but it does not show it in other more magnetized regions. In the Si iii line, the spatial variation of U / I deviates from the above-mentioned antisymmetric shape as the total unsigned photospheric magnetic flux increases. A plausible explanation of this difference is the operation of the Hanle effect. We argue that diagnostic techniques based on the scattering polarization observed simultaneously in two spectral lines with very different sensitivities to the Hanle effect, like Ly α and Si iii, are of great potential interest for exploring the magnetism of the upper solar chromosphere and transition region.

  4. Deep learning of quasar spectra to discover and characterize damped Lyα systems

    Science.gov (United States)

    Parks, David; Prochaska, J. Xavier; Dong, Shawfeng; Cai, Zheng

    2018-05-01

    We have designed, developed, and applied a convolutional neural network (CNN) architecture using multi-task learning to search for and characterize strong H I Lyα absorption in quasar spectra. Without any explicit modelling of the quasar continuum or application of the predicted line profile for Lyα from quantum mechanics, our algorithm predicts the presence of strong H I absorption and estimates the corresponding redshift zabs and H I column density N_{H I}, with emphasis on damped Lyα systems (DLAs, absorbers with N_{H I}≥ 2 × 10^{20} cm^{-2}). We tuned the CNN model using a custom training set of DLAs injected into DLA-free quasar spectra from the Sloan Digital Sky Survey (SDSS), data release 5 (DR5). Testing on a held-back validation set demonstrates a high incidence of DLAs recovered by the algorithm (97.4 per cent as DLAs and 99 per cent as an H I absorber with N_{H I}> 10^{19.5} cm^{-2}) and excellent estimates for zabs and N_{H I}. Similar results are obtained against a human-generated survey of the SDSS DR5 data set. The algorithm yields a low incidence of false positives and negatives but is challenged by overlapping DLAs and/or very high N_{H I} systems. We have applied this CNN model to the quasar spectra of SDSS DR7 and the Baryon Oscillation Spectroscopic Survey (data release 12) and provide catalogues of 4913 and 50 969 DLAs, respectively (including 1659 and 9230 high-confidence DLAs that were previously unpublished). This work validates the application of deep learning techniques to astronomical spectra for both classification and quantitative measurements.

  5. Polyamine transporters and polyamines increase furfural tolerance during xylose fermentation with ethanologenic Escherichia coli strain LY180.

    Science.gov (United States)

    Geddes, Ryan D; Wang, Xuan; Yomano, Lorraine P; Miller, Elliot N; Zheng, Huabao; Shanmugam, Keelnatham T; Ingram, Lonnie O

    2014-10-01

    Expression of genes encoding polyamine transporters from plasmids and polyamine supplements increased furfural tolerance (growth and ethanol production) in ethanologenic Escherichia coli LY180 (in AM1 mineral salts medium containing xylose). This represents a new approach to increase furfural tolerance and may be useful for other organisms. Microarray comparisons of two furfural-resistant mutants (EMFR9 and EMFR35) provided initial evidence for the importance of polyamine transporters. Each mutant contained a single polyamine transporter gene that was upregulated over 100-fold (microarrays) compared to that in the parent LY180, as well as a mutation that silenced the expression of yqhD. Based on these genetic changes, furfural tolerance was substantially reconstructed in the parent, LY180. Deletion of potE in EMFR9 lowered furfural tolerance to that of the parent. Deletion of potE and puuP in LY180 also decreased furfural tolerance, indicating functional importance of the native genes. Of the 8 polyamine transporters (18 genes) cloned and tested, half were beneficial for furfural tolerance (PotE, PuuP, PlaP, and PotABCD). Supplementing AM1 mineral salts medium with individual polyamines (agmatine, putrescine, and cadaverine) also increased furfural tolerance but to a smaller extent. In pH-controlled fermentations, polyamine transporter plasmids were shown to promote the metabolism of furfural and substantially reduce the time required to complete xylose fermentation. This increase in furfural tolerance is proposed to result from polyamine binding to negatively charged cellular constituents such as nucleic acids and phospholipids, providing protection from damage by furfural. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  6. SILVERRUSH. VI. A simulation of Lyα emitters in the reionization epoch and a comparison with Subaru Hyper Suprime-Cam survey early data

    Science.gov (United States)

    Inoue, Akio K.; Hasegawa, Kenji; Ishiyama, Tomoaki; Yajima, Hidenobu; Shimizu, Ikkoh; Umemura, Masayuki; Konno, Akira; Harikane, Yuichi; Shibuya, Takatoshi; Ouchi, Masami; Shimasaku, Kazuhiro; Ono, Yoshiaki; Kusakabe, Haruka; Higuchi, Ryo; Lee, Chien-Hsiu

    2018-05-01

    The survey of Lyman α emitters (LAEs) with the Subaru Hyper Suprime-Cam, called SILVERRUSH (Ouchi et al. 2018, PASJ, 70, S13), is producing massive data of LAEs at z ≳ 6. Here we present LAE simulations to compare the SILVERRUSH data. In 1623 comoving Mpc3 boxes, where numerical radiative transfer calculations of reionization were performed, LAEs have been modeled with physically motivated analytic recipes as a function of halo mass. We have examined 23 models depending on the presence or absence of dispersion of halo Lyα emissivity, dispersion of the halo Lyα optical depth, τα, and halo mass dependence of τα. The unique free parameter in our model, a pivot value of τα, is calibrated so as to reproduce the z = 5.7 Lyα luminosity function (LF) of SILVERRUSH. We compare our model predictions with Lyα LFs at z = 6.6 and 7.3, LAE angular auto-correlation functions (ACFs) at z = 5.7 and 6.6, and LAE fractions in Lyman break galaxies at 5 Based on our best model, we present a formula to estimate the intergalactic neutral hydrogen fraction, x_{H I}, from the observed Lyα luminosity density at z ≳ 6. We finally obtain x_{H I}=0.5_{-0.3}^{+0.1} as a volume-average at z = 7.3.

  7. A New Precision Measurement of the Small-scale Line-of-sight Power Spectrum of the Lyα Forest

    Science.gov (United States)

    Walther, Michael; Hennawi, Joseph F.; Hiss, Hector; Oñorbe, Jose; Lee, Khee-Gan; Rorai, Alberto; O’Meara, John

    2018-01-01

    We present a new measurement of the Lyα forest power spectrum at 1.8 masking missing data, damped Lyα absorption systems, and metal absorption lines. Our measurement results in unprecedented precision on the small-scale modes k> 0.02 {{s}} {{km}}-1, inaccessible to previous SDSS/BOSS analyses. It is well known that these high-k modes are highly sensitive to the thermal state of the intergalactic medium, but contamination by narrow metal lines is a significant concern. We quantify the effect of metals on the small-scale power and find a modest effect on modes with kmasking metals and restricting to kmasking as our data are generated from Lyα forest simulations. These mock spectra are used to build a custom emulator, enabling us to interpolate between a sparse grid of models and perform Markov chain Monte Carlo fits. Our results agree well with BOSS on scales kdata set for precisely constraining the thermal history of the intergalactic medium, cosmological parameters, and the nature of dark matter. The power spectra and their covariance matrices are provided as electronic tables.

  8. PI3K/Akt inhibitor LY294002 potentiates homoharringtonine antimyeloma activity in myeloma cells adhered to stromal cells and in SCID mouse xenograft.

    Science.gov (United States)

    Chen, Ping; Wen, Xiaofang; Wang, Bin; Hou, Diyu; Zou, Hong; Yuan, Qin; Yang, Hui; Xie, Jieqiong; Huang, Huifang

    2018-05-01

    Homoharringtonine (HHT) is a known anti-leukemia drug that inhibits multiple myeloma (MM) cells both in vitro and in vivo. Our prior study demonstrated that the potency of HHT in MM cells was compromised significantly when myeloma cells were co-cultured with BM stromal cells. This study aimed to investigate whether PI3K/Akt inhibitor LY294002 could potentiate the antimyeloma activity of HHT against MM cells adhered to BM stromal cells and in vivo xenograft models. A co-culture system composed of MM cells and human stromal cells was employed to mimic MM cells in bone marrow niche. The inhibitory and pro-apoptotic effect of HHT and LY294002 was determined by CCK-8 assay or flow cytometry. Expression of PI3K/Akt signaling molecules and anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) was assessed by western blot analysis and/or reverse transcription real-time quantitative PCR (RT-qPCR). MM xenografts were used to evaluate antitumor effect of combined therapy with HHT and LY294002. Adhesion to BM stromal cells rendered MM cells resistant to HHT whereas silencing Mcl-1 partly reversed the resistance. LY294002 induced apoptosis in MM cells and potentiated the antimyeloma effects of HHT by inhibiting the PI3K/Akt signal pathway which was abnormally activated during adhesion. LY294002 also enhanced the antimyeloma effect of HHT in in vivo xenograft models. These findings suggest that activation of PI3K/Akt signal pathway was responsible for the resistance to HHT in MM cells adhered to stromal cells. LY294002 can potentiate the antimyeloma activity of HHT both in vitro and in vivo, which may represent a new clinical treatment in MM.

  9. Comparison of Solar Fine Structure Observed Simultaneously in Lyα and Mg II h

    Science.gov (United States)

    Schmit, D.; Sukhorukov, A. V.; De Pontieu, B.; Leenaarts, J.; Bethge, C.; Winebarger, A.; Auchère, F.; Bando, T.; Ishikawa, R.; Kano, R.; Kobayashi, K.; Narukage, N.; Trujillo Bueno, J.

    2017-10-01

    The Chromospheric Lyman Alpha Spectropolarimeter (CLASP) observed the Sun in H I Lyα during a suborbital rocket flight on 2015 September 3. The Interface Region Imaging Telescope (IRIS) coordinated with the CLASP observations and recorded nearly simultaneous and co-spatial observations in the Mg II h and k lines. The Mg II h and Lyα lines are important transitions, energetically and diagnostically, in the chromosphere. The canonical solar atmosphere model predicts that these lines form in close proximity to each other and so we expect that the line profiles will exhibit similar variability. In this analysis, we present these coordinated observations and discuss how the two profiles compare over a region of quiet Sun at viewing angles that approach the limb. In addition to the observations, we synthesize both line profiles using a 3D radiation-MHD simulation. In the observations, we find that the peak width and the peak intensities are well correlated between the lines. For the simulation, we do not find the same relationship. We have attempted to mitigate the instrumental differences between IRIS and CLASP and to reproduce the instrumental factors in the synthetic profiles. The model indicates that formation heights of the lines differ in a somewhat regular fashion related to magnetic geometry. This variation explains to some degree the lack of correlation, observed and synthesized, between Mg II and Lyα. Our analysis will aid in the definition of future observatories that aim to link dynamics in the chromosphere and transition region.

  10. Comparison of Solar Fine Structure Observed Simultaneously in Ly α and Mg ii h

    Energy Technology Data Exchange (ETDEWEB)

    Schmit, D. [Bay Area Environmental Research Institute, 625 2nd Street, Suite 209, Petaluma, CA 94952 (United States); Sukhorukov, A. V.; Leenaarts, J. [Institute for Theoretical Astrophysics, University of Oslo, P.O. Box 1029, Blindern NO-0315 Oslo (Norway); De Pontieu, B. [Lockheed Martin Solar and Astrophysics Laboratory, Building 252, 3176 Porter Drive, Palo Alto, CA 94304 (United States); Bethge, C.; Winebarger, A.; Kobayashi, K. [NASA Marshall Space Flight Center, ZP 13, Huntsville, AL 35812 (United States); Auchère, F. [Institut d’Astrophysique Spatiale, CNRS/Univ. Paris-Sud 11, Bâtiment 121, F-91405 Orsay (France); Bando, T.; Kano, R.; Narukage, N. [National Astronomical Observatory of Japan, National Institutes of Natural Sciences, 2-21-1 Osawa, Mitaka, Tokyo 181-8588 (Japan); Ishikawa, R. [Institute of Space and Astronautical Science, Japan Aerospace Exploration Agency, 3-1-1 Yoshinodai, Chuo-ku, Sagamihara, Kanagawa 252-5210 (Japan); Bueno, J. Trujillo [Instituto de Astrofísica de Canarias, E-38205 La Laguna, Tenerife (Spain)

    2017-10-01

    The Chromospheric Lyman Alpha Spectropolarimeter (CLASP) observed the Sun in H i Ly α during a suborbital rocket flight on 2015 September 3. The Interface Region Imaging Telescope ( IRIS ) coordinated with the CLASP observations and recorded nearly simultaneous and co-spatial observations in the Mg ii h and k lines. The Mg ii h and Ly α lines are important transitions, energetically and diagnostically, in the chromosphere. The canonical solar atmosphere model predicts that these lines form in close proximity to each other and so we expect that the line profiles will exhibit similar variability. In this analysis, we present these coordinated observations and discuss how the two profiles compare over a region of quiet Sun at viewing angles that approach the limb. In addition to the observations, we synthesize both line profiles using a 3D radiation-MHD simulation. In the observations, we find that the peak width and the peak intensities are well correlated between the lines. For the simulation, we do not find the same relationship. We have attempted to mitigate the instrumental differences between IRIS and CLASP and to reproduce the instrumental factors in the synthetic profiles. The model indicates that formation heights of the lines differ in a somewhat regular fashion related to magnetic geometry. This variation explains to some degree the lack of correlation, observed and synthesized, between Mg ii and Ly α . Our analysis will aid in the definition of future observatories that aim to link dynamics in the chromosphere and transition region.

  11. The effectiveness and safety of platinum-based pemetrexed and platinum-based gemcitabine treatment in patients with malignant pleural mesothelioma.

    Science.gov (United States)

    Ak, Guntulu; Metintas, Selma; Akarsu, Muhittin; Metintas, Muzaffer

    2015-07-09

    We aimed to evaluate the efficiency and safety of cis/carboplatin plus gemcitabine, which was previously used for mesothelioma but with no recorded proof of its efficiency, compared with cis/carboplatin plus pemetrexed, which is known to be effective in mesothelioma, in comparable historical groups of malignant pleural mesothelioma. One hundred and sixteen patients received cis/carboplatin plus pemetrexed (group 1), while 30 patients received cis/carboplatin plus gemcitabine (group 2) between June 1999 and June 2012. The two groups were compared in terms of median survival and adverse events to chemotherapy. The mean ages of groups 1 and 2 were 60.7 and 60.8 years, respectively. Most of the patients (78.1%) had epithelial type tumors, and 47% of the patients had stage IV disease. There was no difference between the two groups in terms of age, gender, asbestos exposure, histology, stage, Karnofsky performance status, presence of pleurodesis, prophylactic radiotherapy, second-line chemotherapy and median hemoglobin and serum albumin levels. The median survival time from diagnosis to death or the last day of follow up with a 95% confidence interval was 12 ± 0.95 months (95% CI: 10.15-13.85) for group 1 and 11.0 ± 1.09 months (95% CI: 8.85-13.15) for group 2 (Log-Rank: 0.142; p = 0.706). The median survival time from treatment to death or the last day of follow-up with a 95% confidence interval was 11.0 ± 0.99 months (95% CI: 9.06-12.94) for group 1 and 11.0 ± 1.52 months (95% CI: 8.02-13.97) for group 2 (Log-Rank: 0.584; p = 0.445). The stage and Karnofsky performance status were found to be significant variables on median survival time by univariate analysis. After adjusting for the stage and Karnofsky performance status, the chemotherapy schema was not impressive on median survival time (OR: 0.837; 95% CI: 0.548-1.277; p = 0.409). The progression free survival was 7.0 ± 0.61 months for group I and 6.0 ± 1.56 months for group II (Log-Rank: 0.522; p = 0

  12. A SEARCH FOR OXYGEN IN THE LOW-DENSITY Lyα FOREST USING THE SLOAN DIGITAL SKY SURVEY

    International Nuclear Information System (INIS)

    Pieri, Matthew M.; Frank, Stephan; Mathur, Smita; Weinberg, David H.; York, Donald G.; Oppenheimer, Benjamin D.

    2010-01-01

    We use 2167 Sloan Digital Sky Survey quasar spectra to search for low-density oxygen in the intergalactic medium (IGM). Oxygen absorption is detected on a pixel-by-pixel basis by its correlation with Lyα forest absorption. We have developed a novel locally calibrated pixel (LCP) search method that uses adjacent regions of the spectrum to calibrate interlopers and spectral artifacts, which would otherwise limit the measurement of O VI absorption. Despite the challenges presented by searching for weak O VI within the Lyα forest in spectra of moderate resolution and signal-to-noise, we find a highly significant detection of absorption by oxygen at 2.7 2 = 80 for nine data points). We interpret our results using synthetic spectra generated from a log-normal density field assuming a mixed quasar-galaxy photoionizing background and that it dominates the ionization fraction of detected O VI. The LCP search data can be fit by a constant metallicity model with [O/H] = -2.15 +0.07 -0.09 but also by models in which low-density regions are unenriched and higher density regions have a higher metallicity. The density-dependent enrichment model by Aguirre et al. is also an acceptable fit. All our successful models have similar mass-weighted oxygen abundance, corresponding to [(O/H) MW ] = -2.45 ± 0.06. This result can be used to find the cosmic oxygen density in the Lyα forest, Ω Oxy,IGM = 1.4(±0.2) x 10 -6 ∼ 3 x 10 -4 Ω b . This is the tightest constraint on the mass-weighted mean oxygen abundance and the cosmic oxygen density in the Lyα forest to date and indicates that it contains ∼16% of the total expected metal production by star formation up to z = 3.

  13. Dynamic changes of bacterial community under bioremediation with Sphingobium sp. LY-6 in buprofezin-contaminated soil.

    Science.gov (United States)

    Liu, Yuan; Hou, Qianqian; Liu, Wanru; Meng, Yawen; Wang, Guangli

    2015-08-01

    Buprofezin is a commonly used chemical with satisfactory biological activity against sucking insect pests, but its disposal can cause serious environmental problems. To study the feasibility of remedying contamination by buprofezin, microcosm experiments were carried out to study the effects of various concentrations of buprofezin and Sphingobium sp. LY-6 on soil bacterial communities in soils collected from vegetable fields. In this experiment, the results showed that buprofezin was effectively degraded by Sphingobium sp. LY-6 in incubation soils. Comparing to non-incubated soils, the cumulative degradation ratio of buprofezin was significantly increased, up to the extent of 85 and 51%, in the initial concentration of 10 and 100 mg kg(-1). The abundance and community structure of the bacterial communities were analysed by real-time PCR (qPCR) and terminal-restriction fragment length polymorphism (T-RFLP). The findings suggest that buprofezin had a negative effect on soil bacterial community, and decreases in bacterial abundance were observed in the later part of the incubation period. The bacterial community structure and diversity shifted significantly at each sampling time. In conclusion, the buprofezin-degrading strain LY-6 played a major role in the bioremediation of the buprofezin-contaminated soil and influenced the dynamics and structure of the bacterial community, demonstrating the great potential of exogenous microorganisms for soil remediation.

  14. Safety and efficacy of LY3015014, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9): a randomized, placebo-controlled Phase 2 study

    NARCIS (Netherlands)

    Kastelein, John J. P.; Nissen, Steven E.; Rader, Daniel J.; Hovingh, G. Kees; Wang, Ming-Dauh; Shen, Tong; Krueger, Kathryn A.

    2016-01-01

    Aims The objective of this study was to evaluate the efficacy, safety, and tolerability of LY3015014 (LY), a neutralizing antibody of proprotein convertase subtilisin/kexin type 9 (PCSK9), administered every 4 or 8 weeks in patients with primary hypercholesterolaemia, when added to a background of

  15. THE CHANGING Lyα OPTICAL DEPTH IN THE RANGE 6 < z < 9 FROM THE MOSFIRE SPECTROSCOPY OF Y-DROPOUTS

    International Nuclear Information System (INIS)

    Treu, Tommaso; Schmidt, Kasper B.; Trenti, Michele; Bradley, Larry D.; Stiavelli, Massimo

    2013-01-01

    We present the MOSFIRE spectroscopy of 13 candidate z ∼ 8 galaxies selected as Y-dropouts as part of the Brightest of Reionization Galaxies pure parallel survey. We detect no significant Lyα emission (our median 1σ rest-frame equivalent width sensitivity is in the range 2-16 Å). Using the Bayesian framework derived in a previous paper, we perform a rigorous analysis of a statistical subsample of non-detections for 10 Y-dropouts, including data from the literature, to study the cosmic evolution of the Lyα emission of Lyman break galaxies. We find that Lyα emission is suppressed at z ∼ 8 by at least a factor of three with respect to z ∼ 6 continuing the downward trend found by previous studies of z-dropouts at z ∼ 7. This finding suggests a dramatic evolution in the conditions of the intergalactic or circumgalactic media in just 300 Myr, consistent with the onset of reionization or changes in the physical conditions of the first generations of star-forming regions

  16. The Ly6 protein coiled is required for septate junction and blood brain barrier organisation in Drosophila.

    Science.gov (United States)

    Hijazi, Assia; Haenlin, Marc; Waltzer, Lucas; Roch, Fernando

    2011-03-15

    Genetic analysis of the Drosophila septate junctions has greatly contributed to our understanding of the mechanisms controlling the assembly of these adhesion structures, which bear strong similarities with the vertebrate tight junctions and the paranodal septate junctions. These adhesion complexes share conserved molecular components and have a common function: the formation of paracellular barriers restraining the diffusion of solutes through epithelial and glial envelopes. In this work we characterise the function of the Drosophila cold gene, that codes for a protein belonging to the Ly6 superfamily of extracellular ligands. Analysis of cold mutants shows that this gene is specifically required for the organisation of the septate junctions in epithelial tissues and in the nervous system, where its contribution is essential for the maintenance of the blood-brain barrier. We show that cold acts in a cell autonomous way, and we present evidence indicating that this protein could act as a septate junction component. We discuss the specific roles of cold and three other Drosophila members of the Ly6 superfamily that have been shown to participate in a non-redundant way in the process of septate junction assembly. We propose that vertebrate Ly6 proteins could fulfill analogous roles in tight junctions and/or paranodal septate junctions.

  17. Noninvasive monitoring of the genetic evolution of EGFR-mutant non-small-cell lung cancer by analyzing circulating tumor DNA during combination chemotherapy with gefitinib and pemetrexed or S-1

    Directory of Open Access Journals (Sweden)

    Nakahara Y

    2016-08-01

    Full Text Available Yoshiro Nakahara,1,2 Yusuke Takagi,1,3 Yukio Hosomi,1 Akiko Kagei,4 Tomohiro Yamamoto,4 Takeshi Sawada,5 Makiko Yomota,1 Yusuke Okuma,1 Shinichiro Mikura,1,6 Tatsuru Okamura1 1Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, 2Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, 3Oncology Scientific Affairs, Merck Sharp & Dohme Corp, 4GeneticLab Co., Ltd., Sapporo, 5Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, 6Department of Respiratory Medicine, Fujieda Municipal General Hospital, Fujieda, Japan Background: Repetitive genotyping is useful to assess the genetic evolution of non-small-cell lung cancer (NSCLC during treatment, but the need for sampling by biopsy is a major obstacle. Digital polymerase chain reaction (PCR is a promising procedure for the detection of mutant alleles in plasma of cancer patients.Methods: This prospective study enrolled patients with NSCLC and known epidermal growth factor receptor (EGFR mutations and who had experienced disease progression during ongoing EGFR-tyrosine kinase inhibitor (TKI therapy. Eligible patients received daily gefitinib and either pemetrexed or S-1 every 3 weeks until disease progression or the development of unacceptable toxicity. Peripheral blood was collected before and after the combination therapy for digital PCR and hepatocyte growth factor measurement.Results: From May 2012 to January 2014, nine patients with a median age of 67 (range 52–80 years were enrolled. Patterns of disease progression during adjacent EGFR-TKI therapy were acquired resistance, observed in seven patients, and primary resistance, observed in two patients. Known EGFR mutations were detected in plasma samples of six (67% patients at study enrollment. Of these, T790M mutation was concurrently detected in three (50% patients

  18. SILVERRUSH. V. Census of Lyα, [O III] λ5007, Hα, and [C II] 158 μm Line Emission with ∼1000 LAEs at z = 4.9–7.0 Revealed with Subaru/HSC

    Science.gov (United States)

    Harikane, Yuichi; Ouchi, Masami; Shibuya, Takatoshi; Kojima, Takashi; Zhang, Haibin; Itoh, Ryohei; Ono, Yoshiaki; Higuchi, Ryo; Inoue, Akio K.; Chevallard, Jacopo; Capak, Peter L.; Nagao, Tohru; Onodera, Masato; Faisst, Andreas L.; Martin, Crystal L.; Rauch, Michael; Bruzual, Gustavo A.; Charlot, Stephane; Davidzon, Iary; Fujimoto, Seiji; Hilmi, Miftahul; Ilbert, Olivier; Lee, Chien-Hsiu; Matsuoka, Yoshiki; Silverman, John D.; Toft, Sune

    2018-06-01

    We investigate Lyα, [O III] λ5007, Hα, and [C II] 158 μm emission from 1124 galaxies at z = 4.9–7.0. Our sample is composed of 1092 Lyα emitters (LAEs) at z = 4.9, 5.7, 6.6, and 7.0 identified by Subaru/Hyper-Suprime-Cam (HSC) narrowband surveys covered by Spitzer Large Area Survey with Hyper-Suprime-Cam (SPLASH) and 34 galaxies at z = 5.148–7.508 with deep ALMA [C II] 158 μm data in the literature. Fluxes of strong rest-frame optical lines of [O III] and Hα (Hβ) are constrained by significant excesses found in the SPLASH 3.6 and 4.5 μm photometry. At z = 4.9, we find that the rest-frame Hα equivalent width and the Lyα escape fraction f Lyα positively correlate with the rest-frame Lyα equivalent width {EW}}Lyα }0. The {f}Lyα }{--}{EW}}Lyα }0 correlation is similarly found at z ∼ 0–2, suggesting no evolution of the correlation over z ≃ 0–5. The typical ionizing photon production efficiency of LAEs is log(ξ ion/[Hz erg‑1]) ≃ 25.5, significantly (60%–100%) higher than those of LBGs at a given UV magnitude. At z = 5.7–7.0, there exists an interesting turnover trend that the [O III]/Hα flux ratio increases in {EW}}Lyα }0≃ 0{--}30 \\mathringA and then decreases out to {EW}}Lyα }0≃ 130 \\mathringA . We also identify an anticorrelation between a ratio of [C II] luminosity to star formation rate (L [C II]/SFR) and {EW}}Lyα }0 at the >99% confidence level.. We carefully investigate physical origins of the correlations with stellar-synthesis and photoionization models and find that a simple anticorrelation between {EW}}Lyα }0 and metallicity explains self-consistently all of the correlations of Lyα, Hα, [O III]/Hα, and [C II] identified in our study, indicating detections of metal-poor (∼0.03 Z ⊙) galaxies with {EW}}Lyα }0≃ 200 \\mathringA .

  19. AVERAGE METALLICITY AND STAR FORMATION RATE OF Ly{alpha} EMITTERS PROBED BY A TRIPLE NARROWBAND SURVEY

    Energy Technology Data Exchange (ETDEWEB)

    Nakajima, Kimihiko; Shimasaku, Kazuhiro; Ono, Yoshiaki; Okamura, Sadanori [Department of Astronomy, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); Ouchi, Masami [Institute for the Physics and Mathematics of the Universe (IPMU), TODIAS, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8583 (Japan); Lee, Janice C.; Ly, Chun [Observatories of the Carnegie Institution of Washington, 813 Santa Barbara Street, Pasadena, CA 91101 (United States); Foucaud, Sebastien [Department of Earth Sciences, National Taiwan Normal University, No. 88, Tingzhou Road, Sec. 4, Taipei 11677, Taiwan (China); Dale, Daniel A. [Department of Physics and Astronomy, University of Wyoming, Laramie, WY (United States); Salim, Samir [Department of Astronomy, Indiana University, Bloomington, IN (United States); Finn, Rose [Department of Physics, Siena College, Loudonville, NY (United States); Almaini, Omar, E-mail: nakajima@astron.s.u-tokyo.ac.jp [School of Physics and Astronomy, University of Nottingham, Nottingham (United Kingdom)

    2012-01-20

    We present the average metallicity and star formation rate (SFR) of Ly{alpha} emitters (LAEs) measured from our large-area survey with three narrowband (NB) filters covering the Ly{alpha}, [O II]{lambda}3727, and H{alpha}+[N II] lines of LAEs at z = 2.2. We select 919 z = 2.2 LAEs from Subaru/Suprime-Cam NB data in conjunction with Magellan/IMACS spectroscopy. Of these LAEs, 561 and 105 are observed with KPNO/NEWFIRM near-infrared NB filters whose central wavelengths are matched to redshifted [O II] and H{alpha} nebular lines, respectively. By stacking the near-infrared images of the LAEs, we successfully obtain average nebular-line fluxes of LAEs, the majority of which are too faint to be identified individually by NB imaging or deep spectroscopy. The stacked object has an H{alpha} luminosity of 1.7 Multiplication-Sign 10{sup 42} erg s{sup -1} corresponding to an SFR of 14 M{sub Sun} yr{sup -1}. We place, for the first time, a firm lower limit to the average metallicity of LAEs of Z {approx}> 0.09 Z{sub Sun} (2{sigma}) based on the [O II]/(H{alpha}+[N II]) index together with photoionization models and empirical relations. This lower limit of metallicity rules out the hypothesis that LAEs, so far observed at z {approx} 2, are extremely metal-poor (Z < 2 Multiplication-Sign 10{sup -2} Z{sub Sun }) galaxies at the 4{sigma} level. This limit is higher than a simple extrapolation of the observed mass-metallicity relation of z {approx} 2 UV-selected galaxies toward lower masses (5 Multiplication-Sign 10{sup 8} M{sub Sun }), but roughly consistent with a recently proposed fundamental mass-metallicity relation when the LAEs' relatively low SFR is taken into account. The H{alpha} and Ly{alpha} luminosities of our NB-selected LAEs indicate that the escape fraction of Ly{alpha} photons is {approx}12%-30%, much higher than the values derived for other galaxy populations at z {approx} 2.

  20. AVERAGE METALLICITY AND STAR FORMATION RATE OF Lyα EMITTERS PROBED BY A TRIPLE NARROWBAND SURVEY

    International Nuclear Information System (INIS)

    Nakajima, Kimihiko; Shimasaku, Kazuhiro; Ono, Yoshiaki; Okamura, Sadanori; Ouchi, Masami; Lee, Janice C.; Ly, Chun; Foucaud, Sebastien; Dale, Daniel A.; Salim, Samir; Finn, Rose; Almaini, Omar

    2012-01-01

    We present the average metallicity and star formation rate (SFR) of Lyα emitters (LAEs) measured from our large-area survey with three narrowband (NB) filters covering the Lyα, [O II]λ3727, and Hα+[N II] lines of LAEs at z = 2.2. We select 919 z = 2.2 LAEs from Subaru/Suprime-Cam NB data in conjunction with Magellan/IMACS spectroscopy. Of these LAEs, 561 and 105 are observed with KPNO/NEWFIRM near-infrared NB filters whose central wavelengths are matched to redshifted [O II] and Hα nebular lines, respectively. By stacking the near-infrared images of the LAEs, we successfully obtain average nebular-line fluxes of LAEs, the majority of which are too faint to be identified individually by NB imaging or deep spectroscopy. The stacked object has an Hα luminosity of 1.7 × 10 42 erg s –1 corresponding to an SFR of 14 M ☉ yr –1 . We place, for the first time, a firm lower limit to the average metallicity of LAEs of Z ∼> 0.09 Z ☉ (2σ) based on the [O II]/(Hα+[N II]) index together with photoionization models and empirical relations. This lower limit of metallicity rules out the hypothesis that LAEs, so far observed at z ∼ 2, are extremely metal-poor (Z –2 Z ☉ ) galaxies at the 4σ level. This limit is higher than a simple extrapolation of the observed mass-metallicity relation of z ∼ 2 UV-selected galaxies toward lower masses (5 × 10 8 M ☉ ), but roughly consistent with a recently proposed fundamental mass-metallicity relation when the LAEs' relatively low SFR is taken into account. The Hα and Lyα luminosities of our NB-selected LAEs indicate that the escape fraction of Lyα photons is ∼12%-30%, much higher than the values derived for other galaxy populations at z ∼ 2.

  1. HI column density distribution function at z=0 : Connection to damped Ly alpha statistics

    NARCIS (Netherlands)

    Zwaan, Martin; Verheijen, MAW; Briggs, FH

    We present a measurement of the HI column density distribution function f(N-HI) at the present epoch for column densities > 10(20) cm(-2). These high column densities compare to those measured in damped Ly alpha lines seen in absorption against background quasars. Although observationally rare, it

  2. A quadruple quasar coincident with a giant Ly-alpha nebula and a protocluster at z=2

    Science.gov (United States)

    Vignali, Cristian

    2016-09-01

    We propose to observe the only known quadruple AGN system in the Universe, embedded in a giant Ly-alpha nebula at z 2. These active nuclei and the large number of Ly-alpha emitting galaxies at the same redshift are clear indications that this is one of the most overdense protoclusters known z 2. We request a 140 ks Chandra exposure to (a) define the basic X-ray properties of all the AGN and then their bolometric luminosities and Eddington ratios, and compare these with those of "isolated" quasars at similar redshifts/luminosities; (b) detect the hot gas emission in the protocluster. Chandra is unique for this investigation: the close (few arcsec) distance of some of the AGN needs high spatial resolution, and the extended emission requires low background contribution.

  3. Double-stranded RNA promotes CTL-independent tumor cytolysis mediated by CD11b+Ly6G+ intratumor myeloid cells through the TICAM-1 signaling pathway

    Science.gov (United States)

    Shime, Hiroaki; Matsumoto, Misako; Seya, Tsukasa

    2017-01-01

    PolyI:C, a synthetic double-stranded RNA analog, acts as an immune-enhancing adjuvant that regresses tumors in cytotoxic T lymphocyte (CTL)-dependent and CTL-independent manner, the latter of which remains largely unknown. Tumors contain CD11b+Ly6G+ cells, known as granulocytic myeloid-derived suppressor cells (G-MDSCs) or tumor-associated neutrophils (TANs) that play a critical role in tumor progression and development. Here, we demonstrate that CD11b+Ly6G+ cells respond to polyI:C and exhibit tumoricidal activity in an EL4 tumor implant model. PolyI:C-induced inhibition of tumor growth was attributed to caspase-8/3 cascade activation in tumor cells that occurred independently of CD8α+/CD103+ dendritic cells (DCs) and CTLs. CD11b+Ly6G+ cells was essential for the antitumor effect because depletion of CD11b+Ly6G+ cells totally abrogated tumor regression and caspase activation after polyI:C treatment. CD11b+Ly6G+ cells that had been activated with polyI:C showed cytotoxicity and inhibited tumor growth through the production of reactive oxygen species (ROS)/reactive nitrogen species (RNS). These responses were abolished in either Toll/interleukin-1 receptor domain-containing adaptor molecule-1 (TICAM-1)−/− or interferon (IFN)-αβ receptor 1 (IFNAR1)−/− mice. Thus, our results suggest that polyI:C activates the TLR3/TICAM-1 and IFNAR signaling pathways in CD11b+Ly6G+ cells in tumors, thereby eliciting their antitumor activity, independent of those in CD8α+/CD103+ DCs that prime CTLs. PMID:27834952

  4. The Ly6 protein coiled is required for septate junction and blood brain barrier organisation in Drosophila.

    Directory of Open Access Journals (Sweden)

    Assia Hijazi

    Full Text Available BACKGROUND: Genetic analysis of the Drosophila septate junctions has greatly contributed to our understanding of the mechanisms controlling the assembly of these adhesion structures, which bear strong similarities with the vertebrate tight junctions and the paranodal septate junctions. These adhesion complexes share conserved molecular components and have a common function: the formation of paracellular barriers restraining the diffusion of solutes through epithelial and glial envelopes. METHODOLOGY/PRINCIPAL FINDINGS: In this work we characterise the function of the Drosophila cold gene, that codes for a protein belonging to the Ly6 superfamily of extracellular ligands. Analysis of cold mutants shows that this gene is specifically required for the organisation of the septate junctions in epithelial tissues and in the nervous system, where its contribution is essential for the maintenance of the blood-brain barrier. We show that cold acts in a cell autonomous way, and we present evidence indicating that this protein could act as a septate junction component. CONCLUSION/SIGNIFICANCE: We discuss the specific roles of cold and three other Drosophila members of the Ly6 superfamily that have been shown to participate in a non-redundant way in the process of septate junction assembly. We propose that vertebrate Ly6 proteins could fulfill analogous roles in tight junctions and/or paranodal septate junctions.

  5. The Kodály and Rajkó Methods: Voices, Instruments, Ethnicity, and the Globalization of Hungarian Music Education in the Twentieth Century

    Directory of Open Access Journals (Sweden)

    Lynn M. Hooker

    2016-01-01

    Full Text Available Music is one of the fields in which Hungary has distinguished itself around the world, and music education is an arena in which Hungarian methods have had a profound impact. The basic principles of Hungarian music-pedagogical methods, developed by Zoltán Kodály (1882–1967 and his disciples and thus known as the Kodály method, are systematic instruction in sight-singing using “movable-do” solfège and rhythmic syllables, with the ideal of developing music literacy in all children through high-quality music, mainly classical and folk repertoire for choirs. Another type of well-known Hungarian music, so-called “Gypsy music,” is specifically denied legitimacy both in Kodály’s writings and those of some of his students, for two reasons: much of it is primarily instrumental instead of vocal, and it is considered “bad.” Yet Romani (Gypsy musicians from Hungary have also become famous internationally, some from quite a young age. The Rajkó Ensemble, established in 1952 as the Gypsy Orchestra of the Young Communists’ League, brought Hungarian and Hungarian-Gypsy music to over a hundred countries over the years. Interviews with Rajkó members, some conducted by the author and some previously published, reveal those musicians struggling to claim the legitimacy not only of their music but of their music pedagogy, implicitly comparing the Rajkó method to the Kodály method. After a brief discussion of the Kodály method and its history, this essay gives some examples of how that method has dealt with talented Romani youth in Hungary; compares the Kodály method to methods of teaching instrumental music in Roma communities and in the Rajkó Ensemble; and considers how American ideals of multicultural education challenge some of Kodály’s tenets.

  6. CONSTRAINING DUST AND MOLECULAR GAS PROPERTIES IN Lyα BLOBS AT z ∼ 3

    International Nuclear Information System (INIS)

    Yang Yujin; Decarli, Roberto; Walter, Fabian; Leipski, Christian; Dannerbauer, Helmut; Le Floc'h, Emeric; Weiss, Axel; Menten, Karl M.; Dey, Arjun; Chapman, Scott C.; Prescott, Moire K. M.; Neri, Roberto; Borys, Colin; Matsuda, Yuichi; Yamada, Toru; Hayashino, Tomoki; Tapken, Christian

    2012-01-01

    In order to constrain the bolometric luminosities, dust properties, and molecular gas content of giant Lyα nebulae, the so-called Lyα blobs, we have carried out a study of dust continuum and CO line emission in two well-studied representatives of this population at z ∼ 3: an Lyα blob discovered by its strong Spitzer Multiband Infrared Photometer 24 μm detection (LABd05) and the Steidel blob 1 (SSA22-LAB01). We find that the spectral energy distribution of LABd05 is well described by an active-galactic-nucleus-starburst composite template with L FIR = (4.0 ± 0.5) × 10 12 L ☉ , comparable to high-z submillimeter galaxies and ultraluminous infrared galaxies. New Large APEX Bolometer Camera 870 μm measurements rule out the reported Submillimeter Common-User Bolometer Array detection of the SSA22-LAB01 (S 850μm = 16.8 mJy) at the >4σ level. Consistent with this, ultradeep Plateau de Bure Interferometer observations with ∼2'' spatial resolution also fail to detect any 1.2 mm continuum source down to ≈0.45 mJy beam –1 (3σ). Combined with the existing (sub)millimeter observations in the literature, we conclude that the FIR luminosity of SSA22-LAB01 remains uncertain. No CO line is detected in either case down to integrated flux limits of S ν ΔV ∼ –1 , indicating a modest molecular gas reservoir, M(H 2 ) 10 M ☉ . The non-detections exclude, with high significance (12σ), the previous tentative detection of a CO J = 4-3 line in the SSA22-LAB01. The increased sensitivity afforded by the Atacama Large Millimeter/submillimeter Array will be critical in studying molecular gas and dust in these interesting systems.

  7. Minihalo model for the low-redshift Lyα absorbers revisited

    Directory of Open Access Journals (Sweden)

    Lalović A.

    2008-01-01

    Full Text Available We reconsider the basic properties of the classical minihalo model of Rees and Milgrom in light of the new work, both observational (on 'dark galaxies' and masses of baryonic haloes and theoretical (on the cosmological mass function and the history of star formation. In particular, we show that more detailed models of ionized gas in haloes of dark matter following isothermal and Navarro-Frenk-White density profile can effectively reproduce particular aspects of the observed column density distribution function in a heterogeneous sample of low- and intermediate-redshift Lyα forest absorption lines.

  8. The synthesis of (-)-4-methyl-8-chloro-trans-1,2,3,4,4a,5,6,10b-octahydrobenzo-[f]-quinolin-3-one-[3-14C] (LY300502-[14C]) via a circuitous route

    International Nuclear Information System (INIS)

    Fengjiun Kuo; Wheeler, W.J.

    1994-01-01

    The synthesis of the C-14 labeled isotopomer of LY300502, a potent 5α-reductase inhibitor has been accomplished in four radiochemical steps. The route involves the synthesis of LY300502-[ 14 C] from LY300502 via a circuitous route; the label was introduced with ethyl chloroformate-[carbonyl- 14 C]. (author)

  9. Molecular cloning of Ly-1, a membrane glycoprotein of mouse T lymphocytes and a subset of B cells: molecular homology to its human counterpart Leu-1/T1 (CD5)

    International Nuclear Information System (INIS)

    Huang, H.J.S.; Jones, N.H.; Strominger, J.L.; Herzenberg, L.A.

    1987-01-01

    The authors report the isolation of cDNA clones of the mouse lymphocyte differentiation antigen Ly-1. One of these cDNA clones was confirmed to be full-length by DNA sequencing and by expression of Ly-1 by L cells transfected with this clone. Analysis of the predicted amino acid sequence indicated that the Ly-1 polypeptide is synthesized with a 23 amino acid leader and that the mature protein consists of an amino-terminal region of 347 amino acids, a transmembrane sequence of 30 residues, and a carboxyl-terminal region of 94 amino acids. The amino-terminal region appears to be divided into two subregions by a threonine- and proline-rich sequence of 23 amino acids that is highly conserved between Ly-1 and its human homologue Leu-1 (CD5) in position and amino acid composition. The first amino-terminal subregion of 111 amino acids is predicted to be arranged in a β-pleated sheet structure of six strands. The entire amino-terminal region is rich in cysteine, with all of its 22 cysteine residues conserved between Ly-1 and Leu-1. The carboxyl-terminal region has no cysteins. Ly-1 and Leu-1 are 63% identical, with a gradient of identical residues from 43% for the first amino-terminal to 58% for the second amino-terminal subregion and 90% for the carboxyl-terminal region. The predicted secondary structure of the first amino-terminal subregion and identities of certain conserved residues among most members of the immunoglobulin gene superfamily suggest that Ly-1 and Leu-1 are distant members of this family

  10. Cosmological parameter analysis including SDSS Lyα forest and galaxy bias: Constraints on the primordial spectrum of fluctuations, neutrino mass, and dark energy

    International Nuclear Information System (INIS)

    Seljak, Uros; Makarov, Alexey; McDonald, Patrick; Anderson, Scott F.; Bahcall, Neta A.; Cen, Renyue; Gunn, James E.; Lupton, Robert H.; Schlegel, David J.; Brinkmann, J.; Burles, Scott; Doi, Mamoru; Ivezic, Zeljko; Kent, Stephen; Loveday, Jon; Munn, Jeffrey A.; Nichol, Robert C.; Ostriker, Jeremiah P.; Schneider, Donald P.; Berk, Daniel E. Vanden

    2005-01-01

    We combine the constraints from the recent Lyα forest analysis of the Sloan Digital Sky Survey (SDSS) and the SDSS galaxy bias analysis with previous constraints from SDSS galaxy clustering, the latest supernovae, and 1st year WMAP cosmic microwave background anisotropies. We find significant improvements on all of the cosmological parameters compared to previous constraints, which highlights the importance of combining Lyα forest constraints with other probes. Combining WMAP and the Lyα forest we find for the primordial slope n s =0.98±0.02. We see no evidence of running, dn/dlnk=-0.003±0.010, a factor of 3 improvement over previous constraints. We also find no evidence of tensors, r 2 model is within the 2-sigma contour, V∝φ 4 is outside the 3-sigma contour. For the amplitude we find σ 8 =0.90±0.03 from the Lyα forest and WMAP alone. We find no evidence of neutrino mass: for the case of 3 massive neutrino families with an inflationary prior, eV and the mass of lightest neutrino is m 1 ν λ =0.72±0.02, w(z=0.3)=-0.98 -0.12 +0.10 , the latter changing to w(z=0.3)=-0.92 -0.10 +0.09 if tensors are allowed. We find no evidence for variation of the equation of state with redshift, w(z=1)=-1.03 -0.28 +0.21 . These results rely on the current understanding of the Lyα forest and other probes, which need to be explored further both observationally and theoretically, but extensive tests reveal no evidence of inconsistency among different data sets used here

  11. CD177: A member of the Ly-6 gene superfamily involved with neutrophil proliferation and polycythemia vera

    Directory of Open Access Journals (Sweden)

    Bettinotti Maria

    2004-03-01

    Full Text Available Abstract Genes in the Leukocyte Antigen 6 (Ly-6 superfamily encode glycosyl-phosphatidylinositol (GPI anchored glycoproteins (gp with conserved domains of 70 to 100 amino acids and 8 to 10 cysteine residues. Murine Ly-6 genes encode important lymphocyte and hematopoietic stem cell antigens. Recently, a new member of the human Ly-6 gene superfamily has been described, CD177. CD177 is polymorphic and has at least two alleles, PRV-1 and NB1. CD177 was first described as PRV-1, a gene that is overexpressed in neutrophils from approximately 95% of patients with polycythemia vera and from about half of patients with essential thrombocythemia. CD177 encodes NB1 gp, a 58–64 kD GPI gp that is expressed by neutrophils and neutrophil precursors. NB1 gp carries Human Neutrophil Antigen (HNA-2a. Investigators working to identify the gene encoding NB1 gp called the CD177 allele they described NB1. NB1 gp is unusual in that neutrophils from some healthy people lack the NB1 gp completely and in most people NB1 gp is expressed by a subpopulation of neutrophils. The function of NB1 gp and the role of CD177 in the pathogenesis and clinical course of polycythemia vera and essential thrombocythemia are not yet known. However, measuring neutrophil CD177 mRNA levels has become an important marker for diagnosing the myeloproliferative disorders polycythemia vera and essential thrombocythemia.

  12. Safety and Pharmacokinetics of the Antisense Oligonucleotide (ASO) LY2181308 as a Single-Agent or in Combination with Idarubicin and Cytarabine in Patients with Refractory or Relapsed Acute Myeloid Leukemia (AML)

    Science.gov (United States)

    Erba, Harry P.; Sayar, Hamid; Juckett, Mark; Lahn, Michael; Andre, Valerie; Callies, Sophie; Schmidt, Shelly; Kadam, Sunil; Brandt, John T.; Van Bockstaele, Dirk; Andreeff, Michael

    2014-01-01

    Summary Survivin is expressed in tumor cells, including acute myeloid leukemia (AML), regulates mitosis, and prevents tumor cell death. The antisense oligonucleotide sodium LY2181308 (LY2181308) inhibits survivin expression and may cause cell cycle arrest and restore apoptosis in AML. Methods In this study, the safety, pharmacokinetics, and pharmacodynamics/efficacy of LY2181308 was examined in AML patients, first in a cohort with monotherapy (n=8) and then post-amendment in a cohort with the combination of cytarabine and idarubicin treatment (n=16). LY2181308 was administered with a loading dosage of 3 consecutive daily infusions of 750 mg followed by weekly intravenous (IV) maintenance doses of 750 mg. Cytarabine 1.5 g/m2 was administered as a 4-hour IV infusion on Days 3, 4, and 5 of Cycle 1, and idarubicin 12 mg/m2 was administered as a 30-minute IV infusion on Days 3, 4, and 5 of Cycle 1. Cytarabine and idarubicin were administered on Days 1, 2, and 3 of each subsequent 28-day cycle. Reduction of survivin was evaluated in peripheral blasts and bone marrow. Results Single-agent LY2181308 was well tolerated and survivin was reduced only in patients with a high survivin expression. In combination with chemotherapy, 4/16 patients had complete responses, 1/16 patients had incomplete responses, and 4/16 patients had cytoreduction. Nine patients died on study: 6 (monotherapy), 3 (combination). Conclusions LY2181308 alone is well tolerated in patients with AML. In combination with cytarabine and idarubicin, LY2181308 does not appear to cause additional toxicity, and has shown some clinical benefit needing confirmation in future clinical trials. PMID:23397500

  13. Dihydropyridazinone cardiotonics: discovery of LY195115 and elucidation of structural features necessary for optimal inotropic activity

    International Nuclear Information System (INIS)

    Krushinski, J.H.; Hayes, J.S.; Beedle, E.E.; Pollock, G.D.; Wilson, H.; Robertson, D.W.

    1986-01-01

    A series of 4,5-dihydro-6-aryl-3( 2 H)-pyridazinones has been examined for inotropic activity. The optimal compound of the series, LY195115 (1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)- 2 H-indol-2-one), is one of the most potent and long-acting oral inotropes described to date. ED 50 's of LY195115, CI-914 and milrinone after i.v. administration to pentobarbital anesthetized dogs were 6.8, 46 and 37 μg/kg, respectively. ED 50 's after oral administration to conscious dogs were 25, 1000 and 500 μg/kg, respectively. For optimal positive inotropic activity and oral bioavailability in this series, the following structural features are necessary: (1) dihydropyridazinone ring with the nitrogen unsubstituted; (2) a hydrogen-bond acceptor substituent with a σ value of ca 0.0 para to the dihydropyridazinone moiety; and (3) additional sterically undemanding lipophilic substituents adjacent to the hydrogen-bond acceptor site

  14. Spectroscopic Confirmation of Three z-dropout Galaxies at z = 6.844-7.213: Demographics of Lyα Emission in z ~ 7 Galaxies

    Science.gov (United States)

    Ono, Yoshiaki; Ouchi, Masami; Mobasher, Bahram; Dickinson, Mark; Penner, Kyle; Shimasaku, Kazuhiro; Weiner, Benjamin J.; Kartaltepe, Jeyhan S.; Nakajima, Kimihiko; Nayyeri, Hooshang; Stern, Daniel; Kashikawa, Nobunari; Spinrad, Hyron

    2012-01-01

    We present the results of our ultra-deep Keck/DEIMOS spectroscopy of z-dropout galaxies in the Subaru Deep Field and Great Observatories Origins Deep Survey's northern field. For 3 out of 11 objects, we detect an emission line at ~1 μm with a signal-to-noise ratio of ~10. The lines show asymmetric profiles with high weighted skewness values, consistent with being Lyα, yielding redshifts of z = 7.213, 6.965, and 6.844. Specifically, we confirm the z = 7.213 object in two independent DEIMOS runs with different spectroscopic configurations. The z = 6.965 object is a known Lyα emitter, IOK-1, for which our improved spectrum at a higher resolution yields a robust skewness measurement. The three z-dropouts have Lyα fluxes of 3 × 10-17 erg s-1 cm-2 and rest-frame equivalent widths EWLyα 0 = 33-43 Å. Based on the largest spectroscopic sample of 43 z-dropouts, which is the combination of our and previous data, we find that the fraction of Lyα-emitting galaxies (EWLyα 0 > 25 Å) is low at z ~ 7; 17% ± 10% and 24% ± 12% for bright (M UV ~= -21) and faint (M UV ~= -19.5) galaxies, respectively. The fractions of Lyα-emitting galaxies drop from z ~ 6 to 7 and the amplitude of the drop is larger for faint galaxies than for bright galaxies. These two pieces of evidence would indicate that the neutral hydrogen fraction of the intergalactic medium increases from z ~ 6 to 7 and that the reionization proceeds from high- to low-density environments, as suggested by an inside-out reionization model. Based on data obtained with the Subaru Telescope and the W. M. Keck Observatory. The Subaru Telescope is operated by the National Astronomical Observatory of Japan. The W. M. Keck Observatory is operated as a scientific partnership among the California Institute of Technology, the University of California, and the National Aeronautics and Space Administration.

  15. CONSTRAINING DUST AND MOLECULAR GAS PROPERTIES IN Ly{alpha} BLOBS AT z {approx} 3

    Energy Technology Data Exchange (ETDEWEB)

    Yang Yujin; Decarli, Roberto; Walter, Fabian; Leipski, Christian [Max-Planck-Institut fuer Astronomie, Koenigstuhl 17, Heidelberg (Germany); Dannerbauer, Helmut; Le Floc' h, Emeric [Laboratoire AIM, CEA/DSM-CNRS-Universite Paris Diderot, Irfu/Service d' Astrophysique, CEA-Saclay, Orme des Merisiers, 91191 Gif-sur-Yvette Cedex (France); Weiss, Axel; Menten, Karl M. [Max-Planck-Insitut fuer Radioastronomie, Auf dem Huegel 69, D-53121 Bonn (Germany); Dey, Arjun [National Optical Astronomy Observatory, 950 North Cherry Avenue, Tucson, AZ 85719 (United States); Chapman, Scott C. [Institute of Astronomy, University of Cambridge, Madingley Road, Cambridge CB3 0HA (United Kingdom); Prescott, Moire K. M. [Department of Physics, Broida Hall, Mail Code 9530, University of California, Santa Barbara, CA 93106 (United States); Neri, Roberto [IRAM-Institut de Radio Astronomie Millimetrique, 300 rue de la Piscine, 38406 Saint-Martin d' Heres (France); Borys, Colin [IPAC, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125 (United States); Matsuda, Yuichi [Department of Physics, Durham University, South Road, Durham DH1 3LE (United Kingdom); Yamada, Toru [Astronomical Institute, Tohoku University, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578 (Japan); Hayashino, Tomoki [Research Center for Neutrino Science, Graduate School of Science, Tohoku University, Sendai 980-8578 (Japan); Tapken, Christian [Leibnitz-Institut fuer Astrophysik Potsdam (AIP), An der Sternwarte 16, 14482 Potsdam (Germany)

    2012-01-10

    In order to constrain the bolometric luminosities, dust properties, and molecular gas content of giant Ly{alpha} nebulae, the so-called Ly{alpha} blobs, we have carried out a study of dust continuum and CO line emission in two well-studied representatives of this population at z {approx} 3: an Ly{alpha} blob discovered by its strong Spitzer Multiband Infrared Photometer 24 {mu}m detection (LABd05) and the Steidel blob 1 (SSA22-LAB01). We find that the spectral energy distribution of LABd05 is well described by an active-galactic-nucleus-starburst composite template with L{sub FIR} = (4.0 {+-} 0.5) Multiplication-Sign 10{sup 12} L{sub Sun }, comparable to high-z submillimeter galaxies and ultraluminous infrared galaxies. New Large APEX Bolometer Camera 870 {mu}m measurements rule out the reported Submillimeter Common-User Bolometer Array detection of the SSA22-LAB01 (S{sub 850{mu}m} = 16.8 mJy) at the >4{sigma} level. Consistent with this, ultradeep Plateau de Bure Interferometer observations with {approx}2'' spatial resolution also fail to detect any 1.2 mm continuum source down to Almost-Equal-To 0.45 mJy beam{sup -1} (3{sigma}). Combined with the existing (sub)millimeter observations in the literature, we conclude that the FIR luminosity of SSA22-LAB01 remains uncertain. No CO line is detected in either case down to integrated flux limits of S{sub {nu}}{Delta}V {approx}< 0.25-1.0 Jy km s{sup -1}, indicating a modest molecular gas reservoir, M(H{sub 2}) < (1-3) Multiplication-Sign 10{sup 10} M{sub Sun }. The non-detections exclude, with high significance (12{sigma}), the previous tentative detection of a CO J = 4-3 line in the SSA22-LAB01. The increased sensitivity afforded by the Atacama Large Millimeter/submillimeter Array will be critical in studying molecular gas and dust in these interesting systems.

  16. "Effects of the novel relatively short-acting kappa opioid receptor antagonist LY2444296 in behaviors observed after chronic extended-access cocaine self-administration in rats".

    Science.gov (United States)

    Valenza, Marta; Butelman, Eduardo R; Kreek, Mary Jeanne

    2017-08-01

    The recruitment of the stress circuitry contributes to a shift from positive to negative reinforcement mechanisms sustaining long-term cocaine addiction. The kappa opioid receptor (KOPr) signaling is upregulated by stress and chronic cocaine exposure. While KOPr agonists induce anhedonia and dysphoria, KOPr antagonists display antidepressant and anxiolytic properties. Most of the knowledge on KOPr antagonism is based on drugs with unusual pharmacokinetic and pharmacodynamic properties, complicating interpretation of results. Here we characterized in vivo behavioral and neuroendocrine effects of the novel relatively short-acting KOPr antagonist LY2444296. To date, no study has investigated whether systemic KOPr blockade reduced anxiety-like and depressive-like behaviors in animals previously exposed to chronic extended access cocaine self-administration. We tested the effect of LY2444296 in blocking KOPr-mediated aversive and neuroendocrine effects. Then, we tested acute systemic LY2444296 in reducing anxiety- and depression-like behaviors, as well as releasing the stress hormone corticosterone (CORT), observed after chronic extended access (18 h/day for 14 days) cocaine self-administration. LY2444296 blocked U69,593-induced place aversion and -reduced motor activity as well as U69,593-induced release of serum CORT, confirming its major site of action, without exerting an effect per se. Acute systemic administration of LY2444296 reduced anxiety-like and depressive-like behaviors, as well as CORT release, in rats tested after chronic extended access cocaine self-administration, but not in cocaine-naïve rats. Results suggest that acute blockade of KOPr by a relatively short-acting antagonist produces therapeutic-like effects selectively in rats with a history of chronic extended access cocaine self-administration.

  17. EXCITATION TEMPERATURE OF THE WARM NEUTRAL MEDIUM AS A NEW PROBE OF THE Lyα RADIATION FIELD

    Energy Technology Data Exchange (ETDEWEB)

    Murray, Claire E.; Lindner, Robert R.; Stanimirović, Snežana; Pingel, Nickolas M.; Lawrence, Allen; Babler, Brian L. [Department of Astronomy, University of Wisconsin, Madison, WI 53706 (United States); Goss, W. M.; Jencson, Jacob [National Radio Astronomy Observatory, P.O. Box O, 1003 Lopezville, Socorro, NM 87801 (United States); Heiles, Carl [Radio Astronomy Laboratory, UC Berkeley, 601 Campbell Hall, Berkeley, CA 94720 (United States); Dickey, John [University of Tasmania, School of Maths and Physics, Private Bag 37, Hobart, TAS 7001 (Australia); Hennebelle, Patrick, E-mail: cmurray@astro.wisc.edu [Laboratoire AIM, Paris-Saclay, CEA/IRFU/SAp—CNRS—Université Paris Diderot, F-91191 Gif-sur-Yvette Cedex (France)

    2014-02-01

    We use the Karl G. Jansky Very Large Array to conduct a high-sensitivity survey of neutral hydrogen (H I) absorption in the Milky Way. In combination with corresponding H I emission spectra obtained mostly with the Arecibo Observatory, we detect a widespread warm neutral medium component with excitation temperature 〈T{sub s}〉=7200{sub −1200}{sup +1800} K (68% confidence). This temperature lies above theoretical predictions based on collisional excitation alone, implying that Lyα scattering, the most probable additional source of excitation, is more important in the interstellar medium (ISM) than previously assumed. Our results demonstrate that H I absorption can be used to constrain the Lyα radiation field, a critical quantity for studying the energy balance in the ISM and intergalactic medium yet notoriously difficult to model because of its complicated radiative transfer, in and around galaxies nearby and at high redshift.

  18. Constraining Reionization with the z ˜ 5-6 Lyα Forest Power Spectrum: The Outlook after Planck

    Science.gov (United States)

    Oñorbe, J.; Hennawi, J. F.; Lukić, Z.; Walther, M.

    2017-09-01

    The latest measurements of cosmic microwave background electron-scattering optical depth reported by Planck significantly reduces the allowed space of {{H}} {{I}} reionization models, pointing toward a later ending and/or less extended phase transition than previously believed. Reionization impulsively heats the intergalactic medium (IGM) to ˜ {10}4 {{K}}, and owing to long cooling and dynamical times in the diffuse gas that are comparable to the Hubble time, memory of reionization heating is retained. Therefore, a late-ending reionization has significant implications for the structure of the z˜ 5{--}6 Lyα forest. Using state-of-the-art hydrodynamical simulations that allow us to vary the timing of reionization and its associated heat injection, we argue that extant thermal signatures from reionization can be detected via the Lyα forest power spectrum at 5noise ratio will allow distinguishing between different reionization scenarios.

  19. Discovery of a z = 7.452 High Equivalent Width Lyα Emitter from the Hubble Space Telescope  Faint Infrared Grism Survey

    Science.gov (United States)

    Larson, Rebecca L.; Finkelstein, Steven L.; Pirzkal, Norbert; Ryan, Russell; Tilvi, Vithal; Malhotra, Sangeeta; Rhoads, James; Finkelstein, Keely; Jung, Intae; Christensen, Lise; Cimatti, Andrea; Ferreras, Ignacio; Grogin, Norman; Koekemoer, Anton M.; Hathi, Nimish; O’Connell, Robert; Östlin, Göran; Pasquali, Anna; Pharo, John; Rothberg, Barry; Windhorst, Rogier A.; The FIGS Team

    2018-05-01

    We present the results of an unbiased search for Lyα emission from continuum-selected 5.6 data set consists of 160 orbits of G102 slitless grism spectroscopy obtained with the Hubble Space Telescope(HST)/WFC3 as part of the Faint Infrared Grism Survey (FIGS; PI: Malhotra), which obtains deep slitless spectra of all sources in four fields, and was designed to minimize contamination in observations of previously identified high-redshift galaxy candidates. The FIGS data can potentially spectroscopically confirm the redshifts of galaxies, and as Lyα emission is resonantly scattered by neutral gas, FIGS can also constrain the ionization state of the intergalactic medium during the epoch of reionization. These data have sufficient depth to detect Lyα emission in this epoch, as Tilvi et al. have published the FIGS detection of previously known Lyα emission at z = 7.51. The FIGS data use five separate roll angles of HST to mitigate the contamination by nearby galaxies. We created a method that accounts for and removes the contamination from surrounding galaxies and also removes any dispersed continuum light from each individual spectrum. We searched for significant (>4σ) emission lines using two different automated detection methods, free of any visual inspection biases. Applying these methods on photometrically selected high-redshift candidates between 5.6 7 (140.3 ± 19.0 Å).

  20. Impact of N-acetylcysteine on antitumor activity of doxorubicin and landomycin A in NK/Ly lymphoma-bearing mice

    Directory of Open Access Journals (Sweden)

    Yu. S. Kozak

    2018-04-01

    Full Text Available N-acetylcysteine (NAC is a dietary supplement demonstrating antioxidant and liver protecting effects that is widely used in clinics. NAC is considered to possess potential therapeutic activity for health disorders characterized by generation of free oxygen radicals, as well as potential for decreasing negative side effects of various drugs. However, the mechanisms of such tissue-protective actions of NAC remain poorly understood. The main aim of this work was to study therapeutic effects of NAC applied together with the “gold standard” of chemotherapy doxorubicin (Dx or the novel experimental drug landomycin A (LA to mice bearing NK/Ly lymphoma. It was revealed that NAC significantly decreased the nephrotoxicity of Dx (measured as creatinine level, possessed moderate immunomodulating activity (as revealed by an increase in number of cytotoxic T-lymphocytes, and partially increased survival of NK/Ly lymphoma-bearing animals treated with Dx. On the contrary, there was little tissue-protective effect of NAC towards LA due to the weak side effects of this anticancer drug, however, the combined use of NAC and LA significantly increased survival (60+ days of LA-treated animals with NK/Ly lymphoma. Summarizing, NAC possesses a moderate tissue-protective activity towards Dx action but lacks a major therapeutic effect. However, in the case of LA action, NAC significantly increases its anticancer activity with no impact on its negative side effects. Further studies of the molecular mechanisms underlying that activity of NAC towards the action of LA are in progress.

  1. Effects of Heat Treatment on Resistance to Microplastic Deformation in LY12 Alloy%热处理对LY12合金微塑变抗力的影响

    Institute of Scientific and Technical Information of China (English)

    张帆; 李小璀

    2000-01-01

    Microplastic deformation behavior of LY12 alloy under several typical heat treatment conditions has been investigated in this work.The results showed that the resistance to microplastic strain(σp) of annealed specimens was lower,subsequent was the quenched,the aged and thermal cycled specimens presented higher σp.During aging treatment the σp exhibited “peak aging”changing tendency,suggesting that the microyield strength,as conventional yield strength,is also controlled by the dispersed strengthening phase S’.Thermal cycling treatment decreased the resistance to higher magnitude of plastic strain (σ10-4,σt),but increased that of lower magnitude of plastic strain (σ10-6).%研究了LY12合金在多种热处理制度下的微塑变抗力,发现退火、淬火态的微塑变抗力很低,循环态次之,时效态最高。在时效过程中析出的S’强化相能显著提高微塑变抗力,具有典型峰时效规律。循环处理对低应变下的微塑变抗力有利,而对较高应变下的微塑变抗力却不利。

  2. Dose study of the multikinase inhibitor, LY2457546, in patients with relapsed acute myeloid leukemia to assess safety, pharmacokinetics, and pharmacodynamics

    Directory of Open Access Journals (Sweden)

    Wacheck V

    2011-05-01

    Full Text Available Volker Wacheck1, Michael Lahn2, Gemma Dickinson3, Wolfgang Füreder4, Renata Meyer4, Susanne Herndlhofer4, Thorsten Füreder1, Georg Dorfner5, Sada Pillay2, Valérie André6, Timothy P Burkholder7, Jacqueline K Akunda8, Leann Flye-Blakemore9, Dirk Van Bockstaele9, Richard F Schlenk10, Wolfgang R Sperr4, Peter Valent4,111Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel, Vienna, Austria; 2Early Oncology Clinical Investigation, Eli Lilly and Company, Indianapolis, IN, USA; 3Department of Pharmacokinetics, Eli Lilly and Company, Erl Wood Research Centre, Windlesham, Surrey, UK; 4Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Währinger Gürtel, Vienna, Austria; 5Eli Lilly GesmbH, Medical Department, Vienna, Austria; 6Department of Statistics, Eli Lilly and Company, Erl Wood Research Centre, Surrey, UK; 7Discovery Chemistry Research and Technology, Eli Lilly and Company, Indianapolis, IN, USA; 8Nonclinical Toxicology, Eli Lilly and Company, Indianapolis, IN, USA; 9Flow Cytometry and Cell Analysis, Esoterix Clinical Trials Services, Mechelen, Belgium; 10Universitätsklinikum Ulm, Klinik für Innere Medizin III, Ulm, Germany; 11Ludwig Boltzmann Cluster Oncology, Vienna, AustriaBackground: Acute myeloid leukemia (AML is a life-threatening malignancy with limited treatment options in chemotherapy-refractory patients. A first-in-human dose study was designed to investigate a safe and biologically effective dose range for LY2457546, a novel multikinase inhibitor, in patients with relapsed AML.Methods: In this nonrandomized, open-label, dose escalation Phase I study, LY2457546 was administered orally once a day. Safety, pharmacokinetics, changes in phosphorylation of target kinases in AML blasts, and risk of drug–drug interactions (DDI were assessed.Results: Five patients were treated at the starting and predicted minimal biologically effective dose of 50 mg

  3. Návrh spirály k původní kašnové turbině Katovice.

    OpenAIRE

    Čípa, Jiří

    2009-01-01

    Tato diplomová práce má za úkol určit nesrovnalosti malé vodní elektrárny Katovice. Kašnová vodní turbína je zde provozována na sníženém výkonu, neboť původní rychloběžná Francisova turbína dosahovala podstatně nižšího průtoku než turbína typu Kaplan. Cílem práce je návrh spirály a rozvaděče pro současnou Kaplanovu turbínu, která by pracovala na vyšším průtoku a byla provozována v blízkosti svého optima. Tento návrh bude sloužit jako podklad ke zkonstruování rozvaděče a spirály pro malou vodn...

  4. Splenectomy attenuates murine liver fibrosis with hypersplenism stimulating hepatic accumulation of Ly-6C(lo) macrophages.

    Science.gov (United States)

    Yada, Akito; Iimuro, Yuji; Uyama, Naoki; Uda, Yugo; Okada, Toshihiro; Fujimoto, Jiro

    2015-10-01

    Splenectomy in cirrhotic patients has been reported to improve liver function; however the underlying mechanism remains obscure. In the present study, we investigated the mechanism using a murine model, which represents well the compensated liver cirrhosis. C57BL/6 male mice were allowed to drink water including thioacetamide (TAA: 300 mg/L) ad libitum for 32 weeks. After splenectomy at 32 weeks, mice were sacrificed on days one, seven, and 28, respectively, while TAA-administration was continued. Perioperative changes in peripheral blood and liver tissues were analyzed. TAA treatment of mice for 32 weeks reproducibly achieved advanced liver fibrosis with splenomegaly, thrombocytopenia, and leukocytopenia. After splenectomy, liver fibrosis was attenuated, and macrophages/monocytes were significantly increased in peripheral blood, as well as in the liver. Progenitor-like cells expressing CK-19, EpCAM, or CD-133 appeared in the liver after TAA treatment, and gradually disappeared after splenectomy. Macrophages/monocytes accumulated in the liver, most of which were negative for Ly-6C, were adjacent to the hepatic progenitor-like cells, and quantitative RT-PCR indicated increased canonical Wnt and decreased Notch signals. As a result, a significant amount of β-catenin accumulated in the progenitor-like cells. Moreover, relatively small Ki67-positive hepatic cells were significantly increased. Protein expression of MMP-9, to which Ly-6G-positive neutrophils contributed, was also increased in the liver after splenectomy. The hepatic accumulation of macrophages/monocytes, most of which are Ly-6C(lo), the reduction of fibrosis, and the gradual disappearance of hepatic progenitor-like cells possibly play significant roles in the tissue remodeling process in cirrhotic livers after splenectomy. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  5. Subchronic administration of LY354740 does not modify ketamine-evoked behavior and neuronal activity in rats

    NARCIS (Netherlands)

    Imre, Gabor; Fokkema, Dirk S.; Ter Horst, Gert J.

    2006-01-01

    Acute treatment with LY354740 {1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate}, a potent and selective agonist for group 11 metabotropic glutamate receptors (mGlu2/3), has previously been shown to block some schizophrenia-like effects of N-methyl-D-aspartate (NMDA) receptor

  6. Foreground and Sensitivity Analysis for Broadband (2D) 21 cm-Lyα and 21 cm-Hα Correlation Experiments Probing the Epoch of Reionization

    Science.gov (United States)

    Neben, Abraham R.; Stalder, Brian; Hewitt, Jacqueline N.; Tonry, John L.

    2017-11-01

    A detection of the predicted anticorrelation between 21 cm and either Lyα or Hα from the epoch of reionization (EOR) would be a powerful probe of the first galaxies. While 3D intensity maps isolate foregrounds in low-{k}\\parallel modes, infrared surveys cannot yet match the field of view and redshift resolution of radio intensity mapping experiments. In contrast, 2D (I.e., broadband) infrared intensity maps can be measured with current experiments and are limited by foregrounds instead of photon or thermal noise. We show that 2D experiments can measure most of the 3D fluctuation power at klimit on residual foregrounds of the 21 cm-Lyα cross-power spectrum at z˜ 7 of {{{Δ }}}2text{kJy sr}}-1 {{mK}}) (95%) at {\\ell }˜ 800. We predict levels of foreground correlation and sample variance noise in future experiments, showing that higher-resolution surveys such as LOFAR, SKA-LOW, and the Dark Energy Survey can start to probe models of the 21 cm-Lyα EOR cross spectrum.

  7. Dihydropyridazinone cardiotonics: discovery of LY195115 and elucidation of structural features necessary for optimal inotropic activity

    Energy Technology Data Exchange (ETDEWEB)

    Krushinski, J.H.; Hayes, J.S.; Beedle, E.E.; Pollock, G.D.; Wilson, H.; Robertson, D.W.

    1986-03-05

    A series of 4,5-dihydro-6-aryl-3(/sup 2/H)-pyridazinones has been examined for inotropic activity. The optimal compound of the series, LY195115 (1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-/sup 2/H-indol-2-one), is one of the most potent and long-acting oral inotropes described to date. ED/sub 50/'s of LY195115, CI-914 and milrinone after i.v. administration to pentobarbital anesthetized dogs were 6.8, 46 and 37 ..mu..g/kg, respectively. ED/sub 50/'s after oral administration to conscious dogs were 25, 1000 and 500 ..mu..g/kg, respectively. For optimal positive inotropic activity and oral bioavailability in this series, the following structural features are necessary: (1) dihydropyridazinone ring with the nitrogen unsubstituted; (2) a hydrogen-bond acceptor substituent with a sigma value of ca 0.0 para to the dihydropyridazinone moiety; and (3) additional sterically undemanding lipophilic substituents adjacent to the hydrogen-bond acceptor site.

  8. Inflammatory Ly6Chigh Monocytes Protect against Candidiasis through IL-15-Driven NK Cell/Neutrophil Activation.

    Science.gov (United States)

    Domínguez-Andrés, Jorge; Feo-Lucas, Lidia; Minguito de la Escalera, María; González, Leticia; López-Bravo, María; Ardavín, Carlos

    2017-06-20

    Neutrophils play a crucial role in defense against systemic candidiasis, a disease associated with a high mortality rate in patients receiving immunosuppressive therapy, although the early immune mechanisms that boost the candidacidal activity of neutrophils remain to be defined in depth. Here, we used a murine model of systemic candidiasis to explore the role of inflammatory Ly6C high monocytes in NK cell-mediated neutrophil activation during the innate immune response against C. albicans. We found that efficient anti-Candida immunity required a collaborative response between the spleen and kidney, which relied on type I interferon-dependent IL-15 production by spleen inflammatory Ly6C high monocytes to drive efficient activation and GM-CSF release by spleen NK cells; this in turn was necessary to boost the Candida killing potential of kidney neutrophils. Our findings unveil a role for IL-15 as a critical mediator in defense against systemic candidiasis and hold promise for the design of IL-15-based antifungal immunotherapies. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. The Group 2 Metabotropic Glutamate Receptor Agonist LY379268 Rescues Neuronal, Neurochemical and Motor Abnormalities in R6/2 Huntington’s Disease Mice

    Science.gov (United States)

    Reiner, A.; Lafferty, D.C.; Wang, H.B.; Del Mar, N.; Deng, Y.P.

    2012-01-01

    Excitotoxic injury to striatum by dysfunctional cortical input or aberrant glutamate uptake may contribute to Huntington’s Disease (HD) pathogenesis. Since corticostriatal terminals possess mGluR2/3 autoreceptors, whose activation dampens glutamate release, we tested the ability of the mGluR2/3 agonist LY379268 to improve the phenotype in R6/2 HD mice with 120–125 CAG repeats. Daily subcutaneous injection of a maximum tolerated dose (MTD) of LY379268 (20mg/kg) had no evident adverse effects in WT mice, and diverse benefits in R6/2 mice, both in a cohort of mice tested behaviorally until the end of R6/2 lifespan and in a cohort sacrificed at 10 weeks of age for blinded histological analysis. MTD LY379268 yielded a significant 11% increase in R6/2 survival, an improvement on rotarod, normalization and/or improvement in locomotor parameters measured in open field (activity, speed, acceleration, endurance, and gait), a rescue of a 15–20% cortical and striatal neuron loss, normalization of SP striatal neuron neurochemistry, and to a lesser extent enkephalinergic striatal neuron neurochemistry. Deficits were greater in male than female R6/2 mice, and drug benefit tended to be greater in males. The improvements in SP striatal neurons, which facilitate movement, are consistent with the improved movement in LY379268-treated R6/2 mice. Our data indicate that mGluR2/3 agonists may be particularly useful for ameliorating the morphological, neurochemical and motor defects observed in HD. PMID:22472187

  10. Osteoblastic flare in a patient with advanced gastric cancer after treatment with pemetrexed and oxaliplatin: implications for response assessment with RECIST criteria

    Directory of Open Access Journals (Sweden)

    Simoncini Edda

    2007-06-01

    Full Text Available Abstract Background The RECIST guidelines are commonly used in phase II and III clinical trials. The correct definition of response can be controversial in some situations, as in the case we describe. Case presentation A 43 year-old man with advanced gastric cancer was enrolled in a phase II trial where he was treated with pemetrexed 500 mg/m2 plus oxaliplatin 120 mg/m2 every 3 weeks. At baseline, the target lesions were lymph-nodes, and the non-target lesions were small pulmonary nodules. At first re-evaluation, the target lesions showed partial response and the non-target lesions showed complete response, but new diffuse osteoblastic lesions appeared. The investigator decided to continue treatment until the second re-evaluation. CT scan confirmed the response of the target and non-target lesions, while the osteoblastic lesions did not change. Conclusion The appearance of osteoblastic lesions after an active antitumor treatment, a phenomenon known as flare, can complicate the definition of the best overall response using RECIST criteria. This possibility should be considered by oncologists involved in clinical trials.

  11. Mida teie oma tervise heaks teete? / Ly Jagor, Ülle Mihhailova, Ene Pill, Katrin Käbin...[jt.

    Index Scriptorium Estoniae

    2008-01-01

    Küsimusele vastavad Pärnu Õppenõustamiskeskuse psühholoog Ly Jagor, Maasika lasteaia juhataja asetäitja Ülle Mihhailova, Tallinna Perekeskuse ja Tähetorni lastekeskuse psühholoog Ene Pill, Tallinna Nõmme Noortemaja väikelaste ringijuht Katrin Käbin, Tääksi Põhikooli õpetaja Silva Kolk

  12. A Search for Lyα Emission from Galaxies AT 6 < z < 8 Using Deep HST Grism Observations: Discovery of a z = 7.5 Galaxy

    Science.gov (United States)

    Larson, Rebecca L.; Finkelstein, Steven; Pirzkal, Nor; Ryan, Russell; Tilvi, Vithal; Malhotra, Sangeeta; Rhoads, James; Finkelstein, Keely; Jung, Intae; Christensen, Lise; Cimatti, Andrea; Ferreras, Ignacio; Grogin, Norman; Koekemoer, Anton; Hathi, Nimish; O'Connell, Robert; Östlin, Göran; Pasquali, Anna; Rothberg, Barry; Windhorst, Rogier; FIGS Team

    2018-01-01

    We have built an automated detection method to find Lyα emission lines in HST grism data from 6 state of the intergalactic medium (IGM) during the epoch of reionization. We use 160 orbits of G102 slitless spectroscopy obtained from HST/WFC3 for the Faint Infrared Grism Survey (FIGS; PI: Malhotra) that were optimized to sample previously-identified high-redshift galaxy candidates. This dataset has already been used to identify one of these candidates, at redshift z = 7.51, which has been observed to have Lyα emission detectable with the HST Grism (Finkelstein et al. 2013; Tilvi et al. 2016). The FIGS data use five separate roll-angles of HST in an effort to mitigate the overall contamination effects of nearby galaxies and we have created a method that accounts for and removes the contamination from surrounding galaxies, while also removing any dispersed continuum light from each individual spectrum (Pirzkal et al. 2017). Using our new automated process we searched for significant (> 3σ) emission lines via two different methods. First, we compared the results for each galaxy across all roll angles and identified significant lines detected in more than one roll angle. Second, we performed a fit to all five roll angles simultaneously, accounting for the total flux of the emission line across all of our spectra. We have examined the spectra for 64 z > 7 candidates in our sample and found one new candidate Lyα emission line at a (> 5σ) level at 1.03µm (FIGS ID: GS2 1406 also named CANDELS ID: z7 PAR2 2909). After comparing this emission line with the broadband photometric colors, we conclude that this line is Lyα at z = 7.542 ± 0.003. This galaxy has the highest Lyα rest-frame equivalent width (EWLyα) yet published at z > 7 (110 ± 14 A).

  13. MHC class I Dk locus and Ly49G2+ NK cells confer H-2k resistance to murine cytomegalovirus.

    Science.gov (United States)

    Xie, Xuefang; Stadnisky, Michael D; Brown, Michael G

    2009-06-01

    Essential NK cell-mediated murine CMV (MCMV) resistance is under histocompatibility-2(k) (H-2(k)) control in MA/My mice. We generated a panel of intra-H2(k) recombinant strains from congenic C57L.M-H2(k/b) (MCMV resistant) mice for precise genetic mapping of the critical interval. Recombination breakpoint sites were precisely mapped and MCMV resistance/susceptibility traits were determined for each of the new lines to identify the MHC locus. Strains C57L.M-H2(k)(R7) (MCMV resistant) and C57L.M-H2(k)(R2) (MCMV susceptible) are especially informative; we found that allelic variation in a 0.3-megabase interval in the class I D locus confers substantial difference in MCMV control phenotypes. When NK cell subsets responding to MCMV were examined, we found that Ly49G2(+) NK cells rapidly expand and selectively acquire an enhanced capacity for cytolytic functions only in C57L.M-H2(k)(R7). We further show that depletion of Ly49G2(+) NK cells before infection abrogated MCMV resistance in C57L.M-H2(k)(R7). We conclude that the MHC class I D locus prompts expansion and activation of Ly49G2(+) NK cells that are needed in H-2(k) MCMV resistance.

  14. Anemia predicts thromboembolic events, bleeding complications and mortality in patients with atrial fibrillation : insights from the RE-LY trial

    NARCIS (Netherlands)

    Westenbrink, B. D.; Alings, M.; Connolly, S. J.; Eikelboom, J.; Ezekowitz, M. D.; Oldgren, J.; Yang, S.; Pongue, J.; Yusuf, S.; Wallentin, L.; van Gilst, W. H.

    BackgroundAnemia may predispose to thromboembolic events or bleeding in anticoagulated patients with atrial fibrillation (AF). ObjectivesTo investigate whether anemia is associated with thromboembolic events and bleeding in patients with AF. Patients and methodsWe retrospectively analyzed the RE-LY

  15. Modelling the gas kinematics of an atypical Ly α emitting compact dwarf galaxy

    Science.gov (United States)

    Forero-Romero, Jaime E.; Gronke, Max; Remolina-Gutiérrez, Maria Camila; Garavito-Camargo, Nicolás; Dijkstra, Mark

    2018-02-01

    Star-forming compact dwarf galaxies (CDGs) resemble the expected pristine conditions of the first galaxies in the Universe and are the best systems to test models on primordial galaxy formation and evolution. Here, we report on one of such CDGs, Tololo 1214-277, which presents a broad, single peaked, highly symmetric Ly α emission line that had evaded theoretical interpretation so far. In this paper, we reproduce for the first time these line features with two different physically motivated kinematic models: an interstellar medium composed by outflowing clumps with random motions and an homogeneous gaseous sphere undergoing solid body rotation. The multiphase model requires a clump velocity dispersion of 54.3 ± 0.6 km s-1 with outflows of 54.3 ± 5.1 km s-1 , while the bulk rotation velocity is constrained to be 348^{+75}_{-48} km s-1. We argue that the results from the multiphase model provide a correct interpretation of the data. In that case, the clump velocity dispersion implies a dynamical mass of 2 × 109 M⊙, 10 times its baryonic mass. If future kinematic maps of Tololo 1214-277 confirm the velocities suggested by the multiphase model, it would provide additional support to expect such kinematic state in primordial galaxies, opening the opportunity to use the models and methods presented in this paper to constrain the physics of star formation and feedback in the early generation of Ly α -emitting galaxies.

  16. INFERENCES ON THE DISTRIBUTION OF Ly{alpha} EMISSION OF z {approx} 7 AND z {approx} 8 GALAXIES

    Energy Technology Data Exchange (ETDEWEB)

    Treu, Tommaso; Auger, Matthew W. [Department of Physics, University of California, Santa Barbara, CA 93106 (United States); Trenti, Michele [University of Colorado, Center for Astrophysics and Space Astronomy, 389-UCB, Boulder, CO 80309 (United States); Stiavelli, Massimo; Bradley, Larry D., E-mail: tt@physics.ucsb.edu [Space Telescope Science Institute, 3700 San Martin Dr, Baltimore MD 21218 (United States)

    2012-03-01

    Spectroscopic confirmation of galaxies at z {approx} 7 and above has been extremely difficult, owing to a drop in intensity of Ly{alpha} emission in comparison with samples at z {approx} 6. This crucial finding could potentially signal the ending of cosmic reionization. However, it is based on small data sets, often incomplete and heterogeneous in nature. We introduce a flexible Bayesian framework, useful to interpret such evidence. Within this framework, we implement two simple phenomenological models: a smooth one where the distribution of Ly{alpha} is attenuated by a factor {epsilon}{sub s} with respect to z {approx} 6 and a patchy one where a fraction {epsilon}{sub p} is absorbed/non-emitted while the rest is unabsorbed. From a compilation of 39 observed z {approx} 7 galaxies, we find {epsilon}{sub s} = 0.69 {+-} 0.12 and {epsilon}{sub p} = 0.66 {+-} 0.16. The models can be used to compute fractions of emitters above any equivalent width W. For W > 25 A, we find X{sup 25}{sub z=7} = 0.37 {+-} 0.11 (0.14 {+-} 0.06) for galaxies fainter (brighter) than M{sub UV} = -20.25 for the patchy model, consistent with previous work, but with smaller uncertainties by virtue of our full use of the data. At z {approx} 8 we combine new deep (5{sigma} flux limit 10{sup -17} erg s{sup -1} cm{sup -2}) Keck/NIRSPEC observations of a bright Y-dropout identified by our Brightest of Reionization Galaxies Survey, with those of three objects from the literature and find that the inference is inconclusive. We compute predictions for future near-infrared spectroscopic surveys and show that it is challenging but feasible to constrain the distribution of Ly{alpha} emitters at z {approx} 8 and distinguish between models.

  17. INFERENCES ON THE DISTRIBUTION OF Lyα EMISSION OF z ∼ 7 AND z ∼ 8 GALAXIES

    International Nuclear Information System (INIS)

    Treu, Tommaso; Auger, Matthew W.; Trenti, Michele; Stiavelli, Massimo; Bradley, Larry D.

    2012-01-01

    Spectroscopic confirmation of galaxies at z ∼ 7 and above has been extremely difficult, owing to a drop in intensity of Lyα emission in comparison with samples at z ∼ 6. This crucial finding could potentially signal the ending of cosmic reionization. However, it is based on small data sets, often incomplete and heterogeneous in nature. We introduce a flexible Bayesian framework, useful to interpret such evidence. Within this framework, we implement two simple phenomenological models: a smooth one where the distribution of Lyα is attenuated by a factor ε s with respect to z ∼ 6 and a patchy one where a fraction ε p is absorbed/non-emitted while the rest is unabsorbed. From a compilation of 39 observed z ∼ 7 galaxies, we find ε s = 0.69 ± 0.12 and ε p = 0.66 ± 0.16. The models can be used to compute fractions of emitters above any equivalent width W. For W > 25 Å, we find X 25 z=7 = 0.37 ± 0.11 (0.14 ± 0.06) for galaxies fainter (brighter) than M UV = –20.25 for the patchy model, consistent with previous work, but with smaller uncertainties by virtue of our full use of the data. At z ∼ 8 we combine new deep (5σ flux limit 10 –17 erg s –1 cm –2 ) Keck/NIRSPEC observations of a bright Y-dropout identified by our Brightest of Reionization Galaxies Survey, with those of three objects from the literature and find that the inference is inconclusive. We compute predictions for future near-infrared spectroscopic surveys and show that it is challenging but feasible to constrain the distribution of Lyα emitters at z ∼ 8 and distinguish between models.

  18. The cross-correlation between 21 cm intensity mapping maps and the Lyα forest in the post-reionization era

    Energy Technology Data Exchange (ETDEWEB)

    Carucci, Isabella P. [SISSA—International School for Advanced Studies, Via Bonomea 265, 34136 Trieste (Italy); Villaescusa-Navarro, Francisco [Center for Computational Astrophysics, 160 5th Avenue, New York, NY, 10010 (United States); Viel, Matteo, E-mail: ipcarucci@sissa.it, E-mail: fvillaescusa@simonsfoundation.org, E-mail: viel@oats.inaf.it [INAF—Osservatorio Astronomico di Trieste, Via Tiepolo 11, 34143, Trieste (Italy)

    2017-04-01

    We investigate the cross-correlation signal between 21cm intensity mapping maps and the Lyα forest in the fully non-linear regime using state-of-the-art hydrodynamic simulations. The cross-correlation signal between the Lyα forest and 21cm maps can provide a coherent and comprehensive picture of the neutral hydrogen (HI) content of our Universe in the post-reionization era, probing both its mass content and volume distribution. We compute the auto-power spectra of both fields together with their cross-power spectrum at z = 2.4 and find that on large scales the fields are completely anti-correlated. This anti-correlation arises because regions with high (low) 21cm emission, such as those with a large (low) concentration of damped Lyα systems, will show up as regions with low (high) transmitted flux. We find that on scales smaller than k ≅ 0.2 h Mpc{sup −1} the cross-correlation coefficient departs from −1, at a scale where non-linearities show up. We use the anisotropy of the power spectra in redshift-space to determine the values of the bias and of the redshift-space distortion parameters of both fields. We find that the errors on the value of the cosmological and astrophysical parameters could decrease by 30% when adding data from the cross-power spectrum, in a conservative analysis. Our results point out that linear theory is capable of reproducing the shape and amplitude of the cross-power up to rather non-linear scales. Finally, we find that the 21cm-Lyα cross-power spectrum can be detected by combining data from a BOSS-like survey together with 21cm intensity mapping observations by SKA1-MID with a S/N ratio higher than 3 in k element of [0.06,1] h Mpc{sup −1}. We emphasize that while the shape and amplitude of the 21cm auto-power spectrum can be severely affected by residual foreground contamination, cross-power spectra will be less sensitive to that and therefore can be used to identify systematics in the 21cm maps.

  19. Tissue distribution of a leukotriene antagonist 14C-LY170680, following inhalation exposure in the rat

    International Nuclear Information System (INIS)

    Pohland, R.C.; Beck, J.M.; Carlson, K.H.; Herman, D.R.; Hoppes, J.L.; Vavrek, M.T.; Wolff, R.K.

    1991-01-01

    Dissection and whole-body autoradiographic techniques were used to determine the tissue distribution profile of a leukotriene antagonist, 14 C-LY170680, following nose-only inhalation exposure in the rat. Liquid scintillation spectrometry and whole-body autoradiography indicated that highest concentrations of radiocarbon were present in stomach and small intestine at all time points. Radiocarbon reached maximum levels in stomach (2,259 ng-eq/g) and small intestine (2,399 ng-eq/g) 2 to 4 hours postexposure, respectively, and declined with time. In contrast, maximum radiocarbon concentrations in the head (146 ng-eq/g), trachea (408 ng-eq/g), and lung (534 ng-eq/g) occurred at 0 hours postexposure and steadily declined with time. Low concentrations of radiocarbon were detected in the liver ( 14 C-LY170680 were deposited in the head and within the lung following inhalation exposure. However, higher levels of radiocarbon present in the stomach and small intestine suggested significant nasal deposition followed by rapid clearance and ingestion of inhaled radioactive material. Distribution of radiocarbon limited to the respiratory and gastrointestinal tracts demonstrated minimal systemic absorption and exposure over the time course of this study

  20. Androgüüni kummaline pilk : fotograaf Ly Lestberg uurib androgüüni motiivi kaudu inimese hinge / Kärt Hellerma

    Index Scriptorium Estoniae

    Hellerma, Kärt, 1956-

    1999-01-01

    Kunstnik-fotograafi Ly Lestbergi näitus "Insomnia" Raatuse galeriis ja Cafe Anglais: 9 mustvalget suureformaadilist fotot noorest naisest. Ilmunud ka kogumikus: Avanenud ruum / Kärt Hellerma. Tallinn, 2006, lk. 232-234

  1. Avaliação económica do erlotinib, docetaxel, pemetrexedo e tratamento de suporte no tratamento de segunda ou terceira linhas de doentes com cancro do pulmão de não pequenas células An economic analysis of erlotinib, docetaxel, pemetrexed and best supportive care as second or third line treatment of non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    A Araújo

    2008-12-01

    Full Text Available Objectivo: Avaliar o custo-efectividade de erlotinib na segunda ou terceira linha do tratamento do cancro do pulmão de não pequenas células (CPNPC avançado ou metastizado versus docetaxel, pemetrexedo ou tratamento de suporte. Material e métodos: Análises de minimização de custos e custo-utilidade. Horizonte temporal: dois anos. Perspectiva do Sistema Nacional de Saúde (SNS português. Sobrevivência e tempo até progressão obtidos a partir de três ensaios clínicos. Análise-base inclui doentes com CPNPC avançado ou metastizado em segunda ou terceira linhas. Anos de vida ajustados pela qualidade (ou QALY obtidos a partir de estudo no Reino Unido. Consumo de recursos estimado por painel de peritos portugueses. Incluíram-se apenas custos directos, obtidos a partir de fontes oficiais (preços actualizados para 2008. Taxa de actualização anual: 5%. Análises de sensibilidade: diferentes subpopulações, horizonte temporal a três anos e análise probabilística. Resultados: O custo total/doente foi menor com erlotinib (26 478€ versus docetaxel (29 262€ ou pemetrexedo (32 762€ e superior versus tratamento de suporte (16 112€. Obtiveram-se QALY/doente mais elevados com erlotinib (0,250 versus docetaxel (0,225, pemetrexedo (0,241 ou tratamento de suporte (0,186. Assim, o erlotinib mostrou-se “dominante” em segunda ou terceira linhas versus docetaxel e pemetrexedo. A análise de sensibilidade comprova a robustez dos resultados. Conclusões: A substituição de docetaxel ou pemetrexedo por erlotinib poderia contribuir para uma redução anual dos gastos do SNS que se estima (taxas substituição: 5%-65% com uma variação entre 135 046€-1 755 602€ e entre 291 801€ -3 793 409€, respectivamente, e com ganho em termos de QALY.Aim: Evaluate costs and benefits of erlotinib as 2nd or 3rd line treatment of advanced or metastatic nonsmall cell lung cancer (NSCLC versus docetaxel, pemetrexed and best supportive care. Materials

  2. Materiály pancířů tanků

    OpenAIRE

    Fikar, Ondřej

    2017-01-01

    Tato bakalářská práce s názvem „Materiály pancířů tanků“ se nejprve zabývá protitankovou municí a jejím rozdělením, následuje stručný popis vybraných tanků vyrobených ve Velké Británii, Německu a Rusku a jejich vlivu na vývoj tankové techniky. V další části práce popisuje pancíř, základní principy jeho funkce a rozdělení pancířů podle účelu a podle chemického složení. Závěrem jsou uvedeny konkrétní příklady chemického složení některých pancéřových materiálů. This bachelor’s thesis named „M...

  3. Ectopic expression of miR-34a enhances radiosensitivity of non-small cell lung cancer cells, partly by suppressing the LyGDI signaling pathway

    International Nuclear Information System (INIS)

    Duan Weiming; Xu Yaxiang; Dong Yujin; Cao Lili; Tong Jian; Zhou Xinwen

    2013-01-01

    miR-34a is transcriptionally induced by the tumor suppressor gene p53, which is often downregulated in non-small cell lung cancer (NSCLC). To address whether the downstream signal of miR-34a is sufficient to induce apoptosis and to alter cellular radiosensitivity, a chemical synthetic miR-34a mimic was delivered into A549 and H1299 cells, with or without co-treatment of γ-irradiation. Results showed that ectopic expression of miR-34a induced dose-dependent cell growth inhibition and apoptosis in a p53-independent manner in both NSCLC cell lines. Interestingly, LyGDI was discovered as a new target gene of miR-34a, and downregulation of LyGDI promoted Rac1 activation and membrane translocation, resulting in cell apoptosis. Furthermore, restoration of miR-34a indirectly reduced cyclooxygenase-2 (COX-2) expression. Taken together, these results demonstrate that restoration of miR-34a expression enhances radiation-induced apoptosis, partly by suppressing the LyGDI signaling pathway, and miR-34a could possibly be used as a radiosensitizer for non-small cell lung cancer therapy. (author)

  4. Distinct Upstream Role of Type I IFN Signaling in Hematopoietic Stem Cell-Derived and Epithelial Resident Cells for Concerted Recruitment of Ly-6Chi Monocytes and NK Cells via CCL2-CCL3 Cascade.

    Directory of Open Access Journals (Sweden)

    Erdenebileg Uyangaa

    Full Text Available Type I interferon (IFN-I-dependent orchestrated mobilization of innate cells in inflamed tissues is believed to play a critical role in controlling replication and CNS-invasion of herpes simplex virus (HSV. However, the crucial regulators and cell populations that are affected by IFN-I to establish the early environment of innate cells in HSV-infected mucosal tissues are largely unknown. Here, we found that IFN-I signaling promoted the differentiation of CCL2-producing Ly-6Chi monocytes and IFN-γ/granzyme B-producing NK cells, whereas deficiency of IFN-I signaling induced Ly-6Clo monocytes producing CXCL1 and CXCL2. More interestingly, recruitment of Ly-6Chi monocytes preceded that of NK cells with the levels peaked at 24 h post-infection in IFN-I-dependent manner, which was kinetically associated with the CCL2-CCL3 cascade response. Early Ly-6Chi monocyte recruitment was governed by CCL2 produced from hematopoietic stem cell (HSC-derived leukocytes, whereas NK cell recruitment predominantly depended on CC chemokines produced by resident epithelial cells. Also, IFN-I signaling in HSC-derived leukocytes appeared to suppress Ly-6Ghi neutrophil recruitment to ameliorate immunopathology. Finally, tissue resident CD11bhiF4/80hi macrophages and CD11chiEpCAM+ dendritic cells appeared to produce initial CCL2 for migration-based self-amplification of early infiltrated Ly-6Chi monocytes upon stimulation by IFN-I produced from infected epithelial cells. Ultimately, these results decipher a detailed IFN-I-dependent pathway that establishes orchestrated mobilization of Ly-6Chi monocytes and NK cells through CCL2-CCL3 cascade response of HSC-derived leukocytes and epithelium-resident cells. Therefore, this cascade response of resident-to-hematopoietic-to-resident cells that drives cytokine-to-chemokine-to-cytokine production to recruit orchestrated innate cells is critical for attenuation of HSV replication in inflamed tissues.

  5. On the inversion of the scattering polarization and the Hanle effect signals in the hydrogen Lyα line

    Energy Technology Data Exchange (ETDEWEB)

    Ishikawa, R. [National Astronomical Observatory of Japan, 2-21-1 Osawa, Mitaka, Tokyo 181-8588 (Japan); Asensio Ramos, A.; Manso Sainz, R.; Trujillo Bueno, J. [Instituto de Astrofisica de Canarias, E-38205 La Laguna, Tenerife (Spain); Belluzzi, L. [Istituto Ricerche Solari Locarno (IRSOL), via Patocchi, 6605 Locarno Monti (Switzerland); Štěpán, J. [Astronomical Institute of the Academy of Sciences, Fričova 298, 251 65 Ondřejov (Czech Republic); Goto, M. [National Institute for Fusion Science, 322-6 Oroshi-cho, Toki, Gifu 509-5292 (Japan); Tsuneta, S., E-mail: ryoko.ishikawa@nao.ac.jp [Institute of Space and Astronautical Science, Japan Aerospace Exploration Agency, 3-1-1 Yoshinodai, Chuo, Sagamihara, Kanagawa 252-5210 (Japan)

    2014-06-01

    Magnetic field measurements in the upper chromosphere and above, where the gas-to-magnetic pressure ratio β is lower than unity, are essential for understanding the thermal structure and dynamical activity of the solar atmosphere. Recent developments in the theory and numerical modeling of polarization in spectral lines have suggested that information on the magnetic field of the chromosphere-corona transition region could be obtained by measuring the linear polarization of the solar disk radiation at the core of the hydrogen Lyα line at 121.6 nm, which is produced by scattering processes and the Hanle effect. The Chromospheric Lyman-Alpha SpectroPolarimeter (CLASP) sounding rocket experiment aims to measure the intensity (Stokes I) and the linear polarization profiles (Q/I and U/I) of the hydrogen Lyα line. In this paper, we clarify the information that the Hanle effect can provide by applying a Stokes inversion technique based on a database search. The database contains all theoretical Q/I and U/I profiles calculated in a one-dimensional semi-empirical model of the solar atmosphere for all possible values of the strength, inclination, and azimuth of the magnetic field vector, though this atmospheric region is highly inhomogeneous and dynamic. We focus on understanding the sensitivity of the inversion results to the noise and spectral resolution of the synthetic observations as well as the ambiguities and limitation inherent to the Hanle effect when only the hydrogen Lyα is used. We conclude that spectropolarimetric observations with CLASP can indeed be a suitable diagnostic tool for probing the magnetism of the transition region, especially when complemented with information on the magnetic field azimuth that can be obtained from other instruments.

  6. Boosting Lyα and He II λ1640 Line Fluxes from Population III Galaxies: Stochastic IMF Sampling and Departures from Case-B

    Science.gov (United States)

    Mas-Ribas, Lluís; Dijkstra, Mark; Forero-Romero, Jaime E.

    2016-12-01

    We revisit calculations of nebular hydrogen Lyα and He II λ1640 line strengths for Population III (Pop III) galaxies, undergoing continuous, and bursts of, star formation. We focus on initial mass functions (IMFs) motivated by recent theoretical studies, which generally span a lower range of stellar masses than earlier works. We also account for case-B departures and the stochastic sampling of the IMF. In agreement with previous work, we find that departures from case-B can enhance the Lyα flux by a factor of a few, but we argue that this enhancement is driven mainly by collisional excitation and ionization, and not due to photoionization from the n = 2 state of atomic hydrogen. The increased sensitivity of the Lyα flux to the high-energy end of the galaxy spectrum makes it more subject to stochastic sampling of the IMF. The latter introduces a dispersion in the predicted nebular line fluxes around the deterministic value by as much as a factor of ˜4. In contrast, the stochastic sampling of the IMF has less impact on the emerging Lyman Werner photon flux. When case-B departures and stochasticity effects are combined, nebular line emission from Pop III galaxies can be up to one order of magnitude brighter than predicted by “standard” calculations that do not include these effects. This enhances the prospects for detection with future facilities such as the James Webb Space Telescope and large, ground-based telescopes.

  7. CONSTRAINING THE LIFETIME AND OPENING ANGLE OF QUASARS USING FLUORESCENT Ly α EMISSION: THE CASE OF Q0420–388

    International Nuclear Information System (INIS)

    Borisova, Elena; Lilly, Simon J.; Cantalupo, Sebastiano; Prochaska, J. Xavier; Rakic, Olivera; Worseck, Gabor

    2016-01-01

    A toy model is developed to understand how the spatial distribution of fluorescent emitters in the vicinity of bright quasars could be affected by the geometry of the quasar bi-conical radiation field and by its lifetime. The model is then applied to the distribution of high-equivalent-width Ly α emitters (with rest-frame equivalent widths above 100 Å, threshold used in, e.g., Trainor and Steidel) identified in a deep narrow-band 36 × 36 arcmin 2 image centered on the luminous quasar Q0420–388. These emitters are found near the edge of the field and show some evidence of an azimuthal asymmetry on the sky of the type expected if the quasar is radiating in a bipolar cone. If these sources are being fluorescently illuminated by the quasar, the two most distant objects require a lifetime of at least 15 Myr for an opening angle of 60° or more, increasing to more than 40 Myr if the opening angle is reduced to a minimum of 30°. However, some other expected signatures of boosted fluorescence are not seen at the current survey limits, e.g., a fall off in Ly α brightness, or equivalent width, with distance. Furthermore, to have most of the Ly α emission of the two distant sources to be fluorescently boosted would require the quasar to have been significantly brighter in the past. This suggests that these particular sources may not be fluorescent, invalidating the above lifetime constraints. This would cast doubt on the use of this relatively low equivalent width threshold and thus also on the lifetime analysis in Trainor and Steidel.

  8. CONSTRAINING THE LIFETIME AND OPENING ANGLE OF QUASARS USING FLUORESCENT Ly α EMISSION: THE CASE OF Q0420–388

    Energy Technology Data Exchange (ETDEWEB)

    Borisova, Elena; Lilly, Simon J.; Cantalupo, Sebastiano [Institute for Astronomy, ETH Zurich, Zurich, CH-8093 (Switzerland); Prochaska, J. Xavier [UCO/Lick Observatory, UC Santa Cruz, Santa Cruz, CA 95064 (United States); Rakic, Olivera; Worseck, Gabor, E-mail: borisova@phys.ethz.ch [Max-Planck-Institut für Astronomie, Heidelberg, D-69117 (Germany)

    2016-10-20

    A toy model is developed to understand how the spatial distribution of fluorescent emitters in the vicinity of bright quasars could be affected by the geometry of the quasar bi-conical radiation field and by its lifetime. The model is then applied to the distribution of high-equivalent-width Ly α emitters (with rest-frame equivalent widths above 100 Å, threshold used in, e.g., Trainor and Steidel) identified in a deep narrow-band 36 × 36 arcmin{sup 2} image centered on the luminous quasar Q0420–388. These emitters are found near the edge of the field and show some evidence of an azimuthal asymmetry on the sky of the type expected if the quasar is radiating in a bipolar cone. If these sources are being fluorescently illuminated by the quasar, the two most distant objects require a lifetime of at least 15 Myr for an opening angle of 60° or more, increasing to more than 40 Myr if the opening angle is reduced to a minimum of 30°. However, some other expected signatures of boosted fluorescence are not seen at the current survey limits, e.g., a fall off in Ly α brightness, or equivalent width, with distance. Furthermore, to have most of the Ly α emission of the two distant sources to be fluorescently boosted would require the quasar to have been significantly brighter in the past. This suggests that these particular sources may not be fluorescent, invalidating the above lifetime constraints. This would cast doubt on the use of this relatively low equivalent width threshold and thus also on the lifetime analysis in Trainor and Steidel.

  9. Detection of Three-minute Oscillations in Full-disk Ly α Emission during a Solar Flare

    Energy Technology Data Exchange (ETDEWEB)

    Milligan, Ryan O.; Fletcher, Lyndsay [SUPA, School of Physics and Astronomy, University of Glasgow, Glasgow, G12 8QQ (United Kingdom); Fleck, Bernhard [ESA Directorate of Science, Operations Department, c/o NASA/GSFC Code 671, Greenbelt, MD 20071 (United States); Ireland, Jack; Dennis, Brian R. [Solar Physics Laboratory (Code 671), Heliophysics Science Division, NASA Goddard Space Flight Center, Greenbelt, MD 20771 (United States)

    2017-10-10

    In this Letter we report the detection of chromospheric 3-minute oscillations in disk-integrated EUV irradiance observations during a solar flare. A wavelet analysis of detrended Ly α (from GOES /EUVS) and Lyman continuum (from Solar Dynamics Observatory ( SDO )/EVE) emission from the 2011 February 15 X-class flare (SOL2011-02-15T01:56) revealed a ∼3 minute period present during the flare’s main phase. The formation temperature of this emission locates this radiation at the flare’s chromospheric footpoints, and similar behavior is found in the SDO /Atmospheric Imaging Assembly 1600 and 1700 Å channels, which are dominated by chromospheric continuum. The implication is that the chromosphere responds dynamically at its acoustic cutoff frequency to an impulsive injection of energy. Since the 3-minute period was not found at hard X-ray (HXR) energies (50–100 keV) in Reuven Ramaty High Energy Solar Spectroscopic Imager data we can state that this 3-minute oscillation does not depend on the rate of energization of non-thermal electrons. However, a second period of 120 s found in both HXR and chromospheric lightcurves is consistent with episodic electron energization on 2-minute timescales. Our finding on the 3-minute oscillation suggests that chromospheric mechanical energy should be included in the flare energy budget, and the fluctuations in the Ly α line may influence the composition and dynamics of planetary atmospheres during periods of high activity.

  10. Discovery of Scattering Polarization in the Hydrogen Ly α Line of the Solar Disk Radiation

    International Nuclear Information System (INIS)

    Kano, R.; Narukage, N.; Ishikawa, R.; Bando, T.; Katsukawa, Y.; Kubo, M.; Giono, G.; Hara, H.; Suematsu, Y.; Bueno, J. Trujillo; Winebarger, A.; Kobayashi, K.; Auchère, F.; Ishikawa, S.; Shimizu, T.; Sakao, T.; Tsuneta, S.; Ichimoto, K.; Goto, M.; Belluzzi, L.

    2017-01-01

    There is a thin transition region (TR) in the solar atmosphere where the temperature rises from 10,000 K in the chromosphere to millions of degrees in the corona. Little is known about the mechanisms that dominate this enigmatic region other than the magnetic field plays a key role. The magnetism of the TR can only be detected by polarimetric measurements of a few ultraviolet (UV) spectral lines, the Ly α line of neutral hydrogen at 121.6 nm (the strongest line of the solar UV spectrum) being of particular interest given its sensitivity to the Hanle effect (the magnetic-field-induced modification of the scattering line polarization). We report the discovery of linear polarization produced by scattering processes in the Ly α line, obtained with the Chromospheric Lyman-Alpha Spectro-Polarimeter (CLASP) rocket experiment. The Stokes profiles observed by CLASP in quiet regions of the solar disk show that the Q / I and U / I linear polarization signals are of the order of 0.1% in the line core and up to a few percent in the nearby wings, and that both have conspicuous spatial variations with scales of ∼10 arcsec. These observations help constrain theoretical models of the chromosphere–corona TR and extrapolations of the magnetic field from photospheric magnetograms. In fact, the observed spatial variation from disk to limb of polarization at the line core and wings already challenge the predictions from three-dimensional magnetohydrodynamical models of the upper solar chromosphere.

  11. Discovery of Scattering Polarization in the Hydrogen Ly α Line of the Solar Disk Radiation

    Energy Technology Data Exchange (ETDEWEB)

    Kano, R.; Narukage, N.; Ishikawa, R.; Bando, T.; Katsukawa, Y.; Kubo, M.; Giono, G.; Hara, H.; Suematsu, Y. [National Astronomical Observatory of Japan, 2-21-1 Osawa, Mitaka, Tokyo 181-8588 (Japan); Bueno, J. Trujillo [Instituto de Astrofísica de Canarias, La Laguna, Tenerife, E-38205 (Spain); Winebarger, A.; Kobayashi, K. [Marshall Space Flight Center, National Aeronautics and Space Administration (NASA), Huntsville, AL 35812 (United States); Auchère, F. [Institut d’Astrophysique Spatiale, Université Paris Sud, Batiment 121, F-91405 Orsay (France); Ishikawa, S.; Shimizu, T.; Sakao, T.; Tsuneta, S. [Institute of Space and Astronautical Science, Japan Aerospace Exploration Agency, 3-1-1 Yoshinodai, Chuo, Sagamihara, Kanagawa 252-5210 (Japan); Ichimoto, K. [Hida Observatory, Kyoto University, Takayama, Gifu 506-1314 (Japan); Goto, M. [National Institute for Fusion Science, Toki, Gifu 509-5292 (Japan); Belluzzi, L., E-mail: ryouhei.kano@nao.ac.jp [Istituto Ricerche Solari Locarno, CH-6605 Locarno Monti (Switzerland); and others

    2017-04-10

    There is a thin transition region (TR) in the solar atmosphere where the temperature rises from 10,000 K in the chromosphere to millions of degrees in the corona. Little is known about the mechanisms that dominate this enigmatic region other than the magnetic field plays a key role. The magnetism of the TR can only be detected by polarimetric measurements of a few ultraviolet (UV) spectral lines, the Ly α line of neutral hydrogen at 121.6 nm (the strongest line of the solar UV spectrum) being of particular interest given its sensitivity to the Hanle effect (the magnetic-field-induced modification of the scattering line polarization). We report the discovery of linear polarization produced by scattering processes in the Ly α line, obtained with the Chromospheric Lyman-Alpha Spectro-Polarimeter (CLASP) rocket experiment. The Stokes profiles observed by CLASP in quiet regions of the solar disk show that the Q / I and U / I linear polarization signals are of the order of 0.1% in the line core and up to a few percent in the nearby wings, and that both have conspicuous spatial variations with scales of ∼10 arcsec. These observations help constrain theoretical models of the chromosphere–corona TR and extrapolations of the magnetic field from photospheric magnetograms. In fact, the observed spatial variation from disk to limb of polarization at the line core and wings already challenge the predictions from three-dimensional magnetohydrodynamical models of the upper solar chromosphere.

  12. Multimerization of GPIHBP1 and Familial Chylomicronemia from a Serine-to-Cysteine Substitution in GPIHBP1's Ly6 Domain

    DEFF Research Database (Denmark)

    Plengpanich, Wanee; Young, Stephen G; Khovidhunkit, Weerapan

    2014-01-01

    -fingered structure containing 10 cysteines and a conserved pattern of disulfide bond formation. Here, we report a patient with severe hypertriglyceridemia who was homozygous for a GPIHBP1 point mutation that converted a serine in GPIHBP1's Ly6 domain (Ser-107) to a cysteine. Two hypertriglyceridemic siblings were...

  13. BOOSTING LY α   AND He ii λ 1640 LINE FLUXES FROM POPULATION III GALAXIES: STOCHASTIC IMF SAMPLING AND DEPARTURES FROM CASE-B

    International Nuclear Information System (INIS)

    Mas-Ribas, Lluís; Dijkstra, Mark; Forero-Romero, Jaime E.

    2016-01-01

    We revisit calculations of nebular hydrogen Ly α and He ii λ 1640 line strengths for Population III (Pop III) galaxies, undergoing continuous, and bursts of, star formation. We focus on initial mass functions (IMFs) motivated by recent theoretical studies, which generally span a lower range of stellar masses than earlier works. We also account for case-B departures and the stochastic sampling of the IMF. In agreement with previous work, we find that departures from case-B can enhance the Ly α flux by a factor of a few, but we argue that this enhancement is driven mainly by collisional excitation and ionization, and not due to photoionization from the n  = 2 state of atomic hydrogen. The increased sensitivity of the Ly α flux to the high-energy end of the galaxy spectrum makes it more subject to stochastic sampling of the IMF. The latter introduces a dispersion in the predicted nebular line fluxes around the deterministic value by as much as a factor of ∼4. In contrast, the stochastic sampling of the IMF has less impact on the emerging Lyman Werner photon flux. When case-B departures and stochasticity effects are combined, nebular line emission from Pop III galaxies can be up to one order of magnitude brighter than predicted by “standard” calculations that do not include these effects. This enhances the prospects for detection with future facilities such as the James Webb Space Telescope and large, ground-based telescopes.

  14. Tamoxifen and the Rafoxifene analog LY117018: their effects on arachidonic acid release from cells in culture and on prostaglandin I2 production by rat liver cells

    International Nuclear Information System (INIS)

    Levine, Lawrence

    2004-01-01

    Tamoxifen is being used successfully to treat breast cancer. However, tamoxifen also increases the risk of developing endometrial cancer in postmenopausal women. Raloxifene also decreases breast cancer in women at high risk and may have a lower risk at developing cancer of the uterus. Tamoxifen has been shown to stimulate arachidonic acid release from rat liver cells. I have postulated that arachidonic acid release from cells may be associated with cancer chemoprevention. Rat liver, rat glial, human colon carcinoma and human breast carcinoma cells were labelled with [ 3 H] arachidonic acid. The release of the radiolabel from these cells during incubation with tamoxifen and the raloxifene analog LY117018 was measured. The prostaglandin I 2 produced during incubation of the rat liver cells with μM concentrations of tamoxifen and the raloxifene analog was quantitatively estimated. Tamoxifen is about 5 times more effective than LY117018 at releasing arachidonic acid from all the cells tested. In rat liver cells only tamoxifen stimulates basal prostaglandin I 2 production and that induced by lactacystin and 12-O-tetradecanoyl-phorbol-13-acetate. LY117018, however, blocks the tamoxifen stimulated prostaglandin production. The stimulated prostaglandin I 2 production is rapid and not affected either by preincubation of the cells with actinomycin or by incubation with the estrogen antagonist ICI-182,780. Tamoxifen and the raloxifene analog, LY117018, may prevent estrogen-independent as well as estrogen-dependent breast cancer by stimulating phospholipase activity and initiating arachidonic acid release. The release of arachidonic acid and/or molecular reactions that accompany that release may initiate pathways that prevent tumor growth. Oxygenation of the intracellularly released arachidonic acid and its metabolic products may mediate some of the pharmacological actions of tamoxifen and raloxifene

  15. Bridging the Gap: Capturing the Lyα Counterpart of a Type-II Spicule and Its Heating Evolution with VAULT2.0 and IRIS Observations

    Science.gov (United States)

    Chintzoglou, Georgios; De Pontieu, Bart; Martínez-Sykora, Juan; Pereira, Tiago M. D.; Vourlidas, Angelos; Tun Beltran, Samuel

    2018-04-01

    We present results from an observing campaign in support of the VAULT2.0 sounding rocket launch on 2014 September 30. VAULT2.0 is a Lyα (1216 Å) spectroheliograph capable of providing spectroheliograms at high cadence. Lyα observations are highly complementary to the IRIS observations of the upper chromosphere and the low transition region (TR) but have previously been unavailable. The VAULT2.0 data provide new constraints on upper-chromospheric conditions for numerical models. The observing campaign was closely coordinated with the IRIS mission. Taking advantage of this simultaneous multi-wavelength coverage of target AR 12172 and by using state-of-the-art radiative-MHD simulations of spicules, we investigate in detail a type-II spicule associated with a fast (300 km s‑1) network jet recorded in the campaign observations. Our analysis suggests that spicular material exists suspended high in the atmosphere but at lower temperatures (seen in Lyα) until it is heated and becomes visible in TR temperatures as a network jet. The heating begins lower in the spicule and propagates upwards as a rapidly propagating thermal front. The front is then observed as fast, plane-of-the-sky motion typical of a network jet, but contained inside the pre-existing spicule. This work supports the idea that the high speeds reported in network jets should not be taken as real mass upflows but only as apparent speeds of a rapidly propagating heating front along the pre-existing spicule.

  16. Cost-effectiveness analysis of additional bevacizumab to pemetrexed plus cisplatin for malignant pleural mesothelioma based on the MAPS trial.

    Science.gov (United States)

    Zhan, Mei; Zheng, Hanrui; Xu, Ting; Yang, Yu; Li, Qiu

    2017-08-01

    Malignant pleural mesothelioma (MPM) is a rare malignancy, and pemetrexed/cisplatin (PC) is the gold standard first-line regime. This study evaluated the cost-effectiveness of the addition of bevacizumab to PC (with maintenance bevacizumab) for unresectable MPM based on a phase III trial that showed a survival benefit compared with chemotherapy alone. To estimate the incremental cost-effectiveness ratio (ICER) of the incorporation of bevacizumab, a Markov model based on the MAPS trial, including the disease states of progression-free survival, progressive disease and death, was used. Total costs were calculated from a Chinese payer perspective, and health outcomes were converted into quality-adjusted life year (QALY). Model robustness was explored in sensitivity analyses. The addition of bevacizumab to PC was estimated to increase the cost by $81446.69, with a gain of 0.112 QALYs, resulting in an ICER of $727202.589 per QALY. In both one-way sensitivity and probabilistic sensitivity analyses, the ICER exceeded the commonly accepted willingness-to-pay threshold of 3 times the gross domestic product per capita of China ($23970.00 per QALY). The cost of bevacizumab had the most important impact on the ICER. The combination of bevacizumab with PC chemotherapy is not a cost-effective treatment option for MPM in China. Given its positive clinical value and extremely low incidence of MPM, an appropriate price discount, assistance programs and medical insurance should be considered to make bevacizumab more affordable for this rare patient population. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Pontryagin's maximum principle and optimization of the flight phase in ski jumping [Pontrjaginův princip maxima a optimalizace stylu letu ve skoku na lyžích

    Directory of Open Access Journals (Sweden)

    Radim Uhlář

    2009-09-01

    CHODISKA: Existuje několik faktorů (počáteční poloha skokana na lyžích a její změny v průběhu přechodové fáze letu, velikost a směr vektoru rychlosti pohybu těžiště skokana, velikost aerodynamické odporové a vztlakové síly apod., které určují trajektorii soustavy skokan + lyže a tím i dosaženou délku skoku. CÍLE: Cílem studie je představit metodu řešení úlohy optimálního řízení letové fáze skoku na lyžích se třemi omezenými řídicími proměnnými – úhel náběhu (a, úhel trup vs. lyže (b, úhel levá lyže vs. pravá lyže (V – na základě Pontrjaginova principu maxima. METODIKA: Kritériem optimality byla zvolena délka skoku. Jako zdroj informací o závislosti veličin L (lift area a D (drag area na řídicích proměnných byla použita převzatá regresní funkce s tabelovanými regresními koeficienty. Srovnány byly trajektorie referenčního a optimalizovaného skoku s profilem můstku K = 125 m ve Frenštátě pod Radhoštěm a stanoveny odpovídající délky skoku, aerodynamické odporové a vztlakové síly, velikosti rychlosti pohybu těžiště soustavy skokan + lyže, její vertikální a horizontální složky. Aby byly respektovány reálné polohy v letové fázi skoku, přípustné hodnoty řídicích proměnných náležely v každém okamžiku ohraničené množině. VÝSLEDKY: Bylo zjištěno, že skokan by měl na ohraničené množině přípustných hodnot řídicích proměnných minimalizovat úhly (a a (b, úhel (V naopak maximalizovat. Prodloužení skoku vlivem optimalizace je 17 %. ZÁVĚRY: Pro možnost dalšího výzkumu je nezbytné využití regresní analýzy pro experimentální data při určení závislosti aerodynamických sil působících během letu na soustavu skokan + lyže. To platí také pro aplikaci kontrolních proměnných vztahujících se k základním fyzickým a psychickým vlastnostem skokanů na lyžích.

  18. The anti-tumor effect of the quinoline-3-carboxamide tasquinimod: blockade of recruitment of CD11b+ Ly6Chi cells to tumor tissue reduces tumor growth

    International Nuclear Information System (INIS)

    Deronic, Adnan; Leanderson, Tomas; Ivars, Fredrik

    2016-01-01

    Previous work has demonstrated immunomodulatory, anti-tumor, anti-metastatic and anti-angiogenic effects of the small molecule quinoline-3-carboxamide tasquinimod in pre-clinical cancer models. To better understand the anti-tumor effects of tasquinimod in transplantable tumor models, we have evaluated the impact of the compound both on recruitment of myeloid cells to tumor tissue and on tumor-induced myeloid cell expansion as these cells are known to promote tumor development. Mice bearing subcutaneous 4 T1 mammary carcinoma tumors were treated with tasquinimod in the drinking water. A BrdU-based flow cytometry assay was utilized to assess the impact of short-term tasquinimod treatment on myeloid cell recruitment to tumors. Additionally, long-term treatment was performed to study the anti-tumor effect of tasquinimod as well as its effects on splenic myeloid cells and their progenitors. Myeloid cell populations were also immune-depleted by in vivo antibody treatment. Short-term tasquinimod treatment did not influence the proliferation of splenic Ly6C hi and Ly6G hi cells, but instead reduced the influx of Ly6C hi cells to the tumor. Treatment with tasquinimod for various periods of time after tumor inoculation revealed that the anti-tumor effect of this compound mainly operated during the first few days of tumor growth. Similar to tasquinimod treatment, antibody-mediated depletion of Ly6C hi cells within that same time frame, caused reduced tumor growth, thereby confirming a significant role for these cells in tumor development. Additionally, long-term tasquinimod treatment reduced the splenomegaly and expansion of splenic myeloid cells during a later phase of tumor development. In this phase, tasquinimod normalized the tumor-induced alterations in myeloerythroid progenitor cells in the spleen but had only limited impact on the same populations in the bone marrow. Our results indicate that tasquinimod treatment reduces tumor growth by operating early after tumor

  19. Preparation of 14c- amd 180-labeled 2-[2-methoxy-4-(methylsulfinyl)phenyl]-1H-imidazo[4,5-c]-pyridine hydrochloride (LY175326), a cardiotonic with inotropic and vasodilator activities

    International Nuclear Information System (INIS)

    Kau, Don; Krushinski, J.H.; Robertson, D.W.

    1985-01-01

    Two different forms of 14 C-labeled 2-methoxy-4-(methyl-thio)benzoic acid were prepared and employed in the synthesis of 14 C-labeled 2-:2-methoxy-4-(methylsulfinyl)phenyl:-1H-imidazo-[4,5-c]pyridine hydrochloride (LY175326), a cardiotonic with inotropic and vasodilator activities that is currently in clinical trials. The synthetic procedures described in this report allowed the introduction of the 14 C-label in the antepenultimate step. Additionally, an 18 0-labeled form of LY175326 was synthesized to facilitate kinetic analysis of the formation of its sulfide and sulfone metabolites. (author)

  20. Influence of Aging in Electric Field on Microplastic Deformation Behavior of LY12 Al Alloy%电场时效对LY12铝合金微变形行为的影响

    Institute of Scientific and Technical Information of China (English)

    孙东立; 王美玲; 王秀芳; 武高辉

    2003-01-01

    研究了电场时效处理中电场强度对LY12铝合金的微屈服强度和微变形行为的影响,也研究了直流电场时效和脉冲电场时效对合金微变形行为的影响.结果表明,适当的电场时效可以使合金的微屈服强度明显提高,优选出最佳的电场时效工艺参数是:E=2kV/cm,190℃/10h.

  1. DETECTION OF A HYDROGEN CORONA IN HST Ly α IMAGES OF EUROPA IN TRANSIT OF JUPITER

    Energy Technology Data Exchange (ETDEWEB)

    Roth, Lorenz; Ivchenko, Nickolay; Schlatter, Nicola [KTH Royal Institute of Technology (Sweden); Retherford, Kurt D.; Becker, Tracy M.; Grava, Cesare [Southwest Research Institute, San Antonio, TX (United States); Strobel, Darrell F. [Johns Hopkins University, Baltimore, MD (United States)

    2017-02-01

    We report far-ultraviolet observations of Europa in transit of Jupiter obtained with the Space Telescope Imaging Spectrograph of the Hubble Space Telescope on six occasions between 2014 December and 2015 March. Absorption of Jupiter’s bright hydrogen Ly α dayglow is detected in a region several moon radii above the limb in all observations. The observed extended absorption provides the first detection of an atomic hydrogen corona around Europa. Molecular constituents in Europa’s global sputtered atmosphere are shown to be optically thin to Ly α . The observations are consistent with a radially escaping H corona with maximum densities at the surface in the range of (1.5–2.2) × 10{sup 3} cm{sup −3}, confirming the abundances predicted by Monte Carlo simulations. In addition, we search for anomalies around the limb of Europa from absorption by localized high H{sub 2}O abundances from active plumes. No significant local absorption features are detected. We find that an H{sub 2}O plume with line-of-sight column density in the order of 10{sup 16} cm{sup −2}, as inferred by Roth et al. would not be detectable based on the statistical fluctuations of the transit measurements, and hence is not excluded or further constrained. The presence of plumes with line-of-sight column densities of >2 × 10{sup 17} cm{sup −2} can be excluded at a 3- σ level during five of our six observations.

  2. Disposition of 14C-LY195115 (1,3-dihydro-3,3-dimethyl-5-[1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl-6-14C]-2H-indol-2-one), a potent cardiotonic drug, in several animal species

    International Nuclear Information System (INIS)

    Bernstein, J.R.; Miller, B.J.; Franklin, R.B.

    1986-01-01

    Following the oral administration of 14 C-LY195115 to rats, mice, dogs, and monkeys (25,15,5, and 5 mg/kg, respectively), between 40 and 60% of the radioactivity was excreted into the urine within 24 hr. The elimination half-time of radioactivity from plasma was approximately 5 hr for rats and mice, 8 hr for monkeys, and 14 hr in dogs. Analysis of the 24 hr urine by thin-layer chromatography (tlc) revealed that the predominant radioactive moiety from all species was parent drug (> 30% of the dose). The urinary metabolite profile in the monkey showed parent drug and 2 polar, minor metabolites. The pattern was similar in rats, mice and dogs. Additionally in monkeys there was a very polar metabolite which was not conjugated with β-glucuronic acid. The major metabolite in the urine was isolated and shown to have a molecular weight of 255 (LY195115=257). Synthesis of the dehydro derivative of LY195115 indicated that the metabolite was identical to this material. A tissue distribution study in rats, following an oral dose of 14 C-LY195115 resulted in no apparent accumulation of radioactivity in any particular organ

  3. Korelace mezi délkou lyžařské tratě a rychlostí vrcholových slalomářů Correlation between the length of the ski track and the velocity of top slalom skiers

    Directory of Open Access Journals (Sweden)

    Blaž Lešnik

    2007-02-01

    Full Text Available Teoreticky je nejlepší co nejkratší lyžařská dráha (lyžařská trať. V praxi je to však těžko proveditelné a kromě toho je to velmi riskantní. Může se proto stát pouze součástí taktiky těch nejlepších soutěžících. Pomocí kinematické analýzy byly stanoveny rozdíly mezi volbou lyžařské dráhy u jednotlivých soutěžících, a to na základě vzorku vrcholových soutěžících ve světovém poháru v Kranjske Gore. Snažili jsme se zjistit, zda soutěžící dosahovali na takové lyžařské dráze vyšší rychlosti, tedy zda dosahovali rychlejšího pohybu mezi slalomovými brankami a tudíž v konečném důsledku i lep ších časových výsledků. V první části našeho výzkumu bylo prokázáno, že žádný ze soutěžících neměl v prvních dvou po sobě následujících obratech extrémně krátkou lyžařskou dráhu. Bylo rovněž zjištěno, že soutěžící s nejkratšími lyžařskými drahami v prvním obratu měli zpravidla nejdelší lyžařské dráhy v obratu druhém a naopak. Na základě těchto zjištění bylo možno tvrdit, že za současných podmínek je mimořádně obtížné, a snad dokonce nemožné, lyžovat tak, aby lyžařský oblouk byl v několika po sobě následujících obratech velmi krátký. Druhá část našeho výzkumu se zaměřila na zjišťování korelace mezi trajektorií lyží a rychlostí lyžování. Výpočty korelací prokázaly statisticky významnou korelaci mezi průměrnou rychlostí lyžování a průměrnou vzdáleností délky lyžařské dráhy od osy y v celém měřeném úseku. Bylo zjištěno, že měřený prostor překonávali soutěžící s kratší, tedy přímější, lyžařskou dráhou rychleji. Theoretically, the shortest possible line of skiing (ski track is the best one. But in practice it is very difficult to carry this out and besides it is very risky. It can therefore be only a part of the tactics of the best competitors. With

  4. Activation of Telomerase by Ionizing Radiation: Differential Response to the Inhibition of DNA Double-Strand Break Repair by Abrogation of Poly(ADP-ribosyl)ation, by LY294002, or by Wortmannin

    International Nuclear Information System (INIS)

    Neuhof, Dirk; Zwicker, Felix; Kuepper, Jan-Heiner; Debus, Juergen; Weber, Klaus-Josef

    2007-01-01

    Purpose: Telomerase activity represents a radiation-inducible function, which may be targeted by a double-strand break (DSB)-activated signal transduction pathway. Therefore, the effects of DNA-PK inhibitors (Wortmannin and LY294002) on telomerase upregulation after irradiation were studied. In addition, the role of trans-dominant inhibition of poly(ADP-ribosyl)ation, which strongly reduces DSB rejoining, was assessed in comparison with 3-aminobenzamide. Methods and Materials: COM3 rodent cells carry a construct for the dexamethasone-inducible overexpression of the DNA-binding domain of PARP1 and exhibit greatly impaired DSB rejoining after irradiation. Telomerase activity was measured using polymerase chain reaction ELISA 1 h after irradiation with doses up to 10 Gy. Phosphorylation status of PKB/Akt and of PKCα/β II was assessed by western blotting. Results: No telomerase upregulation was detectable for irradiated cells with undisturbed DSB rejoining. In contrast, incubation with LY294002 or dexamethasone yielded pronounced radiation induction of telomerase activity that could be suppressed by Wortmannin. 3-Aminobenzamide not only was unable to induce telomerase activity but also suppressed telomerase upregulation upon incubation with LY294002 or dexamethasone. Phospho-PKB was detectable independent of irradiation or dexamethasone pretreatment, but was undetectable upon incubations with LY294002 or Wortmannin, whereas phospho-PKC rested detectable. Conclusions: Telomerase activation postirradiation was triggered by different treatments that interfere with DNA DSB processing. This telomerase upregulation, however, was not reflected by the phosporylation status of the putative mediators of TERT activation, PKB and PKC. Although an involvement of PKB in TERT activation is not supported by the present findings, a respective role of PKC isoforms other than α/β II cannot be ruled out

  5. Distribution of 125I-monoclonal antibodies to antigen Ly 2.1 of T-lymphocytes in mice under the influence of immunomodulators

    International Nuclear Information System (INIS)

    Mirolyubova, Sh.Yu.; Fadeev, N.P.; Serzhanina, V.A.; Klimovich, V.B.; Makarenko, M.V.; Korsakova, L.N.

    1991-01-01

    A study was made of the distribution of 125 I (a chloramine method of labelling) monoclonal antibodies to the surface antigen Ly 2.1 T-lymphocytes during action of immunomodulators (tactivin, hydrocortisone, tactivin administered after hydrocortisone) on ACR mice. These antibodies were shown to retain antigen binding capacity, permitting monitoring of the redistribution of the antigen in the body exposed to immunomodulators

  6. The effect of PI3K inhibitor LY294002 and gemcitabine hydrochloride combined with ionizing radiation on the formation of vasculogenic mimicry of Panc-1 cells in vitro and in vivo.

    Science.gov (United States)

    Bai, R; Ding, T; Zhao, J; Liu, S; Zhang, L; Lan, X; Yu, Y; Yin, L

    2016-01-01

    This research's purpose was to explore the existence of vasculogenic mimicry (VM) in both 3-D matrices of Panc-1 cells in vitro and orthotopic Panc-1 xenografts in vivo and to test the hypothesis that PI3K inhibitor LY294002 and gemcitabine hydrochloride would offer clear treatment benefit when integrated into ionizing radiation (IR) therapeutic regimens for treatment of pancreatic cancer. We explored the existence of VM in both 3-D matrices of Panc-1 cells and orthotopic Panc-1 xenografts. We subsequently investigated the activation of the PI3K/MMPs/Ln-5γ2 signaling pathway in response to IR. LY294002 and gemcitabine hydrochloride were then evaluated for their radiosensitizing effect solely and in combination. We found that VM existed in both 3-D matrices of Panc-1 cells in vitro and orthotopic Panc-1 xenografts in vivo. The expressions of p-Akt and MMP- 2 were found to increase in response to IR. LY294002 and gemcitabine hydrochloride combined with IR better inhibited cell migration, VM formation and MMP-2 mRNA expression of Panc-1 cells in vitro, and we also proved that the novel therapeutic regimen better inhibited tumor growth, tumor metastasis and VM formation of orthotopic Panc-1 xenografts by suppressing the PI3K/MMPs/Ln-5γ2 signaling pathway in vivo. Our present study is among the first to prove the VM formation in orthotopic Panc-1 xenografts. Furthermore, our current study is also among the first to provide preliminary evidence for the use of the novel therapeutic regimen LY294002 and gemcitabine hydrochloride combined with IR for treatment of pancreatic cancer.

  7. Depletion of CD11c⁺ cells in the CD11c.DTR model drives expansion of unique CD64⁺ Ly6C⁺ monocytes that are poised to release TNF-α.

    Science.gov (United States)

    Sivakumaran, Shivajanani; Henderson, Stephen; Ward, Sophie; Sousa, Pedro Santos E; Manzo, Teresa; Zhang, Lei; Conlan, Thomas; Means, Terry K; D'Aveni, Maud; Hermine, Olivier; Rubio, Marie-Thérèse; Chakraverty, Ronjon; Bennett, Clare L

    2016-01-01

    Dendritic cells (DCs) play a vital role in innate and adaptive immunities. Inducible depletion of CD11c(+) DCs engineered to express a high-affinity diphtheria toxin receptor has been a powerful tool to dissect DC function in vivo. However, despite reports showing that loss of DCs induces transient monocytosis, the monocyte population that emerges and the potential impact of monocytes on studies of DC function have not been investigated. We found that depletion of CD11c(+) cells from CD11c.DTR mice induced the expansion of a variant CD64(+) Ly6C(+) monocyte population in the spleen and blood that was distinct from conventional monocytes. Expansion of CD64(+) Ly6C(+) monocytes was independent of mobilization from the BM via CCR2 but required the cytokine, G-CSF. Indeed, this population was also expanded upon exposure to exogenous G-CSF in the absence of DC depletion. CD64(+) Ly6C(+) monocytes were characterized by upregulation of innate signaling apparatus despite the absence of inflammation, and an increased capacity to produce TNF-α following LPS stimulation. Thus, depletion of CD11c(+) cells induces expansion of a unique CD64(+) Ly6C(+) monocyte population poised to synthesize TNF-α. This finding will require consideration in experiments using depletion strategies to test the role of CD11c(+) DCs in immunity. © 2015 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Etteheited räsivad pidu / Henri Reeder, Ly Rääsk, Heli Jürgenson ... [jt.] ; intervjueerinud Anneli Aasmäe

    Index Scriptorium Estoniae

    2009-01-01

    Küsimustele tänavusele üldlaulu- ja üldtantsupeole minekust ja peo repertuaari raskusest vastavad Aruküla noortekoori laulja Henri Reeder, Äksi segakoori dirigent Ly Rääsk, üldlaulupeo segakooride liigijuht Heli Jürgenson, Laulu- ja Tantsupeo SA muusikatoimetaja Ave Sopp, Laulu- ja Tantsupeo SA tantsutoimetaja Kadri Tiis , Lüganuse segakoori dirigent Priit-Andres Pärtna ja kolme tantsurühma juhendaja Vändrast Kädi Pärnoja

  9. Zápis šesti až osmiletých dětí do kurzů sjezdového lyžování ve Slovinsku Enrolling 6–8 year old children in alpine skiing courses in Slovenia

    Directory of Open Access Journals (Sweden)

    Nina Makuc

    2010-09-01

    Full Text Available VÝCHODISKA: Lyžování je sportovní aktivitou, kterou většina dětí ráda praktikuje, a proto se rády zapisují do různých kurzů organizovaných lyžařskými školami, společnostmi a kluby. CÍL: Studie měla za cíl analyzovat důvody rodičů a zájmy spojené se zápisem jejich dětí do kurzů sjezdového lyžování a stanovit, jak vzdělání rodičů a jejich měsíční příjem ovlivňují četnost, s jakou jejich děti navštěvují lyžařské kurzy. METODY: Provedli jsme průzkum mezi 250 rodiči dětí ve věku 6–8 let, a to za použití dotazníku se 17 proměnnými. Byly vypočítány frekvenční a kontingentační tabulky. Statistická váha vztahů mezi proměnnými byla ověřena kontingentačním koeficientem. VÝSLEDKY: Výsledky ukázaly, že polovina rodičů alespoň jednou zapsala své dítě do kurzu sjezdového lyžování. Rodiče s vyšším vzděláním a vyšším měsíčním příjmem zapisují své děti do kurzů sjezdového lyžování častěji. Osoba, která v rámci rodiny navrhuje, aby se dítě zapsalo do takového kurzu, je většinou otec. Ve více než polovině rodin oba rodiče lyžují; ovšem tři čtvrtiny rodin spolu nikdy nechodí lyžovat nebo toto praktikují jen zřídka. Otcové hodnotí své lyžařské dovednosti lépe než matky. Důvod nejčastěji uváděný v souvislosti s tím, proč dané dítě nebylo zapsáno do kurzu sjezdového lyžování, byly finanční obtíže. Důvody rodičů pro to, aby se jejich děti naučily lyžovat, byly tyto: více než polovina rodičů si myslí, že by se jejich děti měly naučit dobře lyžovat, a 30 % rodičů přisuzuje velkou důležitost bezpečnosti na lyžařských svazích. Pouze 5 % rodičů by chtělo, aby se jejich dítě účastnilo lyžařských závodů. ZÁVĚRY: Naše zjištění pomohou organizátorům lyžařských kurzů l

  10. A young star-forming galaxy at z = 3.5 with an extended Ly\\,$α$ halo seen with MUSE

    DEFF Research Database (Denmark)

    Patrício, Vera; Richard, Johan; Verhamme, Anne

    2016-01-01

    .5$, observed with MUSE, for which we obtain 2D resolved spatial information of Ly$\\alpha$ and, for the first time, of CIII] emission. The exceptional signal-to-noise of the data reveals UV emission and absorption lines rarely seen at these redshifts, allowing us to derive important physical properties (T$_e......\\sim$15600 K, n$_e\\sim$300 cm$^{-3}$, covering fraction f$_c\\sim0.4$) using multiple diagnostics. Inferred stellar and gas-phase metallicities point towards a low metallicity object (Z$_{\\mathrm{stellar}}$ = $\\sim$ 0.07 Z$_\\odot$ and Z$_{\\mathrm{ISM}}$ $...

  11. Lipid drug conjugate nanoparticle as a potential nanocarrier for the oral delivery of pemetrexed diacid: Formulation design, characterization, ex vivo, and in vivo assessment.

    Science.gov (United States)

    Soni, Kriti; Mujtaba, Ali; Kohli, Kanchan

    2017-10-01

    The present work was to develop lipid drug conjugated (LDC) nanoparticles for the potential oral delivery of pemetrexed diacid (PTX) and evaluation of its in vitro, ex vivo and in vivo potentials. The LDC was prepared by salt formation of PTX with stearic acid and followed by cold homogenization technique to produce the LDC nanoparticles. FTIR analysis of LDC proved the presence of amide bond in LDC powder indicating the conjugation between drug and lipid. LDC nanoparticles was found to have particle size 121.9±1.85nm and zeta potential -51.6mV±1.23 and entrapment efficiency 81.0±0.89%. TEM images revealed spherical morphology and were in corroboration with particle size measurements. Ex vivo gut permeation studies revealed a very good enhancement in permeation of drug present in the LDC as compared to plain drug solution and were confirmed by CLSM. MTT assay conformed significant% toxicity at the end of 24h and 48h. Furthermore, the AUC 0-24 of PTX from the optimized LDC nanoparticels was found to be 4.22 folds higher than that from PTX suspension on oral administration. Thus, LDC has high potential for the oral delivery of PTX in cancer therapy and future prospects for the industrial purpose. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Multimédia a interaktivní studijní materiály na MU

    OpenAIRE

    Brandejs Michal; Brandejsová Jitka; Lunter Ľuboš

    2010-01-01

    Již v roce 2005 implementoval vývojový tým Informačního systému Masarykovy univerzity (IS MU) vlastní nástroje pro elektronickou podporu výuky (e-learningové nástroje) pro tvorbu a spravování kurzů. V té době se začali první učitelé, nadšeni těmito nástroji v IS MU, věnovat zavádění elektronických aktivit do svých předmětů. Postupné zkušenosti ukázaly, že pokud chce univerzita nabídnout svým studenům kvalitní a moderní elektronické studijní materiály, je nutné dlouhodobé vzdělávání a metodick...

  13. [Safety and effectiveness of pemetrexed in patients with non-small cell lung cancer in Japan - analysis of post-marketing surveillance].

    Science.gov (United States)

    Okubo, Sumiko; Kobayashi, Noriko; Taketsuna, Masanori; Kaneko, Naoya; Enatsu, Sotaro; Nishiuma, Shinichi

    2014-04-01

    The safety and effectiveness of pemetrexed(PEM)in patients with non-small cell lung cancer(NSCLC)were reviewed using data from post-marketing surveillance. Among 699 patients registered from June 2009 to May 2010, 683 patients were analyzed(343, first-line therapy: 340, second-line therapy or beyond). Patient backgrounds were as follows: median age=65 years(16.1%B75 years old); 64.7% male; 91.9% performance status 0-1; 83.2% Stage IV; 99.0% non-squamous cell cancer. Also, 86% of the first-line and 20% of the second-line cohort were receiving a concomitant anti-cancer drug(mostly platinum agents). The incidence rate of adverse drug reactions(ADR)was 76.7%, including serious cases(18.0%). The most common ADRs were decreased white blood cell count(26.8%), decreased neutrophil count(25.3%), anemia(19.2%), decreased platelet count(17.0%), and nausea(23.0%). The incidence of interstitial lung disease, which is a concern during chemotherapy, was 2.6%. Peripheral neuropathy and alopecia, events influencing a patient's quality of life, were less than 1%. The estimated median survival time was 23.2 months[95%CI: 19.8 months-not calculable]in the first-line cohort, and 11.8 months[95% CI: 10.5-13.7 months]in the B second-line cohort. The surveillance results showed no apparent difference in total ADRs in this current study compared to the safety profile established in clinical trials previously conducted in Japan and overseas. These results demonstrate the safety and effectiveness of PEM treatment for NSCLC patients in daily clinical settings.

  14. Evaluation of immunogenicity of LY2963016 insulin glargine compared with Lantus® insulin glargine in patients with type 1 or type 2 diabetes mellitus.

    Science.gov (United States)

    Ilag, L L; Deeg, M A; Costigan, T; Hollander, P; Blevins, T C; Edelman, S V; Konrad, R J; Ortmann, R A; Pollom, R K; Huster, W J; Zielonka, J S; Prince, M J

    2016-02-01

    To compare the immunogenicity profiles and the potential effects on clinical outcomes of LY2963016 insulin glargine (LY IGlar) and Lantus® insulin glargine (IGlar), products with identical primary amino acid sequences, in patients with type 1 or type 2 diabetes mellitus (T1DM or T2DM). To assess immunogenicity, anti-insulin glargine antibodies (measured as percent binding) were compared between treatments in 52-week (open-label) and 24-week (double-blind) randomized studies in total study populations of patients with T1DM (N = 535) and T2DM (N = 756), respectively, and two subgroups of patients with T2DM: insulin-naïve patients and those reporting prestudy IGlar treatment (prior IGlar). Relationships between insulin antibody levels and clinical outcomes were assessed using analysis of covariance and partial correlations. Insulin antibody levels were assessed using Wilcoxon rank sum. Treatment comparisons for treatment-emergent antibody response (TEAR) and incidence of detectable antibodies were analysed using Fisher's exact test. No significant treatment differences were observed for insulin antibody levels, incidence of detectable anti-insulin glargine antibodies, or incidence of TEAR [overall and endpoint, by last-observation-carried-forward (LOCF)] in patients with T1DM or patients with T2DM, including the insulin-naïve subgroup. A statistically significant difference was noted in the overall incidence of detectable antibodies but not at endpoint (LOCF) nor in TEAR for the prior IGlar subgroup of patients with T2DM. Insulin antibody levels were low (Insulin antibody levels or developing TEAR was not associated with clinical outcomes. LY IGlar and IGlar have similar immunogenicity profiles; anti-insulin glargine antibody levels were low for both treatments, with no observed effect on efficacy and safety outcomes. © 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

  15. Reseña de la aplicación: Genial.ly. Una herramienta en la nube para crear contenido dinámico e interactivo || Review of the app: Genial.ly. A tool in the cloud to create dynamic and interactive content

    Directory of Open Access Journals (Sweden)

    Ana María Peña-Cabanas

    2017-12-01

    Full Text Available El presente trabajo hace un recorrido por las diferentes funcionalidades que ofrece la herramienta Genial.ly para la creación de recursos interactivos digitales, haciendo especial hincapié en su potencial en el ámbito educativo. Al mismo tiempo, pretende servir de guía para docentes interesados en crear materiales didácticos que propicien un aprendizaje activo, significativo y personalizado, a la vez que resulten atrayentes y motivadores para sus alumnos. Todo ello sin olvidar reseñar también aquellos aspectos de la herramienta que son susceptibles de mejora.

  16. Thymidylate synthase protein expression levels remain stable during paclitaxel and carboplatin treatment in non-small cell lung cancer

    DEFF Research Database (Denmark)

    Jakobsen, Jan Nyrop; Santoni-Rugiu, Eric; Sørensen, Jens Benn

    2014-01-01

    BACKGROUND: Thymidylate synthase (TS) is a potential predictive marker for efficacy of treatment with pemetrexed. The current study aimed at investigating whether TS expression changes during non-pemetrexed chemotherapy of non-small cell lung cancer (NSCLC), thus making rebiopsy necessary for dec...

  17. H-2-incompatible bone marrow chimeras produce donor-H-2-restricted Ly-2 suppressor T-cell factor(s)

    International Nuclear Information System (INIS)

    Noguchi, M.; Onoe, K.; Ogasawara, M.; Iwabuchi, K.; Geng, L.; Ogasawara, K.; Good, R.A.; Morikawa, K.

    1985-01-01

    To study adaptive-differentiation phenomena of T lymphocytes, suppressor T-cell factors (TsF) produced by Ly-2+ splenic T cells from fully allogeneic mouse bone marrow chimeras were analyzed. AKR mice irradiated and reconstituted with B10 marrow cells (B10----AKR chimeras) produced an Ly-2+ TsF after hyperimmunization with sheep erythrocytes. The TsF suppressed primary antibody responses (to sheep erythrocytes) generated with spleen cells of mice of H-2b haplotype but not those of H-2k haplotype. Thus, this suppressor factor was donor-H-2-restricted. The immunoglobulin heavy chain variable region gene (Igh-V)-restricting element was not involved in this form of suppression. Similar results were obtained when TsF from B6----BALB/c and BALB/c----B6 chimeras were analyzed. The TsF from B10----AKR chimeras suppressed responses of B10.A(3R) and B10.A(5R) mice but not those of B10.A(4R). This finding showed that identity between the factor-producing cells and target spleen cells is required on the left-hand side of the E beta locus of the H-2 region and that the putative I-Jb locus is not involved in this form of suppression. The present results support the postulate that post-thymic differentiation in the presence of continued or repeated stimulation with antigen and donor-derived antigen-presenting cells generates donor-H-2-restricted T-cell clones that may predominate within the repertoire of the specific antigen being presented

  18. A cost-effectiveness analysis of first-line induction and maintenance treatment sequences in patients with advanced nonsquamous non-small-cell lung cancer in France

    Directory of Open Access Journals (Sweden)

    Taipale K

    2017-08-01

    Full Text Available Kaisa Taipale,1 Katherine B Winfree,2 Mark Boye,2 Mickael Basson,3 Ghassan Sleilaty,4 James Eaton,5 Rachel Evans,5 Christos Chouaid6 1Global Patient Outcomes and Real World Evidence International, Oy Eli Lilly Finland AB, Helsinki, Finland; 2Global Patient Outcomes and Real World Evidence, Eli Lilly and Company, Indianapolis, IN, USA; 3Corporate Affairs, Lilly France, Neuilly-sur-Seine, 4Bio-Medicines Medical Affairs, Lilly France, Neuilly-sur-Seine, France; 5ICON Health Economics and Epidemiology, ICON Plc, Milton Park, UK; 6Thoracic Oncology, Service de Pneumologie, Centre Hospitalier Intercommunal Créteil, Créteil, France Background: Comparative effectiveness and cost-effectiveness data for induction–maintenance (I–M sequences for the treatment of patients with nonsquamous non-small-cell lung cancer (nsqNSCLC are limited because of a lack of direct evidence. This analysis aimed to compare the cost-effectiveness of I–M pemetrexed with those of other I–M regimens used for the treatment of patients with advanced nsqNSCLC in the French health-care setting. Materials and methods: A previously developed global partitioned survival model was adapted to the France-only setting by restricting treatment sequences to include 12 I–M regimens most relevant to France, and incorporating French costs and resource-use data. Following a systematic literature review, network meta-analyses were performed to obtain hazard ratios for progression-free survival (PFS and overall survival (OS relative to gemcitabine + cisplatin (induction sequences or best supportive care (BSC (maintenance sequences. Modeled health-care benefits were expressed as life-years (LYs and quality-adjusted LYs (QALYs (estimated using French EuroQol five-dimension questionnaire tariffs. The study was conducted from the payer perspective (National Health Insurance. Cost- and benefit-model inputs were discounted at an annual rate of 4%. Results: Base-case results showed pemetrexed

  19. Klassiõpetaja peab särama / Ly Melesk, Kairis Kontus, Leida Talts, Viia Hang...[jt.] ; küsitles Anu Mõttus

    Index Scriptorium Estoniae

    2007-01-01

    Vestlusringis on Tallinna Kuristiku Gümnaasiumi klassiõpetajad Viia Hang ja Ly Melesk, Tallinna Ülikooli 5. kursuse üliõpilane ja Tallinna Lepistiku Lasteaed-Algkooli õpetaja Kairis Kontus, Tallinna Ülikooli algõpetuse õppetooli juhataja Leida Talts ning algõpetuse õppetooli pedagoogika ja algõpetuse metoodika õppejõud Mare Müürsepp. Kui hästi on Tallinna Ülikool ja tema eelkäijad suutnud algklassiõpetajaid ette valmistada ja mis neil igapäevatöös toime tulla aitab

  20. Bridging the Gap: Capturing the Lyα Counterpart of a Type-II Spicule and its Heating Evolution with VAULT2.0 and IRIS Campaign Observations

    Science.gov (United States)

    Chintzoglou, G.; De Pontieu, B.; Martinez-Sykora, J.; Mendes Domingos Pereira, T.; Vourlidas, A.; Tun Beltran, S.

    2017-12-01

    We present the analysis of data from the observing campaign in support to the VAULT2.0 sounding rocket launch on September 30, 2014. VAULT2.0 is a Lyα (1216 Å) spectroheliograph capable of providing fast cadence spectroheliograms of high-spectral purity. High resolution Lyα observations are highly complementary with the IRIS observations of the upper chromosphere and the low transition region but have previously been unavailable. The VAULT2.0 data provide critical, new upper-chromospheric constraints for numerical models. The observing campaign was closely coordinated with the IRIS mission. Taking advantage of this simultaneous multi-wavelength coverage of target AR 12172 and by using state-of-the-art radiative-MHD simulations of spicules, we are able to perform a detailed investigation of a type-II spicule associated with a fast apparent network jet recorded in the campaign observations during the VAULT2.0 flight. Our unique analysis suggests that spicular material exists suspended in lower temperatures until it rapidly gets heated and becomes visible in transition-region temperatures as an apparent network jet.

  1. A METALLICITY-SPIN TEMPERATURE RELATION IN DAMPED Lyα SYSTEMS

    International Nuclear Information System (INIS)

    Kanekar, Nissim; Smette, Alain; Briggs, Frank H.; Chengalur, Jayaram N.

    2009-01-01

    We report evidence for an anti-correlation between spin temperature T s and metallicity [Z/H], detected at 3.6σ significance in a sample of 26 damped Lyα absorbers (DLAs) at redshifts 0.09 s = (-0.68 ± 0.17) x [Z/H] + (2.13 ± 0.21) from a linear regression analysis. Our results indicate that the high T s values found in DLAs do not arise from differences between the optical and radio sightlines, but are likely to reflect the underlying gas temperature distribution. The trend between T s and [Z/H] can be explained by the larger number of radiation pathways for gas cooling in galaxies with high metal abundances, resulting in a high cold gas fraction, and hence, a low spin temperature. Conversely, low-metallicity galaxies have fewer cooling routes, yielding a larger warm gas fraction and a high T s . Most DLAs at z > 1.7 have low metallicities, [Z/H] s and [Z/H] is consistent with the presence of a mass-metallicity relation in DLAs, suggested by the tight correlation between DLA metallicity and the kinematic widths of metal lines. Most high-z DLAs are likely to arise in galaxies with low masses (M vir 10.5 M sun ), low metallicities ([Z/H] <-1), and low cold gas fractions.

  2. Ly α Absorption at Transits of HD 209458b: A Comparative Study of Various Mechanisms Under Different Conditions

    Energy Technology Data Exchange (ETDEWEB)

    Khodachenko, M. L.; Lammer, H.; Kislyakova, K. G.; Fossati, L.; Arkhypov, O. V. [Space Research Institute, Austrian Academy of Sciences, Graz (Austria); Shaikhislamov, I. F.; Berezutsky, A. G.; Miroshnichenko, I. B.; Posukh, V. G. [Institute of Laser Physics SB RAS, Novosibirsk (Russian Federation); Johnstone, C. P., E-mail: maxim.khodachenko@oeaw.ac.at [Department of Astrophysics, University of Vienna (Austria)

    2017-10-01

    To shed more light on the nature of the observed Ly α absorption during transits of HD 209458b and to quantify the major mechanisms responsible for the production of fast hydrogen atoms (the so-called energetic neutral atoms, ENAs) around the planet, 2D hydrodynamic multifluid modeling of the expanding planetary upper atmosphere, which is driven by stellar XUV, and its interaction with the stellar wind has been performed. The model self-consistently describes the escaping planetary wind, taking into account the generation of ENAs due to particle acceleration by the radiation pressure and by the charge exchange between the stellar wind protons and planetary atoms. The calculations in a wide range of stellar wind parameters and XUV flux values showed that under typical Sun-like star conditions, the amount of generated ENAs is too small, and the observed absorption at the level of 6%–8% can be attributed only to the non-resonant natural line broadening. For lower XUV fluxes, e.g., during the activity minima, the number of planetary atoms that survive photoionization and give rise to ENAs increases, resulting in up to 10%–15% absorption at the blue wing of the Ly α line, caused by resonant thermal line broadening. A similar asymmetric absorption can be seen under the conditions realized during coronal mass ejections, when sufficiently high stellar wind pressure confines the escaping planetary material within a kind of bowshock around the planet. It was found that the radiation pressure in all considered cases has a negligible contribution to the production of ENAs and the corresponding absorption.

  3. Synthesis of chondroitin sulfate CC and DD tetrasaccharides and interactions with 2H6 and LY111.

    Science.gov (United States)

    Matsushita, Kenya; Nakata, Tomomi; Takeda-Okuda, Naoko; Nadanaka, Satomi; Kitagawa, Hiroshi; Tamura, Jun-Ichi

    2018-03-01

    We synthesized the biotinylated chondroitin sulfate tetrasaccharides CS-CC [-3)βGalNAc6S(1-4)βGlcA(1-] 2 and CS-DD [-3)βGalNAc6S(1-4)βGlcA2S(1-] 2 which possess sulfate groups at O-6 of GalNAc and an additional sulfate group at O-2 of GlcA, respectively. We also analyzed interactions among CS-CC and CS-DD and the antibodies 2H6 and LY111, both of which are known to bind with CS-A, while CS-DD was shown for the first time to bind with both antibodies. Copyright © 2018 Elsevier Ltd. All rights reserved.

  4. An analysis of Finnish skiing school students' academic education and athletic success [Analýza akademického vzdělání a sportovních úspěchů studentů finských lyžařských škol

    Directory of Open Access Journals (Sweden)

    Jan-Erik Romar

    2012-03-01

    Full Text Available BACKGROUND: Skiing boarding schools provide an opportunity to combine academic education and an athletic career. Many athletes select to go to a boarding school at an age of 16 because they have poor local training possibilities; however, this physical move away from home providesmany challenges. OBJECTIVE: The purpose of this study was to analyze academic education and athletic success of skiing school students in Finland. METHODS: The participants were 49 students (15 girls and 34 boys with an average age of 17 years. They came from three skiing boarding schools, two cross-country and one alpine school. Sixty percent of the alpine skiers were members of the junior national team while only six percent of the cross-country skiers. All participants completed a survey about study success and athletic performance. RESULTS: The results showed that 80% of the students extended their high school studies from three to four years. About 50% of all students were satisfied with their academic success. Fifty-four percent of alpine skiers and 15% of cross-country skiers indicated that their best athletic success were in international competitions. Almost all students perceived that skiing school helped by combining sport and school. However, only 40% of the alpine skiers and 62% of the cross-country skiers were satisfied with their present athletic success. Seventy-three percent of the alpine skiers felt that sport participation affected negatively their success in school. Success in sport, good training possibilities, skilled coaches and caring friends were reason for enjoying life in skiing boarding schools. CONCLUSIONS: These findings support the concept of skiing schools and suggest that there are many things to consider when combining education and an athletic career.[VÝCHODISKA: Lyžařské internátní školy nabízejí možnost spojit akademické vzdělání a sportovní kariéru. Mnozí sportovci odcházejí ve věku 16 let na internátní

  5. Enrichment of Ly6Chi monocytes by multiple GM-CSF injections with HBV vaccine contributes to viral clearance in a HBV mouse model.

    Science.gov (United States)

    Zhao, Weidong; Zhou, Xian; Zhao, Gan; Lin, Qing; Wang, Xianzheng; Yu, Xueping; Wang, Bin

    2017-12-02

    Adjuvants are considered a necessary component for HBV therapeutic vaccines but few are licensed in clinical practice due to concerns about safety or efficiency. In our recent study, we established that a combination protocol of 3-day pretreatments with GM-CSF before a vaccination (3 × GM-CSF+VACCINE) into the same injection site could break immune tolerance and cause over 90% reduction of HBsAg level in the HBsAg transgenic mouse model. Herein, we further investigated the therapeutic potential of the combination in AAV8-1.3HBV-infected mice. After 4 vaccinations, both serum HBeAg and HBsAg were cleared and there was a 95% reduction of HBV-positive hepatocytes, in addition to the presence of large number of infiltrating CD8 + T cells in the livers. Mechanistically, the HBV-specific T-cell responses were elicited via a 3 × GM-CSF+VACCINE-induced conversion of CCR2-dependent CD11b + Ly6C hi monocytes into CD11b + CD11c + DCs. Experimental depletion of Ly6C hi monocytes resulted in a defective HBV-specific immune response thereby abrogating HBV eradication. This vaccination strategy could lead to development of an effective therapeutic protocol against chronic HBV in infected patients.

  6. Effect of Silica Sol on Boric-sulfuric Acid Anodic Oxidation of LY12CZ Aluminum Alloy

    Directory of Open Access Journals (Sweden)

    LIU Hui-cong

    2016-07-01

    Full Text Available Aluminum alloy anodizing coatings were prepared for LY12CZ in the boric-sulfuric acid solution (45g/L sulfuric acid,8g/L boric acid with the addition of 10%,20%,30% (volume fractionsilica sol,with the gradient voltage of 15V. The current and voltage transients of the anodizing process were collected by data collection instrument. The surface morphologies,microstructure and chemical composition of the anodic coatings were characterized by scanning electron microscopy (SEM. The corrosion resistance was examined by neutral salt spray,electrochemical impedance spectroscopy (EIS test and titrating test. The results show that the different concentration of silica sol addition can influence the forming and dissolution of anodizing coatings,improve the compactness smoothness and corrosion resistance during the anodizing process in the boric-sulfuric acid solution.

  7. DISCOVERY OF A DAMPED Lyα ABSORBER AT z = 3.3 ALONG A GALAXY SIGHT-LINE IN THE SSA22 FIELD

    Energy Technology Data Exchange (ETDEWEB)

    Mawatari, K.; Inoue, A. K. [College of General Education, Osaka Sangyo University, 3-1-1, Nakagaito, Daito, Osaka, 574-8530 (Japan); Kousai, K.; Hayashino, T. [Research Center for Neutrino Science, General School of Science, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578 (Japan); Cooke, R.; Prochaska, J. X. [Department of Astronomy and Astrophysics, UCO/Lick Observatory, University of California, 1156 High Street, Santa Cruz, CA 95064 (United States); Yamada, T. [Astronomical Institute, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578 (Japan); Matsuda, Y., E-mail: mawatari@las.osaka-sandai.ac.jp [National Astronomical Observatory of Japan, Osawa 2-21-1, Mitaka, Tokyo 181-8588 (Japan)

    2016-02-01

    Using galaxies as background light sources to map the Lyα absorption lines is a novel approach to study Damped Lyα Absorbers (DLAs). We report the discovery of an intervening z = 3.335 ± 0.007 DLA along a galaxy sight-line identified among 80 Lyman Break Galaxy (LBG) spectra obtained with our Very Large Telescope/Visible Multi-Object Spectrograph survey in the SSA22 field. The measured DLA neutral hydrogen (H i) column density is log(N{sub H} {sub i}/cm{sup −2}) = 21.68 ± 0.17. The DLA covering fraction over the extended background LBG is >70% (2σ), yielding a conservative constraint on the DLA area of ≳1 kpc{sup 2}. Our search for a counterpart galaxy hosting this DLA concludes that there is no counterpart galaxy with star formation rate larger than a few M{sub ⊙} yr{sup −1}, ruling out an unobscured violent star formation in the DLA gas cloud. We also rule out the possibility that the host galaxy of the DLA is a passive galaxy with M{sub *} ≳ 5 × 10{sup 10}M{sub ⊙} or a heavily dust-obscured galaxy with E(B − V) ≳ 2. The DLA may coincide with a large-scale overdensity of the spectroscopic LBGs. The occurrence rate of the DLA is compatible with that of DLAs found in QSO sight-lines.

  8. Impact of Massive Neutrinos and Dark Radiation on the High-redshift Cosmic Web. I. Lyα Forest Observables

    Science.gov (United States)

    Rossi, Graziano

    2017-11-01

    With upcoming high-quality data from surveys such as the Extended Baryon Oscillation Spectroscopic Survey or the Dark Energy Spectroscopic Instrument, improving the theoretical modeling and gaining a deeper understanding of the effects of neutrinos and dark radiation on structure formation at small scales are necessary, to obtain robust constraints free from systematic biases. Using a novel suite of hydrodynamical simulations that incorporate dark matter, baryons, massive neutrinos, and dark radiation, we present a detailed study of their impact on Lyα forest observables. In particular, we accurately measure the tomographic evolution of the shape and amplitude of the small-scale matter and flux power spectra and search for unique signatures along with preferred scales where a neutrino mass detection may be feasible. We then investigate the thermal state of the intergalactic medium (IGM) through the temperature-density relation. Our findings suggest that at k˜ 5 h {{Mpc}}-1 the suppression on the matter power spectrum induced by \\sum {m}ν =0.1 {eV} neutrinos can reach ˜ 4 % at z˜ 3 when compared to a massless neutrino cosmology, and ˜ 10 % if a massless sterile neutrino is included; surprisingly, we also find good agreement (˜ 2 % ) with some analytic predictions. For the 1D flux power spectrum {P}{ F }1{{D}}, the highest response to free-streaming effects is achieved at k˜ 0.005 {[{km}/{{s}}]}-1 when \\sum {m}ν =0.1 {eV}; this k-limit falls in the Lyα forest regime, making the small-scale {P}{ F }1{{D}} an excellent probe for detecting neutrino and dark radiation imprints. Our results indicate that the IGM at z˜ 3 provides the best sensitivity to active and sterile neutrinos.

  9. In vitro study on the schedule-dependency of the interaction between pemetrexed, gemcitabine and irradiation in non-small cell lung cancer and head and neck cancer cells

    International Nuclear Information System (INIS)

    Wouters, An; Pauwels, Bea; Lardon, Filip; Pattyn, Greet GO; Lambrechts, Hilde AJ; Baay, Marc; Meijnders, Paul; Vermorken, Jan B

    2010-01-01

    Based on their different mechanisms of action, non-overlapping side effects and radiosensitising potential, combining the antimetabolites pemetrexed (multitargeted antifolate, MTA) and gemcitabine (2',2'-difluorodeoxycytidine, dFdC) with irradiation (RT) seems promising. This in vitro study, for the first time, presents the triple combination of MTA, dFdC and irradiation using various treatment schedules. The cytotoxicity, radiosensitising potential and cell cycle effect of MTA were investigated in A549 (NSCLC) and CAL-27 (SCCHN) cells. Using simultaneous or sequential exposure schedules, the cytotoxicity and radiosensitising effect of 24 h MTA combined with 1 h or 24 h dFdC were analysed. Including a time interval between MTA exposure and irradiation seemed favourable to MTA immediately preceding or following radiotherapy. MTA induced a significant S phase accumulation that persisted for more than 8 h after drug removal. Among different MTA/dFdC combinations tested, the highest synergistic interaction was produced by 24 h MTA followed by 1 h dFdC. Combined with irradiation, this schedule showed a clear radiosensitising effect. Results from our in vitro model suggest that the sequence 24 h MTA → 1 h dFdC → RT is the most rational design and would, after confirmation in an in vivo setting, possibly provide the greatest benefit in the clinic

  10. [Scope of the latest RE-LY substudies: clinical implications].

    Science.gov (United States)

    Ruiz-Giménez Arrieta, N

    2012-03-01

    The approval of the use of dabiatran in stroke prevention in patients with nonvalvular atrial fibrilation (NVAF) is based on the results of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, one of the largest studies to date in this entity. In this trial, dabigatran showed similar safety and efficacy to warfarin in primary and secondary prevention of stroke in patients with AF. At a dose of 150 mg twice daily, dabigatran was superior to warfarin in the prevention of stroke or systemic embolism and the 110 mg dose twice daily showed similar efficacy and greater safety, given the lower incidence of hemorrhage. These results were consistently found in the various subanalyses, with some slight differences of interest for clinical practice. The ideal candidates for dabiatran are patients with NVAF suitable for cardioversion, who require short periods of anticoagulation, patients in remote geographical areas with difficulty in achieving good anticoagulation control or good control with anti-vitamin K treatment due to IRN fluctuations, and patients with a low risk of hemorrhage and a CHADS score ≥ 3 and/or with prior stroke, whenever there are no contraindications. The choice of dabigatran dose should be evaluated according to the patient's individual characteristics (caution must be exercised when prescribing this drug in the elderly and in renal insufficiency) and embolic and/or hemorrhagic risk. Studies of the long-term safety of this drug, pharmacoeconomic analyses in Spain and post-commercialization pharmacovigilance data are required before the definitive uses of this drug can be established. Copyright © 2012 Elsevier España, S.L. All rights reserved.

  11. Intergalactic medium emission observations with the cosmic web imager. II. Discovery of extended, kinematically linked emission around SSA22 Lyα BLOB 2

    International Nuclear Information System (INIS)

    Christopher Martin, D.; Chang, Daphne; Matuszewski, Matt; Morrissey, Patrick; Rahman, Shahin; Moore, Anna; Steidel, Charles C.; Matsuda, Yuichi

    2014-01-01

    The intergalactic medium (IGM) is the dominant reservoir of baryons, delineates the large-scale structure of the universe at low to moderate overdensities, and provides gas from which galaxies form and evolve. Simulations of a cold-dark-matter- (CDM-) dominated universe predict that the IGM is distributed in a cosmic web of filaments and that galaxies should form along and at the intersections of these filaments. While observations of QSO absorption lines and the large-scale distribution of galaxies have confirmed the CDM paradigm, the cosmic web of IGM has never been confirmed by direct imaging. Here we report our observation of the Lyα blob 2 (LAB2) in SSA22 with the Cosmic Web Imager (CWI). This is an integral field spectrograph optimized for low surface brightness, extended emission. With 22 hr of total on- and off-source exposure, CWI has revealed that LAB2 has extended Lyα emission that is organized into azimuthal zones consistent with filaments. We perform numerous tests with simulations and the data to secure the robustness of this result, which relies on data with modest signal-to-noise ratios. We have developed a smoothing algorithm that permits visualization of data cube slices along image or spectral image planes. With both raw and smoothed data cubes we demonstrate that the filaments are kinematically associated with LAB2 and display double-peaked profiles characteristic of optically thick Lyα emission. The flux is 10-20 times brighter than expected for the average emission from the IGM but is consistent with boosted fluorescence from a buried QSO or gravitation cooling radiation. Using simple emission models, we infer a baryon mass in the filaments of at least 1-4 × 10 11 M ☉ , and the dark halo mass is at least 2 × 10 12 M ☉ . The spatial-kinematic morphology is more consistent with inflow from the cosmic web than outflow from LAB2, although an outflow feature maybe present at one azimuth. LAB2 and the surrounding gas have significant and

  12. Intergalactic medium emission observations with the cosmic web imager. II. Discovery of extended, kinematically linked emission around SSA22 Lyα BLOB 2

    Energy Technology Data Exchange (ETDEWEB)

    Christopher Martin, D.; Chang, Daphne; Matuszewski, Matt; Morrissey, Patrick; Rahman, Shahin [Cahill Center for Astrophysics, California Institute of Technology, 1216 East California Boulevard, Mail Code 278-17, Pasadena, CA 91125 (United States); Moore, Anna [Caltech Optical Observatories, Cahill Center for Astrophysics, California Institute of Technology, 1216 East California Boulevard, Mail Code 11-17, Pasadena, CA 91125 (United States); Steidel, Charles C.; Matsuda, Yuichi, E-mail: cmartin@srl.caltech.edu [Cahill Center for Astrophysics, California Institute of Technology, 1216 East California Boulevard, Mail Code 249-17, Pasadena, CA 91125 (United States)

    2014-05-10

    The intergalactic medium (IGM) is the dominant reservoir of baryons, delineates the large-scale structure of the universe at low to moderate overdensities, and provides gas from which galaxies form and evolve. Simulations of a cold-dark-matter- (CDM-) dominated universe predict that the IGM is distributed in a cosmic web of filaments and that galaxies should form along and at the intersections of these filaments. While observations of QSO absorption lines and the large-scale distribution of galaxies have confirmed the CDM paradigm, the cosmic web of IGM has never been confirmed by direct imaging. Here we report our observation of the Lyα blob 2 (LAB2) in SSA22 with the Cosmic Web Imager (CWI). This is an integral field spectrograph optimized for low surface brightness, extended emission. With 22 hr of total on- and off-source exposure, CWI has revealed that LAB2 has extended Lyα emission that is organized into azimuthal zones consistent with filaments. We perform numerous tests with simulations and the data to secure the robustness of this result, which relies on data with modest signal-to-noise ratios. We have developed a smoothing algorithm that permits visualization of data cube slices along image or spectral image planes. With both raw and smoothed data cubes we demonstrate that the filaments are kinematically associated with LAB2 and display double-peaked profiles characteristic of optically thick Lyα emission. The flux is 10-20 times brighter than expected for the average emission from the IGM but is consistent with boosted fluorescence from a buried QSO or gravitation cooling radiation. Using simple emission models, we infer a baryon mass in the filaments of at least 1-4 × 10{sup 11} M {sub ☉}, and the dark halo mass is at least 2 × 10{sup 12} M {sub ☉}. The spatial-kinematic morphology is more consistent with inflow from the cosmic web than outflow from LAB2, although an outflow feature maybe present at one azimuth. LAB2 and the surrounding gas

  13. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial.

    Science.gov (United States)

    Wallentin, Lars; Yusuf, Salim; Ezekowitz, Michael D; Alings, Marco; Flather, Marcus; Franzosi, Maria Grazia; Pais, Prem; Dans, Antonio; Eikelboom, John; Oldgren, Jonas; Pogue, Janice; Reilly, Paul A; Yang, Sean; Connolly, Stuart J

    2010-09-18

    Effectiveness and safety of warfarin is associated with the time in therapeutic range (TTR) with an international normalised ratio (INR) of 2·0-3·0. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, dabigatran versus warfarin reduced both stroke and haemorrhage. We aimed to investigate the primary and secondary outcomes of the RE-LY trial in relation to each centre's mean TTR (cTTR) in the warfarin population. In the RE-LY trial, 18 113 patients at 951 sites were randomly assigned to 110 mg or 150 mg dabigatran twice daily versus warfarin dose adjusted to INR 2·0-3·0. Median follow-up was 2·0 years. For 18 024 patients at 906 sites, the cTTR was estimated by averaging TTR for individual warfarin-treated patients calculated by the Rosendaal method. We compared the outcomes of RE-LY across the three treatment groups within four groups defined by the quartiles of cTTR. RE-LY is registered with ClinicalTrials.gov, number NCT00262600. The quartiles of cTTR for patients in the warfarin group were: less than 57·1%, 57·1-65·5%, 65·5-72·6%, and greater than 72·6%. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p=0·89) or 150 mg dabigatran (interaction p=0·20) versus warfarin. Neither were any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p=0·71) or 150 mg dabigatran (interaction p=0·89) versus warfarin. There was a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p=0·03), with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR. There were significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all

  14. Journalismin uudet vuorovaikutuskeinot : Eli kuinka joukkoälyä käytetään osana toimituksellista työprosessia

    OpenAIRE

    Riihinen, Eleonoora

    2012-01-01

    Joukkoäly journalistisessa prosessissa on vielä vähän kokeiltu toimitustyökalu, joka yhdistää yleisön hyödyntämisen, tutkivan journalismin ja verkon datasovellukset. Joukkoälyllä tarkoitetaan jonkin tehtävän ulkoistamista ennalta nimeämättömälle joukolle ihmisiä. Tutkielmassani selvitän, millainen prosessi joukkoälyn käyttö on journalistisessa työprosessissa ja kuinka kiinnostuneita pienemmän levikkialueen maakuntalehdet ovat käyttämään yleisöä osana journalistista prosessia uusia toimitu...

  15. Simulation and comparison of progression-free survival among patients with non-squamous non-small-cell lung cancer receiving sequential therapy.

    Science.gov (United States)

    Walzer, Stefan; Chouaid, Christos; Lister, Johanna; Gultyaev, Dmitry; Vergnenegre, Alain; de Marinis, Filippo; Meng, Jie; de Castro Carpeno, Javier; Crott, Ralph; Kleman, Martin; Ngoh, Charles

    2015-01-01

    In recent years, the treatment landscape in advanced non-squamous non-small-cell lung cancer (nsNSCLC) has changed. New therapies (e.g., bevacizumab indicated in first line) have become available and other therapies (e.g., pemetrexed in first line and second line) moved into earlier lines in the treatment paradigm. While there has been an expansion of the available treatment options, it is still a key research question which therapy sequence results in the best survival outcomes for patients with nsNSCLC. A therapy-sequencing disease model that approximates treatment outcomes in up to five lines of treatment was developed for patients with nsNSCLC. The primary source of data for progression-free survival (PFS) and time to death was published pivotal trial data. All patients were treatment-naïve and in the PFS state, received first-line treatment with either bevacizumab-based therapy or doublet chemotherapy (including the option of pemetrexed + cisplatin). Patients would then progress to a subsequent line of therapy, remain in PFS or die. In case of progression, it was assumed that each survivor would receive a subsequent line of therapy, based on EMA licensed therapies. Weibull distribution curves were fitted to the data. All bevacizumab-based first-line therapy sequences analyzed achieved total PFS of around 15 months. Bevacizumab + carboplatin + paclitaxel (first line) → pemetrexed (second line) → erlotinib (third line) → docetaxel (fourth line) resulted in total mean PFS time of 15.7 months, for instance. Sequences with pemetrexed in combination with cisplatin in first line achieved total PFS times between 12.6 and 12.8 months with a slightly higher total PFS time achieved when assuming pemetrexed continuation therapy in maintenance after pemetrexed + cisplatin in first-line induction. Overall survival results followed the same trend as PFS. The model suggests that treatment-sequencing strategies starting with a bevacizumab-based combination in first line

  16. On Hungarian and Slavic linguistics in the collection of papers dedicated to Mihály Péter / Aleksandr Dulitšenko, Szilárd Tóth

    Index Scriptorium Estoniae

    Dulitšenko, Aleksandr, 1941-

    1999-01-01

    Arvustus: Nyelv, stílus, irodalom : köszöntö könyv Péter Mihįly 70. születésnapjára / Banczerowski Janusz, Han Anna, Kassai Ilona, Nyomįrkay Istvįn közremuködésével szerkesztette Zoltán András. Budapest : ELTE BTK Keleti Szláv és Balti Filológiai Tanszék, 1998

  17. STELLAR MASSES OF LYMAN BREAK GALAXIES, Lyα EMITTERS, AND RADIO GALAXIES IN OVERDENSE REGIONS AT z = 4-6

    International Nuclear Information System (INIS)

    Overzier, Roderik A.; Shu Xinwen; Zheng Wei; Rettura, Alessandro; Zirm, Andrew; Ford, Holland; Bouwens, Rychard J.; Illingworth, Garth D.; Miley, George K.; Venemans, Bram; White, Richard L.

    2009-01-01

    We present new information on galaxies in the vicinity of luminous radio galaxies (RGs) and quasars at z≅4, 5, and 6. These fields were previously found to contain overdensities of Lyman Break Galaxies (LBGs) or spectroscopic Lyα emitters, which were interpreted as evidence for clusters-in-formation ('protoclusters'). We use Hubble Space Telescope and Spitzer data to infer stellar masses from stellar synthesis models calibrated against the Millennium Run simulations, and contrast our results with large samples of LBGs in more average environments as probed by the Great Observatories Origins Deep Survey (GOODS). The following results were obtained. First, LBGs in both overdense regions and in the field at z = 4-5 lie on a very similar sequence in a z'-[3.6] versus 3.6 μm color-magnitude diagram. This is interpreted as a sequence in stellar mass (M * ∼ 10 9 -10 11 M sun ) in which galaxies become increasingly red due to dust and age as their star formation rate (SFR) increases, while their specific SFR stays constant. Second, the two RGs are among the most massive objects (M * ∼ 10 11 M sun ) known to exist at z ≅ 4-5, and are extremely rare based on the low number density of such objects as estimated from the ∼25x larger area GOODS survey. We suggest that the presence of the massive (radio) galaxies and associated supermassive black holes has been boosted through rapid accretion of gas or merging inside overdense regions. Third, the total stellar mass found in the z = 4 protocluster TN1338 accounts for 4, based on a comparison with the massive X-ray cluster Cl1252 at z = 1.2. Although future near-infrared observations should determine whether any massive galaxies are currently being missed by our UV/Lyα selections, one possible explanation for this mass difference is that TN1338 evolves into a smaller cluster than Cl1252. This raises the interesting question of whether the most massive protocluster regions at z > 4 remain yet to be discovered.

  18. Quality assurance audit: a prospective non-randomised trial of chemotherapy and radiotherapy for osteolymphoma (TROG 99.04/ALLG LY02).

    Science.gov (United States)

    Christie, D; Le, T; Watling, K; Cornes, D; O'Brien, P; Hitchins, R

    2009-04-01

    A quality assurance (QA) audit of the Trans Tasman Radiation Oncology Group and Australasian Lymphoma and Leukaemia Group trial (TROG 99.04/ALLG LY02) began after accrual of 25 patients. The trial is a prospective non-randomized study of standard treatment for osteolymphoma. Data relating to informed consent, eligibility, chemotherapy and radiotherapy were reviewed. The audit showed a relatively low level of major variations from the protocol, with an overall rate of 3.6%. As this trial has accrued slowly over a long period, the concept of QA has also developed. Amendments were made to the protocol accordingly. In the future, QA procedures should be predetermined, conducted rapidly in real time, and appropriately funded in order to be relevant to the ongoing conduct of the trial.

  19. Synthesis of 14C- and 2H-labeled 1,3 dihydro-3, 3-dimethyl-5-(1,4,5,6,- tetrahydro-6-oxo-3-pyridazinyl)-2H-indol-2-one (LY195115), an orally effective positive inotrope

    International Nuclear Information System (INIS)

    Robertson, D.W.; Krushinski, J.H.; Kau, D.

    1986-01-01

    The synthesis of 14 C- and 2 H-labeled 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H-indol -2-one (LY195115), an extremely potent, orally-effective cardiotonic with inotropic and vasodilator activities is described. The 14 C-label was introduced in the antepenultimate step by reaction of a β-chloroketone precursor with Na 14 CN; acid-catalyzed hydrolysis and cyclization with hydrazine provided the tetrahydropyridazinone bearing the 14 C-label in the oxo-carbon. 1,3-Dihydro-3,3-di(methyl-d 3 ) -2H-indol-2-one was prepared by exhaustive methylation of 1-acetyl-1,3-dihydro-2H-indol-2-one with sodium hydride and iodomethane-d 3 , followed by removal of the nitrogen protecting group. This labeled material was converted in two steps to [ 2 H 6 ]-LY195115. (author)

  20. Clinical development of galunisertib (LY2157299 monohydrate, a small molecule inhibitor of transforming growth factor-beta signaling pathway

    Directory of Open Access Journals (Sweden)

    Herbertz S

    2015-08-01

    Full Text Available Stephan Herbertz,1 J Scott Sawyer,2 Anja J Stauber,2 Ivelina Gueorguieva,3 Kyla E Driscoll,4 Shawn T Estrem,2 Ann L Cleverly,3 Durisala Desaiah,2 Susan C Guba,2 Karim A Benhadji,2 Christopher A Slapak,2 Michael M Lahn21Lilly Deutschland GmbH, Bad Homburg, Germany; 2Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA; 3Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, UK; 4Lilly Research Laboratories, Eli Lilly and Company, New York, NY, USA Abstract: Transforming growth factor-beta (TGF-β signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab

  1. Direct measurement of interstellar extinction toward young stars using atomic hydrogen Lyα absorption

    Energy Technology Data Exchange (ETDEWEB)

    McJunkin, Matthew; France, Kevin; Brown, Alexander [Center for Astrophysics and Space Astronomy, University of Colorado, 389 UCB, Boulder, CO 80309 (United States); Schneider, P. C. [Hamburger Sternwarte, Gojenbergsweg 112, D-21029 Hamburg (Germany); Herczeg, Gregory J. [Kavli Institute for Astronomy and Astrophysics, Peking University, Beijing 100871 (China); Hillenbrand, Lynne [California Institute of Technology, Department of Astrophysics, MC105-24, 1200 E. California Blvd., Pasadena, CA 91125 (United States); Schindhelm, Eric [Southwest Research Institute, 1050 Walnut Street, Suite 300, Boulder, CO 80302 (United States); Edwards, Suzan, E-mail: matthew.mcjunkin@colorado.edu [Five College Astronomy Department, Smith College, Northampton, MA 01063 (United States)

    2014-01-10

    Interstellar reddening corrections are necessary to reconstruct the intrinsic spectral energy distributions (SEDs) of accreting protostellar systems. The stellar SED determines the heating and chemical processes that can occur in circumstellar disks. Measurement of neutral hydrogen absorption against broad Lyα emission profiles in young stars can be used to obtain the total H I column density (N(H I)) along the line of sight. We measure N(H I) with new and archival ultraviolet observations from the Hubble Space Telescope (HST) of 31 classical T Tauri and Herbig Ae/Be stars. The H I column densities range from log{sub 10}(N(H I)) ≈19.6-21.1, with corresponding visual extinctions of A{sub V} =0.02-0.72 mag, assuming an R{sub V} of 3.1. We find that the majority of the H I absorption along the line of sight likely comes from interstellar rather than circumstellar material. Extinctions derived from new HST blue-optical spectral analyses, previous IR and optical measurements, and new X-ray column densities on average overestimate the interstellar extinction toward young stars compared to the N(H I) values by ∼0.6 mag. We discuss possible explanations for this discrepancy in the context of a protoplanetary disk geometry.

  2. The most metal-poor damped Lyα systems: insights into chemical evolution in the very metal-poor regime

    DEFF Research Database (Denmark)

    Cooke, Ryan; Pettini, Max; Steidel, Charles C.

    2011-01-01

    We present a high spectral resolution survey of the most metal-poor damped Lyα absorption systems (DLAs) aimed at probing the nature and nucleosynthesis of the earliest generations of stars. Our survey comprises 22 systems with iron abundance less than 1/100 solar; observations of seven...... agreement with the values measured in Galactic halo stars when the oxygen abundance is measured from the [O i] λ6300 line. We speculate that such good agreement in the observed abundance trends points to a universal origin for these metals. In view of this agreement, we construct the abundance pattern...... the near-solar values of C/O in DLAs at the lowest metallicities probed, and find that their distribution is in agreement with that seen in Galactic halo stars. We find that the O/Fe ratio in VMP DLAs is essentially constant, and shows very little dispersion, with a mean [〈O/Fe〉]=+0.39 ± 0.12, in good...

  3. The z = 0.8596 damped Ly-alpha absorbing galaxy toward PKS 0454+039

    Science.gov (United States)

    Steidel, Charles C.; Bowen, David V.; Blades, J. Chris; Dickenson, Mark

    1995-01-01

    We present Hubble Space Telescope (HST) and ground-based data on the Z(sub abs) = 0.8596 metal-line absorption system along the line of sight to PKS 0454+0356. The system is a moderate-redshift damped Ly-alpha system, with N(H I) = (5.7 +/- 0.3) x 10(exp 20)/sq cm as measured from the Faint Object Spectrograph (FOS) spectrum. We also present ground-based images which we use to identify the galaxy which most probably gives rise to the damped system; the most likely candidate is relatively underluminous by QSO absorber standards M(sub B) approximately -19.0 for A(sub 0) = 0.5 and H(sub 0) = 50 km/s/Mpc) and lies approximately 8.5/h kpc in projection from the QSO sight line. Ground-based measurements of Zn II, Cr II, and Fe II absorption lines from this system allow us to infer abundances of (Zn/H) = -1.1, (Cr/H) = -1.2, and (Fe/H) = -1.2 indicating overall metallicity similar to damped systems at z is greater than 2, and that the depletion of Cr and Fe onto dust grains may be even less important than in many of the high-redshift systems of comparable metallicity. Limits previously placed on the 21 cm optical depth in the z = 0.8596 system, together with our new N(H I) measurement, suggest a very high spin temperature for the H I, T(sub s) is greater than 580 K.

  4. Acinetobacter baumannii FolD ligand complexes --potent inhibitors of folate metabolism and a re-evaluation of the structure of LY374571.

    Science.gov (United States)

    Eadsforth, Thomas C; Maluf, Fernando V; Hunter, William N

    2012-12-01

    The bifunctional N(5),N(10)-methylenetetrahydrofolate dehydrogenase/cyclohydrolase (DHCH or FolD), which is widely distributed in prokaryotes and eukaryotes, is involved in the biosynthesis of folate cofactors that are essential for growth and cellular development. The enzyme activities represent a potential antimicrobial drug target. We have characterized the kinetic properties of FolD from the Gram-negative pathogen Acinetobacter baumanni and determined high-resolution crystal structures of complexes with a cofactor and two potent inhibitors. The data reveal new details with respect to the molecular basis of catalysis and potent inhibition. A unexpected finding was that our crystallographic data revealed a different structure for LY374571 (an inhibitor studied as an antifolate) than that previously published. The implications of this observation are discussed. © 2012 The Authors Journal compilation © 2012 FEBS.

  5. Phase III study by the Norwegian lung cancer study group

    DEFF Research Database (Denmark)

    Grønberg, Bjørn H; Bremnes, Roy M; Fløtten, Oystein

    2009-01-01

    PURPOSE To compare pemetrexed/carboplatin with a standard regimen as first-line therapy in advanced non-small-cell lung cancer NSCLC. PATIENTS AND METHODS Patients with stage IIIB or IV NSCLC and performance status of 0 to 2 were randomly assigned to receive pemetrexed 500 mg/m(2) plus carboplatin......, and fatigue reported on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and the lung cancer-specific module LC13 during the first 20 weeks. Secondary end points were overall survival and toxicity. Results Four hundred thirty-six eligible patients were enrolled...

  6. STELLAR POPULATIONS OF Lyα EMITTERS AT z ∼ 6-7: CONSTRAINTS ON THE ESCAPE FRACTION OF IONIZING PHOTONS FROM GALAXY BUILDING BLOCKS

    International Nuclear Information System (INIS)

    Ono, Yoshiaki; Shimasaku, Kazuhiro; Okamura, Sadanori; Masami Ouchi; Dunlop, James; Farrah, Duncan; McLure, Ross

    2010-01-01

    We investigate the stellar populations of Lyα emitters (LAEs) at z = 5.7 and 6.6 in a 0.65 deg 2 sky of the Subaru/XMM-Newton Deep Survey (SXDS) Field, using deep images taken with the Subaru/Suprime-Cam, United Kingdom Infrared Telescope/Wide Field Infrared Camera, and Spitzer/Infrared Array Camera (IRAC). We produce stacked multiband images at each redshift from 165 (z = 5.7) and 91 (z = 6.6) IRAC-undetected objects to derive typical spectral energy distributions (SEDs) of z ∼ 6-7 LAEs for the first time. The stacked LAEs have as blue UV continua as the Hubble Space Telescope (HST)/Wide Field Camera 3 (WFC3) z-dropout galaxies of similar M UV , with a spectral slope β ∼ -3, but at the same time they have red UV-to-optical colors with detection in the 3.6 μm band. Using SED fitting we find that the stacked LAEs have low stellar masses of ∼(3-10) x 10 7 M sun , very young ages of ∼1-3 Myr, negligible dust extinction, and strong nebular emission from the ionized interstellar medium, although the z = 6.6 object is fitted similarly well with high-mass models without nebular emission; inclusion of nebular emission reproduces the red UV-to-optical colors while keeping the UV colors sufficiently blue. We infer that typical LAEs at z ∼ 6-7 are building blocks of galaxies seen at lower redshifts. We find a tentative decrease in the Lyα escape fraction from z = 5.7 to 6.6, which may imply an increase in the intergalactic medium neutral fraction. From the minimum contribution of nebular emission required to fit the observed SEDs, we place an upper limit on the escape fraction of ionizing photons of f ion esc ∼ 0.6 at z = 5.7 and ∼0.9 at z = 6.6. We also compare the stellar populations of our LAEs with those of stacked HST/WFC3 z-dropout galaxies.

  7. THE ANGULAR DISTRIBUTION OF Lyα RESONANT PHOTONS EMERGING FROM AN OPTICALLY THICK MEDIUM

    International Nuclear Information System (INIS)

    Yang Yang; Shu Chiwang; Roy, Ishani; Fang Lizhi

    2013-01-01

    We investigate the angular distribution of Lyα photons scattering or emerging from an optically thick medium. Since the evolution of specific intensity I in frequency space and angular space are coupled with each other, we first develop the WENO numerical solver to find the time-dependent solutions of the integro-differential equation of I in frequency and angular space simultaneously. We first show that the solutions with the Eddington approximation, which assume that I is linearly dependent on the angular variable μ, yield similar frequency profiles of the photon flux as those without the Eddington approximation. However, the solutions of the μ distribution evolution are significantly different from those given by the Eddington approximation. First, the angular distribution of I is found to be substantially dependent on the frequency of the photons. For photons with the resonant frequency ν 0 , I contains only a linear term of μ. For photons with frequencies at the double peaks of the flux, the μ-distribution is highly anisotropic; most photons are emitted radially forward. Moreover, either at ν 0 or at the double peaks, the μ distributions actually are independent of the initial μ distribution of photons of the source. This is because the photons with frequencies either at ν 0 or the double peaks undergo the process of forgetting their initial conditions due to resonant scattering. We also show that the optically thick medium is a collimator of photons at the double peaks. Photons from the double peaks form a forward beam with a very small opening angle.

  8. DETECTION OF H i IN EMISSION IN THE LY α EMITTING GALAXY HARO 11

    International Nuclear Information System (INIS)

    Pardy, Stephen A.; Cannon, John M.; Östlin, Göran; Hayes, Matthew; Bergvall, Nils

    2016-01-01

    We present the first robust detection of H i 21 cm emission in the blue compact galaxy Haro 11 using the 100 m Robert C. Byrd Green Bank Telescope (GBT). Haro 11 is a luminous blue compact galaxy with emission in both Ly α and the Lyman continuum. We detect (5.1 ± 0.7 × 10 8 ) M ⊙ of H i gas at an assumed distance of 88 Mpc, making this galaxy H i deficient compared to other local galaxies with similar optical properties. Given this small H i mass, Haro 11 has an elevated M H2 / M Hi ratio and a very low gas fraction compared to most local galaxies, and contains twice as much mass in ionized hydrogen as in neutral hydrogen. The H i emission has a linewidth of 71 km s − 1 and is offset 60 km s −1 redward of the optical line center. It is undergoing a starburst after a recent merger that has elevated the star formation rate, and will deplete the gas supply in <0.2 Gyr. Although this starburst has elevated the star formation rate (SFR) compared to galaxies with similar H i masses and line widths, Haro 11 matches a trend of lower gas fractions toward higher SFRs and is below the general trend of increasing H i mass with increasing luminosity. Taken together, our results paint Haro 11 as a standard low-mass galaxy that is undergoing an unusually efficient star formation episode.

  9. Ly108 expression distinguishes subsets of invariant NKT cells that help autoantibody production and secrete IL-21 from those that secrete IL-17 in lupus prone NZB/W mice.

    Science.gov (United States)

    Tang, Xiaobin; Zhang, Bo; Jarrell, Justin A; Price, Jordan V; Dai, Hongjie; Utz, Paul J; Strober, Samuel

    2014-05-01

    Lupus is a systemic autoimmune disease characterized by anti-nuclear antibodies in humans and genetically susceptible NZB/W mice that can cause immune complex glomerulonephritis. T cells contribute to lupus pathogenesis by secreting pro-inflammatory cytokines such as IL-17, and by interacting with B cells and secreting helper factors such as IL-21 that promote production of IgG autoantibodies. In the current study, we determined whether purified NKT cells or far more numerous conventional non-NKT cells in the spleen of NZB/W female mice secrete IL-17 and/or IL-21 after TCR activation in vitro, and provide help for spontaneous IgG autoantibody production by purified splenic CD19(+) B cells. Whereas invariant NKT cells secreted large amounts of IL-17 and IL-21, and helped B cells, non-NKT cells did not. The subset of IL-17 secreting NZB/W NKT cells expressed the Ly108(lo)CD4(-)NK1.1(-) phenotype, whereas the IL-21 secreting subset expressed the Ly108(hi)CD4(+)NK1.1(-) phenotype and helped B cells secrete a variety of IgG anti-nuclear antibodies. α-galactocylceramide enhanced the helper activity of NZB/W and B6.Sle1b NKT cells for IgG autoantibody secretion by syngeneic B cells. In conclusion, different subsets of iNKT cells from mice with genetic susceptibility to lupus can contribute to pathogenesis by secreting pro-inflammatory cytokines and helping autoantibody production. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Trimodality strategy for treating malignant pleural mesothelioma: results of a feasibility study of induction pemetrexed plus cisplatin followed by extrapleural pneumonectomy and postoperative hemithoracic radiation (Japan Mesothelioma Interest Group 0601 Trial).

    Science.gov (United States)

    Hasegawa, Seiki; Okada, Morihito; Tanaka, Fumihiro; Yamanaka, Takeharu; Soejima, Toshinori; Kamikonya, Norihiko; Tsujimura, Tohru; Fukuoka, Kazuya; Yokoi, Kohei; Nakano, Takashi

    2016-06-01

    We conducted a prospective multi-institutional study to determine the feasibility of trimodality therapy (TMT) comprising induction chemotherapy followed by extrapleural pneumonectomy (EPP) and radiation therapy in Japanese patients with malignant pleural mesothelioma (MPM). Major eligibility criteria were histologically confirmed diagnosis of MPM, including clinical subtypes T0-3, N0-2, M0 disease; no prior treatment for the disease; age 20-75 years; Eastern Cooperative Oncology Group performance status 0 or 1; predicted postoperative forced expiratory volume >1000 ml in 1 s; written informed consent. Treatment methods comprised induction chemotherapy using pemetrexed (500 mg/m(2)) plus cisplatin (60 mg/m(2)) for three cycles, followed by EPP and postoperative hemithoracic radiation therapy (54 Gy). Primary endpoints were macroscopic complete resection (MCR) rate for EPP and treatment-related mortality for TMT. Forty-two eligible patients were enrolled: median age 64.5 (range 43-74) years; M:F = 39:3, clinical stage I:II:III = 14:13:15; histological type epithelioid were sarcomatoid; biphasic; others = 28:1:9:4. Of 42 patients, 30 completed EPP with MCR and 17 completed TMT. The trial met the primary endpoints, with an MCR rate of 71 % (30/42) and treatment-related mortality of 9.5 % (4/42). Overall median survival time and 2-year survival rate for 42 registered patients were 19.9 months and 42.9 %, respectively. Two-year relapse-free survival rate of 30 patients who completed EPP with MCR was 37.0 %. This phase II study met the predefined primary endpoints, but its risk/benefit ratio was not satisfactory.

  11. Comparison of semiquantitative fluorescence imaging and PET tracer uptake in mesothelioma models as a monitoring system for growth and therapeutic effects

    International Nuclear Information System (INIS)

    Saito, Yuriko; Furukawa, Takako; Arano, Yasushi; Fujibayashi, Yasuhisa; Saga, Tsuneo

    2008-01-01

    Introduction: Various techniques are available for in vivo imaging, and precise understanding of their characteristics is essential for effective use of the imaging results. We established human mesothelioma cell lines expressing red fluorescent protein (RFP) and examined their fluorescence intensity and uptake of positron emission tomography (PET) tracer analogs to compare their characteristics and assess their usefulness in the evaluation of therapeutics. Method: A human mesothelioma cell line was stably transfected to express RFP. Fluorescence, cell number and protein amount were measured during cell growth and treatment with cytotoxic reagents. In in vivo experiments, RFP-expressing cells were injected subcutaneously or into the pleural cavity of nude mice, and fluorescence images were taken with or without pemetrexed treatment. The uptake of [ 3 H]3'-deoxy-3'-fluorothymidine ([ 3 H]FLT) and [ 14 C]2-fluoro-2-deoxy-D-glucose ([ 14 C]FDG) under treatment with the above reagents in vitro and in vivo were examined. Results: Strong correlation was observed between fluorescence intensity and total cell number with or without cytotoxic treatment. The uptake of [ 3 H]FLT and [ 14 C]FDG decreased rapidly after the initiation of treatment with actinomycin D or cycloheximide. When treated with pemetrexed, the uptake of [ 3 H]FLT temporarily increased. The cells formed subcutaneous and orthotopic tumors, with fluorescence intensity correlating with tumor volume. The correlation was sustained under pemetrexed treatment. The uptake of [ 3 H]FLT in vivo increased significantly early after pemetrexed treatment. Conclusion: Fluorescence imaging could be used to semiquantitatively monitor tumor size, whereas PET could be used to monitor tumor response to therapeutic treatments, and especially, FLT might be a good marker of the response to anti-folate chemotherapeutics

  12. The Mean Metal-line Absorption Spectrum of Damped Ly α Systems in BOSS

    Energy Technology Data Exchange (ETDEWEB)

    Mas-Ribas, Lluís [Institute of Theoretical Astrophysics, University of Oslo, Postboks 1029, NO-0315 Oslo (Norway); Miralda-Escudé, Jordi; Pérez-Ràfols, Ignasi; Arinyo-i-Prats, Andreu [Institut de Ciències del Cosmos, Universitat de Barcelona (UB-IEEC), Barcelona E-08028, Catalonia (Spain); Noterdaeme, Pasquier; Petitjean, Patrick [Institut d’Astrophysique de Paris, UPMC and CNRS, UMR7095 98bis Boulevard Arago, F-75014—Paris (France); Schneider, Donald P. [Department of Astronomy and Astrophysics, The Pennsylvania State University, University Park, PA 16802 (United States); York, Donald G. [Department of Astronomy and Astrophysics and the Enrico Fermi Institute, University of Chicago, 5640 South Ellis Avenue, Chicago, IL 60637 (United States); Ge, Jian, E-mail: l.m.ribas@astro.uio.no [Department of Astronomy, University of Florida, Bryant Space Science Center, Gainesville, FL 32611-2055 (United States)

    2017-09-01

    We study the mean absorption spectrum of the Damped Ly α (DLA) population at z ∼ 2.6 by stacking normalized, rest-frame-shifted spectra of ∼27,000 DLA systems from the DR12 of the Baryon Oscillation Spectroscopic Survey (BOSS)/SDSS-III. We measure the equivalent widths of 50 individual metal absorption lines in five intervals of DLA hydrogen column density, five intervals of DLA redshift, and overall mean equivalent widths for an additional 13 absorption features from groups of strongly blended lines. The mean equivalent width of low-ionization lines increases with N {sub H} {sub i}, whereas for high-ionization lines the increase is much weaker. The mean metal line equivalent widths decrease by a factor ∼1.1–1.5 from z ∼ 2.1 to z ∼ 3.5, with small or no differences between low- and high-ionization species. We develop a theoretical model, inspired by the presence of multiple absorption components observed in high-resolution spectra, to infer mean metal column densities from the equivalent widths of partially saturated metal lines. We apply this model to 14 low-ionization species and to Al iii, S iii, Si iii, C iv, Si iv, N v, and O vi. We use an approximate derivation for separating the equivalent width contributions of several lines to blended absorption features, and infer mean equivalent widths and column densities from lines of the additional species N i, Zn ii, C ii*, Fe iii, and S iv. Several of these mean column densities of metal lines in DLAs are obtained for the first time; their values generally agree with measurements of individual DLAs from high-resolution, high signal-to-noise ratio spectra when they are available.

  13. IMPACT STUDY: MK-0646 (DALOTUZUMAB, INSULIN GROWTH FACTOR 1 RECEPTOR (IGF-1R ANTIBODY COMBINED WITH PEMETREXED AND CISPLATIN IN STAGE IV METASTATIC NON-SQUAMOUS LUNG CANCER

    Directory of Open Access Journals (Sweden)

    Chao H Huang

    2016-01-01

    Full Text Available Background: Insulin-like growth factor 1 receptor (IGF-1R regulates cell growth, proliferation and apoptosis. Adenocarcinoma and never-smokers have a higher expression of IGF-1R, which is associated with worse overall survival. Dalotuzumab-MK0646 (D is a humanized monoclonal antibody that targets IGF-1R. Pemetrexed (P has higher activity in non-squamous lung cancer (NSQL. We initiated a randomized phase II trial to test the combination of P and Cisplatin (C +/- D in NSQL.Methods: Eligibility criteria: untreated NSQL stage IIIB or IV, ECOG 0 or 1, measurable disease, adequate renal, hepatic and hematologic function, and no other intercurrent illness. P at 500mg/m2 and C at 75mg/m2 IV were given every 3 weeks. D was given at 10mg/kg IV weekly on days 1, 8 and 15 of every 3-week cycle in the experimental group. The patients had a radiographic assessment after every 2 cycles and were treated for a maximum of 6 cycles if there was a response or stable disease. The primary objective of the study was to compare the clinical response rates of PC vs PC+D. Results: From 1/2009 to 2/2011, the study accrued 26 subjects: 16 male and 10 female, with a median age of 59; 14 were treated with PC and 12 were treated with PC+D. We observed 2 partial responses (PR, 7 stable disease (SD, 3 progressive disease (PD, and 2 were not evaluable (NE in the PC arm. In comparison, for the PC+D arm there were: 3 PR, 4 SD, 4 PD and 1 NE. The hematologic toxicity was similar in both groups. There higher incidence of hyperglycemia the experimental group; 4 cases with grade 3 and 1 case with grade 4. Conclusion: PC+D had a similar response rate compared to PC, with a higher rate of hyperglycemia. Identification of responders using predictive markers would be key to continuing the study of D in NSQL.

  14. N uSTAR Hard X-Ray Data and Gemini 3D Spectra Reveal Powerful AGN and Outflow Histories in Two Low-redshift Lyα Blobs

    Science.gov (United States)

    Kawamuro, Taiki; Schirmer, Mischa; Turner, James E. H.; Davies, Rebecca L.; Ichikawa, Kohei

    2017-10-01

    We have shown that Lyα blobs (LABs) may still exist even at z˜ 0.3, about seven billion years later than most other LABs known (Shirmer et al.). Their luminous Lyα and [O III] emitters at z˜ 0.3 offer new insights into the ionization mechanism. This paper focuses on the two X-ray brightest LABs at z˜ 0.3, SDSS J0113+0106 (J0113) and SDSS J1155-0147 (J1155), comparable in size and luminosity to “B1,” one of the best-studied LABs at z≳ 2. Our NuSTAR hard X-ray (3-30 keV) observations reveal powerful active galactic nuclei (AGN) with {L}2{--10{keV}}=(0.5{--}3)× {10}44 erg s-1. J0113 also faded by a factor of ˜5 between 2014 and 2016, emphasizing that variable AGN may cause apparent ionization deficits in LABs. Joint spectral analyses including Chandra data constrain column densities of {N}{{H}}={5.1}-3.3+3.1× {10}23 cm-2 (J0113) and {N}{{H}}={6.0}-1.1+1.4× {10}22 cm-2 (J1155). J0113 is likely buried in a torus with a narrow ionization cone, but ionizing radiation is also leaking in other directions, as revealed by our Gemini/GMOS 3D spectroscopy. The latter shows a bipolar outflow over 10 kpc, with a peculiar velocity profile that is best explained by AGN flickering. X-ray analysis of J1155 reveals a weakly absorbed AGN that may ionize over a wide solid angle, consistent with our 3D spectra. Extinction-corrected [O III] log-luminosities are high, ˜43.6. The velocity dispersions are low, ˜100-150 km s-1, even at the AGN positions. We argue that this is a combination of high extinction hiding the turbulent gas and previous outflows that have cleared the escape paths for their successors.

  15. Furfural Inhibits Growth by Limiting Sulfur Assimilation in Ethanologenic Escherichia coli Strain LY180▿

    Science.gov (United States)

    Miller, Elliot N.; Jarboe, Laura R.; Turner, Peter C.; Pharkya, Priti; Yomano, Lorraine P.; York, Sean W.; Nunn, David; Shanmugam, K. T.; Ingram, Lonnie O.

    2009-01-01

    A wide variety of commercial products can be potentially made from monomeric sugars produced by the dilute acid hydrolysis of lignocellulosic biomass. However, this process is accompanied by side products such as furfural that hinder microbial growth and fermentation. To investigate the mechanism of furfural inhibition, mRNA microarrays of an ethanologenic strain of Escherichia coli (LY180) were compared immediately prior to and 15 min after a moderate furfural challenge. Expression of genes and regulators associated with the biosynthesis of cysteine and methionine was increased by furfural, consistent with a limitation of these critical metabolites. This was in contrast to a general stringent response and decreased expression of many other biosynthetic genes. Of the 20 amino acids individually tested as supplements (100 μM each), cysteine and methionine were the most effective in increasing furfural tolerance with serine (precursor of cysteine), histidine, and arginine of lesser benefit. Supplementation with other reduced sulfur sources such as d-cysteine and thiosulfate also increased furfural tolerance. In contrast, supplementation with taurine, a sulfur source that requires 3 molecules of NADPH for sulfur assimilation, was of no benefit. Furfural tolerance was also increased by inserting a plasmid encoding pntAB, a cytoplasmic NADH/NADPH transhydrogenase. Based on these results, a model is proposed for the inhibition of growth in which the reduction of furfural by YqhD, an enzyme with a low Km for NADPH, depletes NADPH sufficiently to limit the assimilation of sulfur into amino acids (cysteine and methionine) by CysIJ (sulfite reductase). PMID:19684179

  16. Enzastaurin (LY317615), a Protein Kinase C Beta Selective Inhibitor, Enhances Antiangiogenic Effect of Radiation

    International Nuclear Information System (INIS)

    Willey, Christopher D.; Xiao Dakai; Tu Tianxiang; Kim, Kwang Woon; Moretti, Luigi; Niermann, Kenneth J.; Tawtawy, Mohammed N.; Quarles, Chad C. Ph.D.; Lu Bo

    2010-01-01

    Purpose: Angiogenesis has generated interest in oncology because of its important role in cancer growth and progression, particularly when combined with cytotoxic therapies, such as radiotherapy. Among the numerous pathways influencing vascular growth and stability, inhibition of protein kinase B(Akt) or protein kinase C(PKC) can influence tumor blood vessels within tumor microvasculature. Therefore, we wanted to determine whether PKC inhibition could sensitize lung tumors to radiation. Methods and Materials: The combination of the selective PKCβ inhibitor Enzastaurin (ENZ, LY317615) and ionizing radiation were used in cell culture and a mouse model of lung cancer. Lung cancer cell lines and human umbilical vascular endothelial cells (HUVEC) were examined using immunoblotting, cytotoxic assays including cell proliferation and clonogenic assays, and Matrigel endothelial tubule formation. In vivo, H460 lung cancer xenografts were examined for tumor vasculature and proliferation using immunohistochemistry. Results: ENZ effectively radiosensitizes HUVEC within in vitro models. Furthermore, concurrent ENZ treatment of lung cancer xenografts enhanced radiation-induced destruction of tumor vasculature and proliferation by IHC. However, tumor growth delay was not enhanced with combination treatment compared with either treatment alone. Analysis of downstream effectors revealed that HUVEC and the lung cancer cell lines differed in their response to ENZ and radiation such that only HUVEC demonstrate phosphorylated S6 suppression, which is downstream of mTOR. When ENZ was combined with the mTOR inhibitor, rapamycin, in H460 lung cancer cells, radiosensitization was observed. Conclusion: PKC appears to be crucial for angiogenesis, and its inhibition by ENZ has potential to enhance radiotherapy in vivo.

  17. Analysis of the beginning of the early flight phase of the ski jump in athletes with different performance levels [Analýza fáze přechodu do letu ve skoku na lyžích u skupin závodníků s různou výkonností

    Directory of Open Access Journals (Sweden)

    Eva Janurová

    2011-09-01

    Full Text Available BACKGROUND: Obtaining a long jumping distance is necessary in order to succeed among the best competitors in the Nordic combined. The body movement during the take-off and early flight is considered to be the most important factor for length of the jump. OBJECTIVE: The purpose of this study was to assess the technique of the start of the early flight phase among three groups of Nordic combined competitors representing different performance levels, and to compare them with a group of ski jumpers. METHODS: Thirty competitors from both sport disciplines (Nordic combined and ski jumping, who performed ski jumps using an HS-134 m jumping hill during the 2009 Nordic World Ski Championships in Liberec, were divided into three subgroups based on jump length. Two-dimensional kinematic data were collected for the lower extremities, the trunk, and the skis of the competitors. RESULTS: The elite Nordic combined group showed a greater in-run velocity than did the two other performance groups (p CONCLUSIONS: The results indicated that ski jumping competitors took a better aerodynamic position in the section 0-5 m behind the edge of the jumping hill. The Nordic combined competitors used a higher average in-run velocity to achieve ski jump length comparable to those of ski jumpers.[VÝCHODISKA: Dosažení kvalitního výkonu ve skoku na lyžích je nezbytným předpokladem pro výsledné umístění v závodech severské kombinace. Za rozhodující pro provedení skoku na lyžích bývá označována fáze odrazu a následného přechodu do letu. Kinematická analýza těchto fází skoku pro skokany na lyžích byla provedena mnoha autory. Pro závodníky v severské kombinaci je počet výstupů minimální. Vysoké požadavky na provedení pohybu v odrazové fázi skoku (maximální síla odrazu, extrémně krátký čas realizace způsobují, při různých antropomotorických parametrech skokanů, vysokou interindividuální variabilitu provedení nejen

  18. Comparison of semiquantitative fluorescence imaging and PET tracer uptake in mesothelioma models as a monitoring system for growth and therapeutic effects

    Energy Technology Data Exchange (ETDEWEB)

    Saito, Yuriko [Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, 263-8555 (Japan); Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675 (Japan); Furukawa, Takako [Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, 263-8555 (Japan); Biomedical Imaging Research Center, University of Fukui, Yoshida, Fukui, 910-1193 (Japan); Arano, Yasushi [Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675 (Japan); Fujibayashi, Yasuhisa [Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, 263-8555 (Japan); Biomedical Imaging Research Center, University of Fukui, Yoshida, Fukui, 910-1193 (Japan); Saga, Tsuneo [Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, 263-8555 (Japan)

    2008-11-15

    Introduction: Various techniques are available for in vivo imaging, and precise understanding of their characteristics is essential for effective use of the imaging results. We established human mesothelioma cell lines expressing red fluorescent protein (RFP) and examined their fluorescence intensity and uptake of positron emission tomography (PET) tracer analogs to compare their characteristics and assess their usefulness in the evaluation of therapeutics. Method: A human mesothelioma cell line was stably transfected to express RFP. Fluorescence, cell number and protein amount were measured during cell growth and treatment with cytotoxic reagents. In in vivo experiments, RFP-expressing cells were injected subcutaneously or into the pleural cavity of nude mice, and fluorescence images were taken with or without pemetrexed treatment. The uptake of [{sup 3}H]3'-deoxy-3'-fluorothymidine ([{sup 3}H]FLT) and [{sup 14}C]2-fluoro-2-deoxy-D-glucose ([{sup 14}C]FDG) under treatment with the above reagents in vitro and in vivo were examined. Results: Strong correlation was observed between fluorescence intensity and total cell number with or without cytotoxic treatment. The uptake of [{sup 3}H]FLT and [{sup 14}C]FDG decreased rapidly after the initiation of treatment with actinomycin D or cycloheximide. When treated with pemetrexed, the uptake of [{sup 3}H]FLT temporarily increased. The cells formed subcutaneous and orthotopic tumors, with fluorescence intensity correlating with tumor volume. The correlation was sustained under pemetrexed treatment. The uptake of [{sup 3}H]FLT in vivo increased significantly early after pemetrexed treatment. Conclusion: Fluorescence imaging could be used to semiquantitatively monitor tumor size, whereas PET could be used to monitor tumor response to therapeutic treatments, and especially, FLT might be a good marker of the response to anti-folate chemotherapeutics.

  19. Multiparametric analysis of host response to murine cytomegalovirus in MHC class I-disparate mice reveals primacy of Dk-licensed Ly49G2+ NK cells in viral control.

    Science.gov (United States)

    Prince, Jessica; Lundgren, Alyssa; Stadnisky, Michael D; Nash, William T; Beeber, Amira; Turner, Stephen D; Brown, Michael G

    2013-11-01

    MHC class I D(k) and Ly49G2 (G2) inhibitory receptor-expressing NK cells are essential to murine CMV (MCMV) resistance in MA/My mice. Without D(k), G2(+) NK cells in C57L mice fail to protect against MCMV infection. As a cognate ligand of G2, D(k) licenses G2(+) NK cells for effector activity. These data suggested that D(k)-licensed G2(+) NK cells might recognize and control MCMV infection. However, a role for licensed NK cells in viral immunity is uncertain. We combined classical genetics with flow cytometry to visualize the host response to MCMV. Immune cells collected from individuals of a diverse cohort of MA/My × C57L offspring segregating D(k) were examined before infection and postinfection, including Ly49(+) NK subsets, receptor expression features, and other phenotypic traits. To identify critical NK cell features, automated analysis of 110 traits was performed in R using the Pearson correlation, followed with a Bonferroni correction for multiple tests. Hierarchical clustering of trait associations and principal component analyses were used to discern shared immune response and genetic relationships. The results demonstrate that G2 expression on naive blood NK cells was predictive of MCMV resistance. However, rapid G2(+) NK cell expansion following viral exposure occurred selectively in D(k) offspring; this response was more highly correlated with MCMV control than all other immune cell features. We infer that D(k)-licensed G2(+) NK cells efficiently detected missing-self MHC cues on viral targets, which elicited cellular expansion and target cell killing. Therefore, MHC polymorphism regulates licensing and detection of viral targets by distinct subsets of NK cells required in innate viral control.

  20. Cost and effectiveness studies in non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Pinar Yalcin-Balcik

    2015-02-01

    Full Text Available Lung cancer disease diagnosis and treatment is costly. As the numbers of inflicted rise so does the economic burden assumed for this cancer type. When the treatment expenditures are considered for all types of cancer, the lung cancer is thought to occupy a 20% share. The disease examined in two basic groups as small-cell lung cancer and non-small cell lung cancer (NSCLC is the most frequently encountered type of its kind nationally and in the World. This study considers the cost, effectiveness and cost effectiveness of platinum based chemotherapy medications with active ingredients pemetrexed and gemcitabine used for NSCLC. A review of studies relevant to the advanced stage NSCLC where majority of patients are positioned is foreseen to be useful to the decision makers since policy makers, regulating authorities and physicians require more information due to increased overall finance and costs, as well as treatment cost effectiveness. Furthermore, due to the entry attempt of pemetrexed active ingredient to the list of reimbursed medications for the first stage lung cancer treatment, it is assumed that a review of studies containing pemetrexed and gemcitabine will draw the attention of decision makers at the Social Security Instutition. [TAF Prev Med Bull 2015; 14(1.000: 55-64

  1. Clinical roundtable monograph: Recent advances in taxanes for the first-line treatment of advanced non-small cell lung cancer.

    Science.gov (United States)

    Socinski, Mark A; Govindan, Ramaswamy; Spigel, David

    2012-10-01

    Treatments for non-small cell lung cancer (NSCLC) are based on the broad categories of squamous or non-squamous histology. Frontline treatment options include pemetrexed and cisplatin, pemetrexed and a taxane, gemcitabine with cisplatin, and the addition of bevacizumab to a taxane and carboplatin. Pemetrexed is used for maintenance therapy for non-squamous NSCLC, whereas patients with squamous NSCLC lack easy options for maintenance therapy. nab-Paclitaxel overcomes the solubility and toxicity issues of solvent-based paclitaxel, and the albumin in nab-paclitaxel improves the concentration of the drug in the tumor. A recent phase III trial in NSCLC compared nab-paclitaxel with carboplatin versus solvent-based paclitaxel with carboplatin, and found improved overall response rates (ORRs) in the nab-paclitaxel arm (33% vs 25%; P=.005). In a subset analysis, NSCLC patients with squamous histology had a higher ORR (41%) with nab-paclitaxel than with solvent-based paclitaxel (24%; P<.001). Another subset analysis found that patients ages 70 years and older had improved overall survival (median 19.9 months) with nab-paclitaxel compared with solvent-based paclitaxel (median 10.4 months; P=.009). Patients in the nab-paclitaxel arm had less neuropathy, less hearing loss, and fewer interruptions in daily living than patients in the solvent-based paclitaxel arm.

  2. Joint Bayesian Estimation of Quasar Continua and the Lyα Forest Flux Probability Distribution Function

    Science.gov (United States)

    Eilers, Anna-Christina; Hennawi, Joseph F.; Lee, Khee-Gan

    2017-08-01

    We present a new Bayesian algorithm making use of Markov Chain Monte Carlo sampling that allows us to simultaneously estimate the unknown continuum level of each quasar in an ensemble of high-resolution spectra, as well as their common probability distribution function (PDF) for the transmitted Lyα forest flux. This fully automated PDF regulated continuum fitting method models the unknown quasar continuum with a linear principal component analysis (PCA) basis, with the PCA coefficients treated as nuisance parameters. The method allows one to estimate parameters governing the thermal state of the intergalactic medium (IGM), such as the slope of the temperature-density relation γ -1, while marginalizing out continuum uncertainties in a fully Bayesian way. Using realistic mock quasar spectra created from a simplified semi-numerical model of the IGM, we show that this method recovers the underlying quasar continua to a precision of ≃ 7 % and ≃ 10 % at z = 3 and z = 5, respectively. Given the number of principal component spectra, this is comparable to the underlying accuracy of the PCA model itself. Most importantly, we show that we can achieve a nearly unbiased estimate of the slope γ -1 of the IGM temperature-density relation with a precision of +/- 8.6 % at z = 3 and +/- 6.1 % at z = 5, for an ensemble of ten mock high-resolution quasar spectra. Applying this method to real quasar spectra and comparing to a more realistic IGM model from hydrodynamical simulations would enable precise measurements of the thermal and cosmological parameters governing the IGM, albeit with somewhat larger uncertainties, given the increased flexibility of the model.

  3. Maintenance treatment with chemotherapy and immunotherapy in non-small cell lung cancer:A case report.

    Directory of Open Access Journals (Sweden)

    Anabella eLlanos

    2012-10-01

    Full Text Available A 53-year-old woman was diagnosed with lung adenocarcinoma state IV (synchronous pleural involvement in April 2009. First-line systemic treatment included 6 cycles of Carboplatin, Paclitaxel, and Bevacizumab. Partial response was achieved. Maintenance therapy with Bevacizumab and Pemetrexed was given from September 2009 to February 2010. No response changes were observed. Immunotherapy was initiated, and then Pemetrexed was given with the same disease status. Both treatments were well tolerated. Immunotherapy toxicity included reaction at the site of injection grade 2. At present, the patient is still on this treatment. Given the poor prognosis of patients with advanced lung cancer, the combination of both treatments during the stable phase of the disease may improve progression-free survival.

  4. A requirement for CD45 distinguishes Ly49D-mediated cytokine and chemokine production from killing in primary natural killer cells

    Science.gov (United States)

    Huntington, Nicholas D.; Xu, Yuekang; Nutt, Stephen L.; Tarlinton, David M.

    2005-01-01

    Engagement of receptors on the surface of natural killer (NK) cells initiates a biochemical cascade ultimately triggering cytokine production and cytotoxicity, although the interrelationship between these two outcomes is currently unclear. In this study we investigate the role of the cell surface phosphatase CD45 in NK cell development and intracellular signaling from activating receptors. Stimulation via the major histocompatibility complex I–binding receptor, Ly49D on CD45 −/− primary NK cells resulted in the activation of phosphoinositide-3-kinase and normal cytotoxicity but failed to elicit a range of cytokines and chemokines. This blockage is associated with impaired phosphorylation of Syk, Vav1, JNK, and p38, which mimics data obtained using inhibitors of the src-family kinases (SFK). These data, supported by analogous findings after CD16 and NKG2D stimulation of CD45 −/− primary NK cells, place CD45 upstream of SFK in NK cells after stimulation via immunoreceptor tyrosine-based activation motif-containing receptors. Thus we identify CD45 as a pivotal enzyme in eliciting a precise subset of NK cell responses. PMID:15867094

  5. [PARAMOUNT trial: clinical meaning of continuous maintenance therapy in lung cancer].

    Science.gov (United States)

    Gridelli, Cesare

    2015-05-01

    Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer related deaths worldwide across both sex. Patients with Advanced -NSCLC (A-NSCLC) do not have curative treatment options, so the primary endpoint of every therapeutic decision aims to prolong survival, improving or maintain a good Quality of Life (QoL). Histology could represent a positive predictive factor for patients with Non squamous NSCLC (Nsq-NSCLC) respect to pemetrexed treatment. Pemetrexed is an antifolate that inhibits primarily thymidylate synthase (TS), together with dihydrofolate reductase and glycinamide ribonucleotide formyl transferase. Pemetrexed in combination with cisplatin is approved in the first line setting and as monotherapy in the switch or continuous maintenance of Non Squamous A-NSCLC. Maintenance therapy is a widely used therapeutic option in other solid and hematologic malignancies, but in the A-NSCLC represent an innovative approach. The rationale in this new setting of patients is based on the evidence that patients who benefit from an initial induction therapy platinum based may benefit from maintenance therapy with the third generation agent dropping the platinum drug after four to six cycles. We can define two types of maintenance therapy: continuation maintenance and switch maintenance. Major results in prolonging Overall Survival (OS) was reported with the continuation maintenance strategy as in the PARAMOUNT trial.

  6. Toxicity of algicidal extracts from Mangrovimonas yunxiaonensis strain LY01 on a HAB causing Alexandrium tamarense

    International Nuclear Information System (INIS)

    Li, Yi; Zhu, Hong; Zhang, Huajun; Chen, Zhangran; Tian, Yun; Xu, Hong; Zheng, Tianling; Zheng, Wei

    2014-01-01

    Highlights: • Stable and eco-environmental algicidal extracts were used to HABs-control. • Algicidal extracts induced cell-death and nuclear damage in Alexandrium tamarense. • Algicidal process and nuclear damage were confirmed by TEM and CLSM. • The transcription of rbcS, hsp and PCNA genes were influenced by algicidal extracts. - Abstract: Toxicity of algicidal extracts from Mangrovimonas yunxiaonensis strain LY01 on Alexandrium tamarense were measured through studying the algicidal procedure, nuclear damage and transcription of related genes. Medium components were optimized to improve algicidal activity, and characteristics of algicidal extracts were determined. Transmission electron microscope analysis revealed that the cell structure was broken. Cell membrane integrity destruction and nuclear structure degradation were monitored using confocal laser scanning microscope, and the rbcS, hsp and proliferating cell nuclear antigen (PCNA) gene expressions were studied. Results showed that 1.0% tryptone, 0.4% glucose and 0.8% MgCl 2 were the optimal nutrient sources. The algicidal extracts were heat and pH stable, non-protein and less than 1 kD. Cell membrane and nuclear structure integrity were lost, and the transcription of the rbcS and PCNA genes were significantly inhibited and there was up-regulation of hsp gene expression during the exposure procedure. The algicidal extracts destroyed the cell membrane and nuclear structure integrity, inhibited related gene expression and, eventually, lead to the inhibition of algal growth. All the results may elaborate firstly the cell death process and nuclear damage in A. tamarense which was induced by algicidal extracts, and the algicidal extracts could be potentially used as bacterial control of HABs in future

  7. The UCSD HIRES/Keck I Damped Lyα Abundance Database. II. The Implications

    Science.gov (United States)

    Prochaska, Jason X.; Wolfe, Arthur M.

    2002-02-01

    We present a comprehensive analysis of the damped Lyα (DLA) abundance database presented in the first paper of this series. This database provides a homogeneous set of abundance measurements for many elements including Si, Cr, Ni, Zn, Fe, Al, S, Co, O, and Ar from 38 DLA systems with zabs>1.5. With little exception, these DLA systems exhibit very similar relative abundances. There is no significant correlation in X/Fe with [Fe/H] metallicity, and the dispersion in X/Fe is small at all metallicity. We search the database for trends indicative of dust depletion and in a few cases find strong evidence. Specifically, we identify a correlation between [Si/Ti] and [Zn/Fe] which is unambiguous evidence for depletion. Following Hou and colleagues, we present [X/Si] abundances against [Si/H]+logN(HI) and note trends of decreasing X/Si with increasing [Si/H]+logN(HI) which argue for dust depletion. Similarly, comparisons of [Si/Fe] and [Si/Cr] against [Si/H] indicate significant depletion at [Si/H]>-1 but suggest essentially dust-free damped systems at [Si/H]0.25 dex as [Zn/Fe]-->0 and that the [Si/Fe] values exhibit a plateau of ~0.3 dex at [Si/H]good agreement with our previous work, but we emphasize two differences: (1) the unweighted and N(H I)-weighted [Fe/H] mean metallicities now have similar values at all epochs except z>3.5, where small number statistics dominate the N(H I)-weighted mean; and (2) there is no evolution in the mean [Fe/H] metallicity from z=1.7 to 3.5 but possibly a marked drop at higher redshift. We conclude with a general discussion on the physical nature of the DLA systems. We stress the uniformity of the DLA chemical abundances which indicates that the protogalaxies identified with DLA systems have very similar enrichment histories, i.e., a nearly constant relative contribution from Type Ia and Type II supernovae. The DLA systems also show constant relative abundances within a given system, which places strict constraints on the mixing timescales

  8. Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the CGRP Binding Monoclonal Antibody LY2951742 (Galcanezumab in Healthy Volunteers

    Directory of Open Access Journals (Sweden)

    David Monteith

    2017-10-01

    Full Text Available Background: Calcitonin gene-related peptide (CGRP is pivotal in the pathophysiology of migraine headaches and represents a promising target for migraine treatment. The humanized monoclonal antibody galcanezumab (LY2951742 binds to CGRP and may be effective in migraine prophylaxis.Objectives: The primary objective was to evaluate the safety and tolerability of single and multiple doses of galcanezumab in humans. Secondary objectives included assessing the pharmacokinetics and evaluating target engagement.Methods: A double-blind, randomized, placebo-controlled study (NCT 01337596 with single escalating and multiple subcutaneous (SC doses of galcanezumab was performed in healthy male volunteers. Single doses of 1, 5, 25, 75, 200, and 600 mg of galcanezumab (n = 7/dose or placebo (n = 2/dose were injected SC in six consecutive cohorts of nine subjects each. One cohort of nine subjects received multiple (4 150 mg doses of galcanezumab or placebo every other week. Target engagement was evaluated by measuring inhibition of capsaicin-induced increase in dermal blood flow (DBF.Findings: Sixty-three subjects were randomized and included in the safety analyses. Galcanezumab was well tolerated in single doses (1–600 mg SC and consecutive doses (150 mg SC. There was no dose-dependent difference in type or frequency of treatment-emergent adverse events, and no clinically meaningful difference when compared with placebo. Pharmacokinetics were linear. Galcanezumab induced a robust, dose-dependent, and durable inhibition of capsaicin-induced increase in DBF, supporting the continued clinical development of galcanezumab for prophylaxis in migraine patients.

  9. Metal Abundances at z<1.5: Fresh Clues to the Chemical Enrichment History of Damped Lyα Systems

    Science.gov (United States)

    Pettini, Max; Ellison, Sara L.; Steidel, Charles C.; Bowen, David V.

    1999-01-01

    We explore the redshift evolution of the metal content of damped Lyα systems (DLAs) with new observations of four absorbers at zintermediate redshifts for which the abundance of Zn has been measured. The main conclusion is that the column density-weighted mean metallicity, []=-1.03+/-0.23 (on a logarithmic scale), is not significantly higher at zaccounted for, leaves no room for the enhancement of the α elements over iron seen in metal-poor stars in the Milky Way. This is contrary to previous assertions that DLAs have been enriched solely by Type II supernovae, but it can be understood if the rate of star formation in the systems studied proceeded more slowly than in the early history of our Galaxy. These results add to a growing body of data pointing to the conclusion that known DLAs do not trace the galaxy population responsible for the bulk of star formation. Possible reasons are that sight lines through metal-rich gas are systematically underrepresented, because the background QSOs are reddened, and that the most actively star-forming galaxies are also the most compact, presenting too small a cross-section to have been probed yet with the limited statistics of current samples. Most of the data presented herein were obtained at the W. M. Keck Observatory, which is operated as a scientific partnership among Caltech, the University of California, and NASA. The Observatory was made possible by the generous financial support of the W. M. Keck Foundation.

  10. THE LYMAN ALPHA REFERENCE SAMPLE: EXTENDED LYMAN ALPHA HALOS PRODUCED AT LOW DUST CONTENT

    International Nuclear Information System (INIS)

    Hayes, Matthew; Östlin, Göran; Duval, Florent; Guaita, Lucia; Melinder, Jens; Sandberg, Andreas; Schaerer, Daniel; Verhamme, Anne; Orlitová, Ivana; Mas-Hesse, J. Miguel; Otí-Floranes, Héctor; Adamo, Angela; Atek, Hakim; Cannon, John M.; Herenz, E. Christian; Kunth, Daniel; Laursen, Peter

    2013-01-01

    We report on new imaging observations of the Lyman alpha emission line (Lyα), performed with the Hubble Space Telescope, that comprise the backbone of the Lyman alpha Reference Sample. We present images of 14 starburst galaxies at redshifts 0.028 P20 , Lyα radii are larger than those of Hα by factors ranging from 1 to 3.6, with an average of 2.4. The average ratio of Lyα-to-FUV radii is 2.9. This suggests that much of the Lyα light is pushed to large radii by resonance scattering. Defining the Relative Petrosian Extension of Lyα compared to Hα, ξ Lyα = R Lyα P20 /R Hα P20 , we find ξ Lyα to be uncorrelated with total Lyα luminosity. However, ξ Lyα is strongly correlated with quantities that scale with dust content, in the sense that a low dust abundance is a necessary requirement (although not the only one) in order to spread Lyα photons throughout the interstellar medium and drive a large extended Lyα halo.

  11. THE MOST METAL-POOR DAMPED Lyα SYSTEMS: AN INSIGHT INTO DWARF GALAXIES AT HIGH-REDSHIFT

    International Nuclear Information System (INIS)

    Cooke, Ryan J.; Pettini, Max; Jorgenson, Regina A.

    2015-01-01

    In this paper we analyze the kinematics, chemistry, and physical properties of a sample of the most metal-poor damped Lyα systems (DLAs), to uncover their links to modern-day galaxies. We present evidence that the DLA population as a whole exhibits a ''knee'' in the relative abundances of the α-capture and Fe-peak elements when the metallicity is [Fe/H] ≅ –2.0, assuming that Zn traces the buildup of Fe-peak elements. In this respect, the chemical evolution of DLAs is clearly different from that experienced by Milky Way halo stars, but resembles that of dwarf spheroidal galaxies in the Local Group. We also find a close correspondence between the kinematics of Local Group dwarf galaxies and of high-redshift metal-poor DLAs, which further strengthens this connection. On the basis of such similarities, we propose that the most metal-poor DLAs provide us with a unique opportunity to directly study the dwarf galaxy population more than ten billion years in the past, at a time when many dwarf galaxies were forming the bulk of their stars. To this end, we have measured some of the key physical properties of the DLA gas, including their neutral gas mass, size, kinetic temperature, density, and turbulence. We find that metal-poor DLAs contain a warm neutral medium with T gas ≅ 9600 K predominantly held up by thermal pressure. Furthermore, all of the DLAs in our sample exhibit a subsonic turbulent Mach number, implying that the gas distribution is largely smooth. These results are among the first empirical descriptions of the environments where the first few generations of stars may have formed in the universe

  12. Cellular determinants of the inverse cross sensitivity of mouse lymphoma L5178Y cell lines to ionizing radiation and hydrogen peroxide

    International Nuclear Information System (INIS)

    Kruszewski, M.

    1999-01-01

    The pair of L5178Y sublines (LY-R and LY-S) is exceptional among mammalian cell lines because of their unique inverse cross-sensitivity to ionizing radiation and hydrogen peroxide. The high sensitivity of LY-S cells to ionizing radiation is reasonably explained by the impairment of DNA double strand breaks rejoining. Although the enzymatic defect of LY-S cells is not yet identified, the more pronounced effect of DNA-dependent protein kinase (DNA-PK) inhibitor (OK-1035) on DNA damage repair after 8 Gy x-irradiation in LY-R cells than in LY-S cells, suggests that LY-S cells may be defective in DNA-PK activity or in the other enzymatic activities downstream from DNA-PK. An additional feature is a higher protection of DNA against ionizing radiation by nuclear proteins in LY-R cells. These data support the concept that nuclear matrix organization may contribute to the cellular susceptibility to DNA damaging agents. Ionizing radiation-sensitive LY-S cells suffer also more DNA base damage than ionizing radiation-resistant LY-R cells. However, the repair rates of the γ-ray-induced DNA base damage in LY sublines are related neither to the initial amounts of the damaged bases nor to the lethal or mutagenic effects of ionizing radiation. In contrast, hydrogen peroxide (H 2 O 2 ) sensitive LY-R cells suffer more DNA base damage after H 2 O 2 treatment. This may be due to the lower activity of catalase and/or the lower level of glutathione and other monobromobimane-reactive thiols in LY-R cells than in LY-S cells. However, the main cause of LY-R cells' sensitivity to H 2 O 2 seems to be a higher iron ion content in these cells as compared to LY-S cells. A higher content of iron ions and a higher iron:copper ratio is found in isolated nuclei of LY-R cells than in those of LY-S cells. This is further confirmed by a higher ''labile iron'' pool in LY-R cells than in LY-S cells. Further evidence of different ions content in LY cells and its influence on nuclear matrix organization

  13. 9-AAA inhibits growth and induces apoptosis in human melanoma A375 and rat prostate adenocarcinoma AT-2 and Mat-LyLu cell lines but does not affect the growth and viability of normal fibroblasts.

    Science.gov (United States)

    Korohoda, Włodzimierz; Hapek, Anna; Pietrzak, Monika; Ryszawy, Damian; Madeja, Zbigniew

    2016-11-01

    The present study found that, similarly to 5-fluorouracil, low concentrations (1-10 µM) of 9-aminoacridine (9-AAA) inhibited the growth of the two rat prostate cancer AT-2 and Mat-LyLu cell lines and the human melanoma A375 cell line. However, at the same concentrations, 9-AAA had no effect on the growth and apoptosis of normal human skin fibroblasts (HSFs). The differences between the cellular responses of the AT-2 and Mat-LyLu cell lines, which differ in malignancy, were found to be relatively small compared with the differences between normal HSFs and the cancer cell lines. Visible effects on the cell growth and survival of tumor cell lines were observed after 24-48 h of treatment with 9-AAA, and increased over time. The inhibition of cancer cell growth was found to be due to the gradually increasing number of cells dying by apoptosis, which was observed using two methods, direct counting and FlowSight analysis. Simultaneously, cell motile activity decreased to the same degree in cancer and normal cells within the first 8 h of incubation in the presence of 9-AAA. The results presented in the current study suggest that short-lasting tests for potential anticancer substances can be insufficient; which may result in cell type-dependent differences in the responses of cells to tested compounds that act with a delay being overlooked. The observed differences in responses between normal human fibroblasts and cancer cells to 9-AAA show the requirement for additional studies to be performed simultaneously on differently reacting cancer and normal cells, to determine the molecular mechanisms responsible for these differences.

  14. Mechanism for enhanced absorption of a solid dispersion formulation of LY2300559 using the artificial stomach duodenum model.

    Science.gov (United States)

    Polster, Christopher S; Wu, Sy-Juen; Gueorguieva, Ivelina; Sperry, David C

    2015-04-06

    An artificial stomach duodenum (ASD) model has been used to demonstrate the performance difference between two formulations of LY2300559, a low-solubility acidic developmental drug. The two formulations investigated were a conventional high-shear wet granulation (HSWG) formulation and a solid dispersion formulation. A pharmacokinetic study in humans demonstrated the enhanced performance of the solid dispersion formulation relative to the HSWG formulation. The Cmax and AUC of the solid dispersion was 2.6 and 1.9 times greater, respectively, compared to the HSWG formulation. In the ASD, the solid dispersion formulation performance was characterized by three main phases: (1) rapid release in the stomach, creating a supersaturated concentration of drug, (2) precipitation in the stomach, and (3) rapid redissolution of the precipitate in the duodenum to concentration levels that are supersaturated relative to crystalline drug. A series of complementary experiments were employed to describe this performance behavior mechanistically. Imaging experiments with a pH indicating dye showed that local pH gradients from meglumine in the solid dispersion formulation were responsible for creating a high initial supersaturation concentration in the stomach. Upon dissipation of meglumine, the drug precipitated in the stomach as an amorphous solid. Because the precipitated drug is in an amorphous form, it can then rapidly redissolve as it transits to the more neutral environment of the duodenum. This unexpected sequence of physical state changes gives a mechanistic explanation for the enhanced in vivo performance of the solid dispersion formulation relative to the HSWG formulation.

  15. The b Distribution and the Velocity Structure of Absorption Peaks in the Lyα Forest

    International Nuclear Information System (INIS)

    Hui, L.; Rutledge, R.E.

    1999-01-01

    A theory is developed that relates the observed b parameter of a Lyα absorption line to the velocity curvature of the corresponding peak in the optical depth fluctuation. Its relation to the traditional interpretation of b as the thermal broadening width is discussed. It is demonstrated that, independent of the details of the cosmological model, the differential b distribution has a high-b asymptote of dN/db∝b -m , where m≥5, when we make the reasonable assumption that low-curvature fluctuations are statistically favored over high-curvature ones. There in general always exist lines much broader than the thermal width. We develop a linear perturbative analysis of the optical depth fluctuation, which yields a single-parameter prediction for the full b distribution. In addition to exhibiting the high-velocity tail, it qualitatively explains the observed sharp low-b cutoff a simple reflection of the fact that high-curvature fluctuations are relatively rare. Although the existence of the high-b asymptote, which is independent of the validity of the linear expansion, is consistent with the observed b distribution, a detailed comparison of the linear prediction with six observational data sets indicates that higher order corrections are not negligible. The perturbative analysis nonetheless offers valuable insights into the dependence of the b distribution on cosmological parameters such as Ω and the power spectrum. A key parameter is the effective smoothing scale of the optical depth fluctuation, which is in turn determined by three scales: the thermal broadening width, the baryon smoothing scale (approximately the Jeans scale), and the observation/simulation resolution. The first two are determined by reionization history, but are comparable in general, whereas the third varies by about an order of magnitude in current hydrodynamic simulations. Studies with non resolution-dominated b distributions can be used to probe the reionization history of the universe

  16. THE LYMAN ALPHA REFERENCE SAMPLE: EXTENDED LYMAN ALPHA HALOS PRODUCED AT LOW DUST CONTENT

    Energy Technology Data Exchange (ETDEWEB)

    Hayes, Matthew [Universite de Toulouse, UPS-OMP, IRAP, Toulouse (France); Oestlin, Goeran; Duval, Florent; Guaita, Lucia; Melinder, Jens; Sandberg, Andreas [Department of Astronomy, Oskar Klein Centre, Stockholm University, AlbaNova University Centre, SE-106 91 Stockholm (Sweden); Schaerer, Daniel [CNRS, IRAP, 14, avenue Edouard Belin, F-31400 Toulouse (France); Verhamme, Anne; Orlitova, Ivana [Geneva Observatory, University of Geneva, 51 Chemin des Maillettes, CH-1290 Versoix (Switzerland); Mas-Hesse, J. Miguel; Oti-Floranes, Hector [Centro de Astrobiologia (CSIC-INTA), Departamento de Astrofisica, POB 78, 28691 Villanueva de la Canada (Spain); Adamo, Angela [Max Planck Institute for Astronomy, Koenigstuhl 17, D-69117 Heidelberg (Germany); Atek, Hakim [Laboratoire d' Astrophysique, Ecole Polytechnique Federale de Lausanne (EPFL), Observatoire, CH-1290 Sauverny (Switzerland); Cannon, John M. [Department of Physics and Astronomy, Macalester College, 1600 Grand Avenue, Saint Paul, MN 55105 (United States); Herenz, E. Christian [Leibniz-Institut fuer Astrophysik (AIP), An der Sternwarte 16, D-14482 Potsdam (Germany); Kunth, Daniel [Institut d' Astrophysique de Paris, UMR 7095 CNRS and UPMC, 98 bis Bd Arago, F-75014 Paris (France); Laursen, Peter, E-mail: matthew@astro.su.se [Dark Cosmology Centre, Niels Bohr Institute, University of Copenhagen, Juliane Maries Vej 30, DK-2100 Copenhagen (Denmark)

    2013-03-10

    We report on new imaging observations of the Lyman alpha emission line (Ly{alpha}), performed with the Hubble Space Telescope, that comprise the backbone of the Lyman alpha Reference Sample. We present images of 14 starburst galaxies at redshifts 0.028 < z < 0.18 in continuum-subtracted Ly{alpha}, H{alpha}, and the far ultraviolet continuum. We show that Ly{alpha} is emitted on scales that systematically exceed those of the massive stellar population and recombination nebulae: as measured by the Petrosian 20% radius, R{sub P20}, Ly{alpha} radii are larger than those of H{alpha} by factors ranging from 1 to 3.6, with an average of 2.4. The average ratio of Ly{alpha}-to-FUV radii is 2.9. This suggests that much of the Ly{alpha} light is pushed to large radii by resonance scattering. Defining the Relative Petrosian Extension of Ly{alpha} compared to H{alpha}, {xi}{sub Ly{alpha}} = R {sup Ly{alpha}}{sub P20}/R {sup H{alpha}}{sub P20}, we find {xi}{sub Ly{alpha}} to be uncorrelated with total Ly{alpha} luminosity. However, {xi}{sub Ly{alpha}} is strongly correlated with quantities that scale with dust content, in the sense that a low dust abundance is a necessary requirement (although not the only one) in order to spread Ly{alpha} photons throughout the interstellar medium and drive a large extended Ly{alpha} halo.

  17. Cellular determinants of the inverse cross sensitivity of mouse lymphoma L5178Y cell lines to ionizing radiation and hydrogen peroxide; Podloze odwrotnej krzyzowej opornosci komorek L5178Y na promieniowanie jonizujace i nadtlenek wodoru

    Energy Technology Data Exchange (ETDEWEB)

    Kruszewski, M [Dept. of Radiobiology and Health Protection, Inst. of Nuclear Chemistry and Technology, Warsaw (Poland)

    1999-07-01

    The pair of L5178Y sublines (LY-R and LY-S) is exceptional among mammalian cell lines because of their unique inverse cross-sensitivity to ionizing radiation and hydrogen peroxide. The high sensitivity of LY-S cells to ionizing radiation is reasonably explained by the impairment of DNA double strand breaks rejoining. Although the enzymatic defect of LY-S cells is not yet identified, the more pronounced effect of DNA-dependent protein kinase (DNA-PK) inhibitor (OK-1035) on DNA damage repair after 8 Gy x-irradiation in LY-R cells than in LY-S cells, suggests that LY-S cells may be defective in DNA-PK activity or in the other enzymatic activities downstream from DNA-PK. An additional feature is a higher protection of DNA against ionizing radiation by nuclear proteins in LY-R cells. These data support the concept that nuclear matrix organization may contribute to the cellular susceptibility to DNA damaging agents. Ionizing radiation-sensitive LY-S cells suffer also more DNA base damage than ionizing radiation-resistant LY-R cells. However, the repair rates of the {gamma}-ray-induced DNA base damage in LY sublines are related neither to the initial amounts of the damaged bases nor to the lethal or mutagenic effects of ionizing radiation. In contrast, hydrogen peroxide (H{sub 2}O{sub 2}) sensitive LY-R cells suffer more DNA base damage after H{sub 2}O{sub 2} treatment. This may be due to the lower activity of catalase and/or the lower level of glutathione and other monobromobimane-reactive thiols in LY-R cells than in LY-S cells. However, the main cause of LY-R cells' sensitivity to H{sub 2}O{sub 2} seems to be a higher iron ion content in these cells as compared to LY-S cells. A higher content of iron ions and a higher iron:copper ratio is found in isolated nuclei of LY-R cells than in those of LY-S cells. This is further confirmed by a higher ''labile iron'' pool in LY-R cells than in LY-S cells. Further evidence of different ions content in LY cells and its influence

  18. From Corpus to Dictionary: A Hybrid Prescriptive, Descriptive and Proscriptive Undertaking Okulondoola engeli Eitu ly'Olusoga bwe Linaatuusibwa mu Iwanika: Omutindo ogulaga Olulimi bwe luli, bwe luteekwa okuba oba bwe lube lutwalibwe.

    Directory of Open Access Journals (Sweden)

    Minah Nabirye

    2012-01-01

    :

    Obufunze: Empandiika y'Olusoga ekaali inhuma inho waile nga waliwooku obubonelo obulaga enkola y'obuzila mu kugizimba. Olusoga lukaawagamiile wansi w'ennimi nga Oluganda n'olulimi olw'eiwanga, Olungeleza. Ensonga endala ku dhikaalemeisa Olusoga okwetengelela n'okuba nti lulina ebigambo ebilwingila buli olukeile. Eky'embi, enkyukakyuka ebigambo bino ebiyaaka by'eleetawo eli kwidha mu kiseela nga Olusoga lwene lukaali kufunilwaku mpandiika ntongole. Waile walifu dh'Olusoga buti dhiliwo kamaala, wazila ndala ku dho eli kugobelelwa mu kuwandiika kubanga abantu bakaawandiika nga bwe babona. Ebiwandiiko ebili ku Lusoga oba mu lulimi Olusoga byetaagibwa okulaga Olusoga bwe lulina okuba ela n'ebilina okwebuuzibwaku. Eibula ly'ebiwandiiko oti ni bino litegeeza nti omunoonheleza alina okwefunila entambi dh'Olusoga olwogelwa ela yeewanulila Olusoga oluli mu ntambi edho okusobola okutegeela engeli olulimi olwo bwe luli mu kiseela ekyo. Kino kileeseewo obuzibu obundi nti Olusoga olwogelwa tilutongoze ate lulimu emigote kamaala egyandibaile gilondoolwa okusinziila ku mutindo omusengeke singa lubailem mu buwandiike. Ekika ky'Olusoga oluli mu mbeela eyogelwa kya ndhawulo ku kili mu mbeela y'obuwandiike. Okuwanula Olusoga okuva mu ntambi kw'aba nti kugiililiile kwagayaga na kunoga kibala kikaali kwenga bukalamu. Aye engeli ye kili nti Olusoga lulina aboogezi abaswika mu bukaile obubili, abanoonheleza ku Lusoga baalisaine kutandiika li? Olupapula luno lulambulula enzimba y'eitu ly'Olusoga nga ekitundutundu ky'eitu lino kiviile mu Lusoga olwawanulwa okuva mu mbeela eyogelwa. Obuzibu obwayagaanibwa mu mpandiika y'ebigambo ebyawanulwa n'obusimbiibwaku eisila. Okulaga engeli y'okuzigula obuzibu bw'empandiika mu isomo ly'amawanika kwetaagisa enkola eteekubila inho ku nsonga ndala aye enoonheleza engeli esinga kugasa omutendela gw'obuzibu obulondoolebwa. Waile nga obuzibu obundi busobola okugondhoolwa okugiila ku mutendela oguteebwawo, gwalaga olulimi nga bwe luteekwa okuba, obuzibu

  19. Glycaemic adverse drug reactions from anti-neoplastics used in ...

    African Journals Online (AJOL)

    235625 records ... Glycaemic adverse drug reactions from anti-neoplastics used in treating pancreatic cancer. ... Based on the emphasized nine antineoplastic drugs with high hyperglycemic ADR incidence, we found: fluorouracil, sorafenib and pemetrexed with high ADR record of metabolism and nutrition disorders; ...

  20. Kinetic modelling of in vitro data of PI3K, mTOR1, PTEN enzymes and on-target inhibitors Rapamycin, BEZ235, and LY294002.

    Science.gov (United States)

    Goltsov, Alexey; Tashkandi, Ghassan; Langdon, Simon P; Harrison, David J; Bown, James L

    2017-01-15

    The phosphatidylinositide 3-kinases (PI3K) and mammalian target of rapamycin-1 (mTOR1) are two key targets for anti-cancer therapy. Predicting the response of the PI3K/AKT/mTOR1 signalling pathway to targeted therapy is made difficult because of network complexities. Systems biology models can help explore those complexities but the value of such models is dependent on accurate parameterisation. Motivated by a need to increase accuracy in kinetic parameter estimation, and therefore the predictive power of the model, we present a framework to integrate kinetic data from enzyme assays into a unified enzyme kinetic model. We present exemplar kinetic models of PI3K and mTOR1, calibrated on in vitro enzyme data and founded on Michaelis-Menten (MM) approximation. We describe the effects of an allosteric mTOR1 inhibitor (Rapamycin) and ATP-competitive inhibitors (BEZ235 and LY294002) that show dual inhibition of mTOR1 and PI3K. We also model the kinetics of phosphatase and tensin homolog (PTEN), which modulates sensitivity of the PI3K/AKT/mTOR1 pathway to these drugs. Model validation with independent data sets allows investigation of enzyme function and drug dose dependencies in a wide range of experimental conditions. Modelling of the mTOR1 kinetics showed that Rapamycin has an IC 50 independent of ATP concentration and that it is a selective inhibitor of mTOR1 substrates S6K1 and 4EBP1: it retains 40% of mTOR1 activity relative to 4EBP1 phosphorylation and inhibits completely S6K1 activity. For the dual ATP-competitive inhibitors of mTOR1 and PI3K, LY294002 and BEZ235, we derived the dependence of the IC 50 on ATP concentration that allows prediction of the IC 50 at different ATP concentrations in enzyme and cellular assays. Comparison of drug effectiveness in enzyme and cellular assays showed that some features of these drugs arise from signalling modulation beyond the on-target action and MM approximation and require a systems-level consideration of the whole PI3K

  1. Antimutagenic action of the live yeast can be transmitted to the offspring of Drosophila melanogaster. A genetic study using the wing spot assay.

    Science.gov (United States)

    Pimentel, Emilio; Cruces, Martha P

    2018-01-01

    The present study evaluates whether the protective effect of live yeast (LY) against direct and indirect mutagenic agents, persists in the offspring from individuals fed with LY. The wing-spot test in Drosophila was used; four different mates were performed: a) neither females nor males were fed with LY-enriched food (NLYxNLY); b) only females were fed (LYxNLY); c) males were fed (NLYxLY) or d) both progenitors were fed (LYxLY). Results confirm that LY strongly stimulates fecundity in females but not in males and provides strength to the egg for survive. A greater reduction in mutation rate was observed when females were feed, in the following relationship: LYxNLY>LYxLY>NLYxLY. No protection was found against action in any of the p